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UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl) UvA-DARE (Digital Academic Repository) Colonization and invasion of human epithelia by Neisseria meningitidis. Bacterial surface variation and exploitation of host defense molecules de Vries, F.P. Link to publication Citation for published version (APA): de Vries, F. P. (2001). Colonization and invasion of human epithelia by Neisseria meningitidis. Bacterial surface variation and exploitation of host defense molecules. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 23 May 2020

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UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Colonization and invasion of human epithelia by Neisseria meningitidis. Bacterial surfacevariation and exploitation of host defense molecules

de Vries, F.P.

Link to publication

Citation for published version (APA):de Vries, F. P. (2001). Colonization and invasion of human epithelia by Neisseria meningitidis. Bacterial surfacevariation and exploitation of host defense molecules.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.

Download date: 23 May 2020

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ChapterChapter 1

Generall introduction

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GeneralGeneral introduction

NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection

NeisseriaNeisseria meningitidis

NeisseriaNeisseria meningitidis belongs to the genus Neisseria, which harbors several closely related

speciess of Gram-negative diplococci. These include the exclusively human pathogen N.

gonorrhoeaegonorrhoeae and a number of other Neisseria species that colonize the mucosae of men and

otherr mammals without causing disease (1). Pathogenic and commensal Neisseria are alike in

thatt both groups of bacteria may use similar mechanisms to facilitate successful colonization

off their particular niches. The pathogenic Neisseria and probably many commensal Neisseria

speciess are naturally transformable. DNA released from autolytic bacteria can be taken up and

integratedd into the chromosomes of recipient bacteria (34,171). Neisseria recognize a specific

DNAA sequence, 10 bp in length, commonly found in neisserial genes, that serves as a signal

forr high frequency uptake of DNA. Bacterial transformation with unrelated DNA is

exceptionall (21,61,102). Transformation can account for a continuous horizontal exchange of

geneticc material within and between different neisserial species (52,58,73,173). This

mechanismm provides a genetic plasticity that enables long-term adaptation to even gross

environmentall changes encountered during evolution and to microenvironmental changes in

thee host. In addition, it may generate mosaic genes and thus promote the development of

phenotypicc variants (52,58,73,110). Newly generated variants may rapidly spread into the

humann population in a clonal manner. Horizontal gene transfer and frequent recombination

events,, in which small segments of genomes are exchanged, result in the relatively rapid

diversificationn of clones. In case of Neisseria meningitidis, this ongoing microevolution has

ledd to a population structure where occasional clonal outgrowths occur in an otherwise

panmicticc context. In Europe and North America, for example, the genetic diversity of

(predominantlyy serogroup B and C) meningococci commonly isolated from cases and carriers

is,, with a few exceptions, extreme and the population genetic structure is non-clonal. In

contrast,, meningococci that cause epidemics and outbreaks of disease belong to fairly uniform

clonall groupings. These hypervirulent organisms include most serogroup A meningococci but

alsoo a limited number of pandemic/hyperendemic serogroup C and B lineages. Meningococci

off such subgroups often carry mosaic cell surface antigens as a result of recombination

events,, but retain distinctive epidemiologies and virulence potential (3,31). Some clonal

groupings,, like strains from the (mainly serogroup B) electrophoretic type (ET-5) and the ET-

377 complex persist in the population for decades, sometimes in the same region, without

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evidencee for inter-genetic exchange (36). The existence of different restriction/modification

systemss within clonal lineages may represent a barrier for horizontal gene transfer between

distinctt clonal groupings and stabilize their clonal expansion(66).

Thee host-parasite relationship

Inn order to understand the host-parasite relationship, the evolutionary background of a long-

standingg adaptation between the meningococcus and its human host has to be considered.

Outsidee its host, the meningococcus is very vulnerable, it does not have the ability to become

aa spore and lacks the hardiness to survive in the environment. As the host range of the

microorganismm is limited to a single species, there is a strong negative selective pressure

againstt meningococci that are overwhelmingly virulent. Infection with such clones will result

inn decimation of the host species, a lower probability of transmission from a dead to a live

host,, and nowadays, increased chances that the clone will be eliminated by antibiotic

treatment.. The adaptive process favors a moderate meningococcal virulence, such that a

bacteriall density is reached that maximizes transmission between hosts with normal

antimicrobiall defenses. Whenever the organism encounters a host whose defenses are below

average,, serious disease ensues, but the ability of the meningococcus to find a new host is

diminishedd or abrogated (62). The dichotomy between the main reservoir where selection is

operatingg and disease is illustrated by the almost complete absence of nasopharyngeal

carriagee in children below age four, yet this population has by far the highest frequency of

systemicc meningococcal disease (33,37).

Whenn we try to understand the selected advantage afforded by certain virulence factors,

itt might be important to consider the anatomical localization at which selective forces have

operatedd in evolution (62). When meningococci enter the systemic circulation, encapsulated

organismss are protected against the bactericidal effect of normal human serum, while non-

encapsulatedd bacteria are almost invariably killed (75,82,93,206,207). However, it is very

unlikelyy that such a mechanism evolved to serve this purpose. It is more likely that the

advantagee of the capsule to the organism lies in its functions during colonization of the

mucosa,, or during transmission between hosts. Remarkably, not a single gene or bacterial

attributee has been identified and shown to contribute to or increase transmission efficiency,

althoughh this is a key event in the meningococcal life style.

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Coursee of infection

Uponn acquisition, Neisseria meningitidis colonizes the mucosal surface of the human oro- and

nasopharynx,, the only known habitat and reservoir for this bacterium. Meningococci are

efficientlyy transmitted between hosts by inhalation of respiratory droplet aerosols. This is

reflectedd in a mean carriage rate of 5-15 % of the healthy human population during non-

epidemicc periods (28,60). The carrier-state normally elicits host antibodies within 7-10 days,

butt the host may remain carrier of a specific strain for months (29). Occasionally, the balance

betweenn host defenses and bacterial virulence is disturbed and the meningococcus

disseminatess to the bloodstream and may eventually reach the central nervous system. As a

resultt of released outer membrane vesicles (blebs) and fragmentation of bacterial cell

membranes,, both of which contain high amounts of lipopolysaccharide (LPS), meningococcal

septicemiaa can lead to excessively high endotoxin concentrations in plasma and cerebrospinal

fluidd (10,26,27,48). These events can induce a cascade of inflammatory and often

disproportionall anti-inflammatory responses that can lead to pathogenic changes, like

purulentt infection of the meninges, septic shock, disseminated intravascular coagulation,

multiplee organ failure and ultimately, death (9,27,48,78,138,146,208,209).

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Virulencee repertoire of the meningococcus.

Inn order to cause systemic disease, meningococci colonizing the nasopharynx have to invade,

survivee and proliferate in the intravascular space and tissues. In case of meningitis, the blood-

brainn barrier must be crossed and the bacteria have to survive in the cerebro-spinal fluid

(CSF).. Attachment and mucosal cell invasion are probably normal events in colonization, but

alsoo logical first steps in a process that can lead to bacterial invasion of the bloodstream (175).

Inn this respect, meningococcal components mediating interaction with the mucosal epithelium

shouldd be considered as virulence factors. A major difficulty in identifying putative virulence

factorss is the strong intra- and inter-strain variation in surface constituents displayed by the

bacteria,, in vitro as well during carriage and disease. Ongoing phase switching and antigenic

variationn of factors such as capsule (33,42,76,77,88,116), pili (4,7,129,187,201), opacity

associatedd proteins (Opa and Ope) (5,6,43,135,161,212), porins (PorA and PorB)

(4,52,57,110,212)) and lipopolysaccharide (LPS) (85,88,217) have been described. The

antigenicc heterogeneity of some of these cell surface components constitute the basis of a

phenotypicc classification system for epidemiological purposes (57).

Capsulee polysaccharides

Meningococcii can be divided into serogroups based on the antigenic differences of the

polysaccharidee capsules they produce. Although for a long time considered as a stable

attribute,, an increasing body of evidence suggests that meningococci can switch their capsule

polysaccharidee type as a result of horizontal gene transfer of part(s) of the capsule gene

clusterr (35,58,109,184). Polysaccharide capsules can consist of homopolymers of sialic acid

(serogroupp B and C) (19,63), polymers of sialic acid with galactose (W135) (19) and sialic

acidd with glucose (serogroup Y) (19). Homopolymers of modified N-acetyl mannosamine-

phosphatee and of N-acetylglucosamine-phosphate can be found on serogroup A (30,63) and X

(30)) meningococci, respectively. Serogroup Z polysaccharide consists of N-

acetylgalactosaminee and glycerol-phosphate (84), while N-acetylgalactosamine and modified

KDOO form the repeating disaccharide of serogroup 29-E polysaccharide (18). In addition,

severall less frequently isolated serogroups, which are generally not associated with disease,

havee been described (D,E,H-L) (107).

Whilee the majority (>50%) of isolates obtained from healthy carriers lack a capsule

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andd are thus non-groupable, meningococci isolated from blood and liquor are almost

invariablyy encapsulated (37,38,88). It has been widely accepted that the capsule is

indispensablee for survival and proliferation of the bacteria in the bloodstream of

immunologicallyy naive hosts (75,82,93,206,207) and confers resistance against the human

complementt system. Polysaccharides prevent proper insertion of the membrane attack

complexx in the bacterial outer membrane, rather than reducing the deposition of C3b (206).

Serogroupp B polysaccharide is by itself poorly immunogenic, because of structural

similaritiess with sialic acid epitopes on fetal and infant brain tissue (N-CAM) (54,55,213).

Capsulee also reduces the exposure of subcapsular antigens to the immune system. This

maskingg effect inhibits non-opsonic phagocytosis (48,119), but also the meningococcal

invasionn of epithelial and endothelial cells (44,45,75-77,203). The apparent conflict between a

bacteriall phenotype that is protected against complement mediated lysis during systemic

infectionn but hampered in its interaction with certain host cells, is resolved through phase

variationn of capsule expression. Variation in capsule synthesis appears to be controlled both

byy environmental signals (116) and reversible variation of capsule gene expression. The latter

occurss through reversible insertion of the IS 1301-like element in the first gene of the capsule

synthesiss operon (siaA) (76) and/or via a slipped strand-mispairing event in the siaD gene

encodingg the polysialyltransferase (77).

AA putative and potentially important function of the hydrophilic capsules that thus far

hass received littl e attention is the protection of meningococci against desiccation during

transmissionn between hosts.

Pili i

Pilii (fimbriae) are hair-like structures, composed of protein subunits, which emanate from the

bacteriall surface. These organelles probably play an important initial role in neisserial

colonizationn and are the prime attachment promoting factor on encapsulated meningococci

(49,129,174,176,200).. Pili also mediate bacterial auto-agglutination (45,115,159), twitching

motilityy (movement of bacterial cells across a solid surface) (25,81) and are associated with

increasedd transformation competence (20). Because of their exposed location and prime

importancee for the initiation of infection, pili are expected to be main targets for host defense.

Thiss probably explains the strong antigenic variability of pili . The molecular basis for pilin

variabilityy depends in part on a large family of (up to 20 in N. gonorrhoeae) variant pilS genes

onn the neisseria chromosome (168). These silent (pilS) genes are truncated at the amino-

terminuss and lack promoter sites. As the result of a non-reciprocal, homologous, intragenic

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recombinationn of silent pilin copies into the expression locus pilE, the coding sequence of the

expressedd gene copy can be changed (67,183). Alternatively, antigenic variation can arise

fromm transformation-mediated recombination or allelic replacement (59,169). N. meningitidis

cann express Class I pili which closely resemble gonococcal pili and Class II pili , with identity

too pilin genes of the human commensal species Neisseria lactamica and Neisseria cinerea

(7,144,201).. All predicted protein sequences display features typical of type IV (or N-

methylphenylalanine)) pilins. Class II pili are composed of pilin with smaller subunit size and

lackk reactivity with the broadly cross-reacting (for class I pilin) monoclonal antibody SMI

(201).. Both class I and class II pili producing meningococci can act as pathogens, and contain

silentt (pilS) genes.

Apartt from antigenic variation, the pilus biosynthesis is also subjected to phase

variation.. Reversible phase variants are frequently observed as non-piliated interfaces

betweenn the expression of two successive, antigenically distinct pilus variants. Loss of pili

cann results from an alternative processing of propilin, which results in truncated subunits that

cann not polymerize and are excreted in the growth medium as soluble (S-) pilin (67,68,101).

Followingg the identification and characterization of the minor pilin subunit PilC, a new

mechanismm for pilus phase-variation was proposed (90). Gonococcal and meningococcal

strainss usually express two pilC loci, encoding PilCl and PilC2. These variants usually are

moree than 70% identical (90-92,128,160). It has been reported that expression of PilC

correlatedd with the presence of assembled pili (P+). PilC" gonococcal variants were non-

piliatedd (P) and either secreted S-pilin or produced no pilin at all, as a result of promoter

deletionss in the pilE gene (91). PilC expression is controlled by frequent deletions and

insertionss in a tract of repetitive G residues located at the 5' end of the gene, generating

frameshiftt variants (90). Usually, the on-off-on transition of PilC and pili (PilC+P+- PilCT-

PilC+P+)) correlates with the expression of altered pilins due to rearrangements in the pilin

subunitt gene {pilE) (91). These results show that PilC may have a significant effect on pilus

variation. .

Apartt from primary sequence changes within the neisserial pilin molecule itself, post-

translationall modifications of the pilin subunit with saccharide (65,132), phosphorylcholine

(211)) and a-glycerophosphate (153,165,180) have been found. These surface-exposed

modificationss may contribute to antigenic variation (56) and immune escape (74) of the intact

piluss fibers, but as yet no noticeable effects on pili expression, maturation or functions have

beenn detected (56).Pili of pathogenic neisseria have distinct specificities for attachment to a

varietyy of different host cells, including epithelial cells (42,89,117,128,159,203), erythrocytes

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(62,105,159,189)) and endothelial cells (128,200,200). Recently, the complement regulatory

proteinn CD46, a human-specific protein, has been recognized as a pilus receptor for

pathogenicc neisseria (96). The pilus molecule(s) responsible for this attachment have not been

identified.. Early studies suggested direct involvement of a conserved domain on the major

subunit,, pilin (PilE) in the adherence of Neisseria gonorhoeae to epithelial cells (165). PilE

peptidess (in the region between residues 41 and 84) were shown to bind to epithelial cells,

whilee antibodies directed against some of these peptides (residue 69-84) (50) blocked the

adherencee of an unrelated piliated gonococcal strain to endometrial ENCA-4 epithelial cells

(154).. Only a small area of this pilin sequence however, representing amino acid 73 to78 is

conservedd between all known pilin sequences (67,69,102,130,159). A peptide containing the

centrall region of the pilin molecule (CNBr-2) also competitively inhibited haemagglutination

causedd by purified pili of different gonococcal strains (62). This erythrocyte-binding ability

seemss to be conserved and independent of pilin variation (105,106,159).

Too investigate whether minor pilus subunits (mainly PilC ) are responsible for

adherencee specificity, binding studies were performed with derivatives and mutants of TV.

gonorrhoeaegonorrhoeae MS11, carrying structurally defined PilE and PilC proteins. (89,159). The

bindingg efficiencies of piliated gonococcal clones containing different pilE sequences varied

dramaticallyy for corneal and conjunctival tissues, but were unchanged when cervical and

endometriall tissues were used (89,159). Expression of either PilCl or PilC2 containing pili

didd not change binding properties. PilC expression without assembled pili did not result in

bindingg of bacteria to host cells (89). Additional information on two serogroup B

meningococcall strains indicated that modification in pilin subunit structure resulted in altered

adhesionn phenotype, although PilC was unchanged (204). Together, these data suggest that

sequencee alterations in the pilE gene can result in a quantitative change in pilus mediated

adherencee and in differences in tissue tropism. More recent data suggest a central role for the

minorr pilus subunit PilC in pilus-mediated adherence (128,156,159,160,204). Gonococci and

mostt meningococci, producing either class I or class II pili express two different pilC loci,

encodingg PilCl and PilC2 (92,128,155,160). These proteins have been located both at the tip

off pilus fibers (156) and in the outer membrane (147). They have been implicated to function

inn pilus assembly (90,128,160), adherence to epithelial cells (128,156,160) and natural

transformationn competence (155). The same PilC can function in both class I (gonococcal)

andd class II (meningococcal) pili backgrounds (160). At least in one Mc strain (8013) only

PilCll seems to be associated with adherence, regardless of PilC2 phenotype (128). Recently,

aa transient upregulation of transcription of this adhesive pilCl allele, but not pilC2, has been

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reportedd to result from initial meningococcal-host cell interactions (46,185,186). In some

meningococcall strains, only a single PilC could be detected (145,204). The strongest support

forr a direct role of PilC in pilus mediated adherence comes from data, showing that purified

gonococcall PilC2 inhibits the adherence of either PilCl or PÏ1C2 expressing piliated

gonococcii to epithelial cells (156). In conclusion, PilC probably plays an important role in

piluss expression, antigenic variation, epithelial and endothelial cell adherence and competence

forr DNA transformation. Still, the mechanistic roles of PilCl and PilC2 in some of these

processess have not been convincingly demonstrated.

Inn analogy to the P fimbriae of uropathogenic E. coli (79,80,181), it has been suggested

thatt the type IV pili of pathogenic neisseriae can mediate pathogen-host cross-talk at the

epitheliall cell surface (2,95,215). Although direct evidence is missing, these observations

suggestt a role for both the pilus receptor CD46 and meningococcal PilCl in fimbriae

mediatedd signal transduction. The membrane co-factor protein CD46 is a human-specific

proteinn that is expressed on virtually any cell type except on erythrocytes. Pathogenic

neisseriaa however can bind erythrocytes in a pilus specific, PilC independent way

(105,106,159,166),, indicating that at least one additional binding domain exists, conserved on

thee major pilus subunit pilin, that recognizes a second (non-CD46) host cell receptor.

Outerr membrane proteins

Opa/Opc Opa/Opc

Inn vitro experiments have shown that non-encapsulated meningococci that lack pili can still

adheree to and invade host cells provided that they carry the appropriate surface

adhesins/invasins,, including the Ope protein and/or certain members of the opacity (Opa)

outerr membrane protein family (44,45,202,203). Ope and Opa are basic 24-35 kDa neisserial

surfacee proteins that share many features although their corresponding genes and predicted

two-dimensionall structures are unrelated (5,8,121,131). Both types of proteins may exist as

multimers,, confer colonial opacity and have been implicated in facilitating meningococcal

adherencee and invasion into various types of host cells (5,44,45,119,120,182,202,203). Both

typess of proteins are variable expressed. The transcription of the opcA gene (encoding Ope)

variess from zero to intermediate or high (5), dependent on the number of C residues in a

variablee homopolymer positioned between the -10 and -35 boxes of the ope A promoter

(161).. Several opc-like (pseudo-) genes have recently been described in N. gonorrhoeae and

NeisseriaNeisseria meningitidis, but expression of functional amounts of Ope protein is probably

restrictedd to a subset of meningococcal strains (216). Opa proteins are subject to both phase-

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andd antigenic variation (40,97). Multiple, unlinked opa genes each carrying their own

promoterr can be found in N. gonorrhoeae (strain MS11, 11 genes), in N. meningitidis (3-4

genes)) and in N. lactamica (2 genes) and are constitutively expressed (8,17,97,104,178,179).

Phasee variation results from frequent phase transitions that occur via a RecA-independent

DNA-slippagee mechanism involving a variable number of CTCTT repeats in the signal-

peptidee encoding region of the genes (126,177,178). In this way, a heterogeneous population

off bacteria, expressing none, one or multiple different opa proteins can be generated.

Recombinationn events between opa genes do occur and are probably responsible for the often

mosaicc structure of the genes, in which (parts of) semi variable (SV), but especially of

hypervariablee regions (HV1 and HV2) are exchanged between individual Opa's

(8,17,40,177).. The variable expression of Ope and Opa's at the meningococcal surface occurs

inn the human host during infection (5,6,43,135,212). It may serve as an adaptive mechanism

thatt enables the bacteria to spread to different anatomical niches by creating phenotypes with

differentt receptor specificities.

MajorMajor porins, Por A and PorB

Twoo major classes of neisserial outer membrane proteins are the pore forming proteins PorA

(onlyy in Neisseria meningitidis) and PorB, which enable the flux of ions and small

macromoleculess across the outer membrane (24,214). These proteins form a trimeric

configurationn of porin monomers, which span the membrane in amphipatic P-sheets (41).

Theirr trimeric structure and sequence similarities place them in a group with other gram-

negativee bacterial porins like OmpC, OmF (cation selective) (16,124) and PhoE (anion

selective)) (15). Topological models for neisserial porins predict 16 membrane spanning

regionss with 8 surface exposed loops (47,195). Several of these loops carry variable regions

(VRs).. Within each serogroup (capsule type), these VRs form the basis for a serological

typingg (PorB) or subtyping (PorA) scheme for the Mc (57). Genetically, two different porB

alleless have been described for N. meningitidis, porB2 (class 2 OMP: 40-42 kDa) and porB3

(classs 3 OMP: 37-39 kDa), which correspond with the porB la (PI A) and porB lb (P1B)

alleless of the single gonococcal PI porin, respectively (14,53,210). Expression of the different

allelicc forms of porB is mutually exclusive so that a strain produces either one of these porins

(57). .

Besidess its function as a transporter molecule, the PorB protein has been implicated in

thee interaction of bacteria with mammalian cells. Purified PorB can insert into model lipid

bilayerss and into plasma membranes of eukaryotic cells, where they can cause a transient

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changee in transmembrane potential and modulate cell signaling events (22,70,71,157,193).

Thee observation that these proteins can transfer from viable bacteria directly into target cell

membraness further contributed to the idea that PorB can trigger uptake of neisseria into host

cellss (108). Direct evidence for a role of PorB in neisserial invasion of human cells was

obtainedd with the identification of a new invasion mechanism, driven by a subtype of the

PorBB proteins, the gonococcal PI A (PorB la). This invasion event mediated by Gc PI A but

nott P1B (PorBlb) was only apparent under conditions of low phosphate availability (197).

Currentt hypotheses assume that non-covalent binding of phosphate by PI A porin prevents its

interactionn with or proper insertion into mammalian cell membranes. Alternatively, phosphate

mayy interfere with the gating function of inserted porins, reminiscent of the reported closing

effectt of nucleoside triphosphates on neisserial porins (158). As yet, no porin driven invasion

mechanismm has been described for the meningococcus or commensal neisseria.

Expressionn of the PI A porin by gonococci is correlated with serum resistance (32) and

thee ability to cause disseminated gonococcal infection (DGI) (125). Preferential binding of the

complementt regulatory factor H to loop 5 of the gonococcal PI A porin correlates with an

increasedd conversion of C3b to iC3b and decreased complement mediated killing of the

bacteriaa (149). It is currently unclear whether meningococcal PorB (class 2 or class 3) porins

cann bind factor H. A binding site identical to the one present in the loop 5 of the gonococcal

porinn is absent from meningococcal porins (206).

Althoughh a porA pseudogene has been identified in N. gonorrhoeae, PorA is only

expressedd by N. meningitidis (53). In contrast to PorB, the expression level of the

meningococcall PorA protein is subject to phase variation, caused by a change in the number

off nucleotides positioned between the -10 and -35 region of the porA promoter (194). In

addition,, even within a group of genetically related meningococci as the ET5 complex, gene

replacement,, horizontal exchange of gene fragments, and accumulation of new mutations

havee been observed. These events have resulted in the evolvement of a wide variety of

antigenicallyy different PorA proteins among clinical isolates. Despite its antigenic diversity

PorAA is a prime vaccine candidate antigen. This choice is largely based on the observation

thatt porA elicits bactericidal antibodies. These antibodies are usually directed against the

mostt exposed, variable regions (VRs) of the protein (23,122). Sero-subtyping monoclonal

antibodiess which are used for phenotyping of disease strains, are directed against these same

epitopess (118,195), are bactericidal and confer protection in infant rat infection experiments

(162,163).. To overcome the induction of strain-specific protection by a PorA-based vaccine,

thee most prevalent disease associated PorA variants (representing 70-80% of Dutch serogroup

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BB and C case isolates) have been included in a vesicle vaccine (39,196). Field trials with this

hexavalentt PorA based vaccine have been performed (137).

Phasee switching of PorA does occur in vivo, especially during carriage but also in

clinicall isolates (4,212). It is currently unclear whether PorA contributes to meningococcal

virulence.. Meningococci grow much faster on solid culture media than the closely related

gonococci,, which do not carry a PorA protein. Although the growth of cultured

meningococcall PorA mutants is not reduced compared to the wildtype (188), the presence of

thiss additional meningococcal porin may allow faster growth under certain environmental

conditionss in vivo. It has been argued that meningococci can express PorA/PorB porin

heterotrimerss (123). In this respect, PorA may contribute to the functionality of the major

meningococcall porin. It can however not be excluded that PorA has developed into an

immunologicall decoy, directing host immune defenses to a phase variable antigen without

essentiall function. Unlike PorB epitopes, which are immunologically shielded by full chain

lengthh LPS (1,141), the highly immunogenic PorA epitopes are not shielded or protected.

Lipopolysaccharide e

Thee outermost layer of the asymmetric outer membrane of the neisserial cell envelope

consistss largely of lipopolysaccharide (LPS). Neisseria express LPS lacking O-specific side-

chains.. The glycolipid consists of a hydrophilic oligo-saccharide core, linked to lipid A,

whichh anchors the molecule in the outer membrane. Lipid A of the pathogenic neisseria

consistss of a l,4'-biphosphorylated, p(l-6)-linked glucosamine disaccharide backbone,

substitutedd with six (predominantly) or five fatty acid residues (103,136). Neisserial lipid A

differss from the well-studied enterobacterial lipid A in the nature and the position of fatty

acids.. N.meningitidis lipid A differs from its gonococcal counterpart in that the phosphate

groupss of the lipid A backbone are largely substituted with 0-phosphorylethanolamine

(103,136).. In some (serogroup B) isolates the 4' phosphate may be lacking (148).

Thee oligosaccharide core region of meningococci contains a conserved part consisting

off two heptoses (the first being the one fixed to KDO) and two KDO molecules, which link

thee variable terminal saccharide chain(s) to the lipid A. Structural studies (83,139,140,199),

electromorphicc profiles and the use of monoclonal antibodies have demonstrated considerable

heterogeneityy of the oligosaccharide moiety of neisserial LPS (11,12,114). This variation

formss the basis for the identification of twelve different LPS immunotypes (LI-LI2 )

(99,192,217,218).. Observed variations include the presence, length and composition of the

oligosaccharidee antennas (64). Additional structural differences may arise from the presence

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orr absence of phosphorylethanolamine substituents and their location in the inner core

(136,199).. A single bacterium may simultaneously carry a heterogeneous population of low

molecularr mass LPS molecules (164,190). LPS variation is caused by a high frequency

switchingg in the availability and/or activity of glycosyltransferases (85,86,94). Some of the

enzymess involved in oligosaccharide synthesis are variably expressed as a result of

transcriptional/translationall frame shifting in genes encoding those transferases (94). The

availabilityy of LPS precursor molecules (like modified hexoses), depends on many genes of

centrall metabolism and can be influenced by growth conditions and growth phase of the

bacteriaa (141,190).

AA determinant present at the non-reducing end of the L2, L3, 7,9, L4 and L5

immunotypee LPS and also highly conserved among strains of N. gonorrhoeae, is the terminal

tetrasaccharidee lacto-iV-neotetraose (LNnT) (87,98,112,191). This structure,

(Gaipi^4GlcNAcpl-»3Galfil-»-4Glc)) is identical to the carbohydrate portion of

paraglobosidee (nLc4Cer), a glycophingolipid precursor of the major human (ABH)

bloodgroupp antigens (72,172). Monoclonal antibodies (3F11, 06B4) demonstrated the

immunochemicall similarity between epitopes on this neisserial LPS and antigens present on

humann erythrocytes (111). This molecular mimicry may prevent an effective immune

responsee to this bacterial antigen.

Ann additional in vivo modification of neisserial LPS was first discovered for N.

gonorrhoeae.gonorrhoeae. It was observed that gonococci in urethral exudates are serum resistant, a

virulencee factor that is lost upon subculture onto an artificial medium (13,113,127,133,134).

Thee component responsible for this sero-conversion was identified as N-acetylneuraminic- or

sialicc acid, a-(2-3)- linked to the terminal galactopyranosyl residue of the 4.5 kDa

paragloboside-likee LPS component. A bacterial membrane associated oc-2,3-sialyltransferase

mediatedd this sialylation, using the host derived nucleotide sugar, cytidine 5'-monophospho-

yV-acetylneuraminicc acid (CMP-NANA) as a substrate (113). Most strains of meningococci

thatt synthesize a sialic acid capsule (serogroups B, C, W135 and Y) have the intrinsic ability

too synthesize CMP-NANA, and thus sialylate their LPS when the 4.5 kDa LPS acceptor is

presentt (112,191). Mutants unable to produce CMP-NANA can not endogenously sialylate

theirr LPS, but sialylation is restored when exogenous CMP-NANA is available (112).

Inn gonococci, sialylation of LPS results in an increased binding of complement factor H

whichh causes a reduced deposition of C3b and contributes to the inducible serum resistance

phenotypee (150). Thus, the increased binding of factor H by two closely associated surface

20 0

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moleculess in the gonococcal outer membrane, the sialylated LPS and the PI A porin (loop 5,

seee before), protects the bacterium from alternative pathway-mediated killing (206). In

addition,, LPS sialylation reduces complement dependent opsonophagocytosis of pathogenic

neisseriaa by human neutrophils (100,151). In meningococci, the biological effects of

sialylationn are less well defined. LPS sialylation appears to be of minor importance for serum

resistancee compared with the polysaccharide capsules. Isogenic oc-2,3 sialyltransferase knock-

outt mutants of several capsulated serogroup B and C strains, only marginally differed in

serumm resistance from their wild type counterparts (93,205). However, in several serum-

sensitivee serogroup C isolates, obtained from healthy carriers, exogenous sialylation of the

LPSS enhanced serum resistance (51). So, it is hypothesized that the more susceptible the

neisseriall strain, the higher the benefit of LPS sialylation for serum resistance (205).

Interestingly,, truncation of the LNnT structure by a galE mutation, rendered several

previouslyy serum resistant encapsulated serogroup B and C strains (B1940, MC58, 2120,

C:NT:P1.2,5)) highly susceptible to normal human serum (NHS). The massive C3b deposition

onn these encapsulated strains with truncated LPS resulted from the concerted action of the

alternativee and classical pathway and correlated with increased binding of natural IgM and

mannosee binding lectin (MBL) (207). GalE mutation however, had no effect on the serum

resistancee of another serogroup B strain (NMB) or on the gonococcal strain MSI 1 (93,152).

Thesee results indicate that strain-specific differences have to be taken into account, when

investigatingg meningococcal serum resistance.

Theree are data implying that the LPS phenotype of the pathogenic neisseria may be a

criticall factor for cellular invasion. Studies in experimental models indicated that mutations

resultingg in LPS truncations that extend into the core region result in reduced or abrogated

invasionn of Chang epithelial cells, despite expression of an invasion-promoting Opa protein

(167,198).. Other experiments indicate that the paraglobosyl-like LPS (LNnT) is necessary for

invasionn of genitourinary (170) and HEP2 liver cells (142,143) by gonococci.

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Aimss and outline of this thesis

Meningococcall disease probably represents an evolutionary dead end and the bacteria are

optimallyy adapted to the human nasopharynx, their sole habitat and natural reservoir.

Colonizationn of the human host generally elicits a specific immune response towards the

bacteria.. For variable periods of time however, such antibodies seem unable to eliminate the

homologouss strain from the nasopharynx, as the bacteria may persist in the human upper

airwayss for periods of over 20 months. An important factor that may contribute to the

prolongedd carrier state is the extensive variation in surface constituents expressed by

meningococcii colonizing the human host. It can be envisioned that this variability serves as

ann immune escape mechanism. At the time of design of this study, knowledge of putative

otherr biological functions of the phenotypic variation was rudimentary. However, in several

instancess reversible phase transitions of surface antigens had been observed during the course

off the carriage state. This may reflect a functional adaptation of the bacteria to frequent, often-

recurrentt microenvironmental changes encountered during colonization and transmission.

Inn the underlying study we investigated whether the phenotypic variation of

meningococcii surface constituents contributed to the ability of meningococci to adhere to and

invadee nasopharyngeal epithelial cells, and whether local host cell factors are major

determinantss of the bacteria-host cell interaction. Identification and characterization of

invasivee meningococci should answer the question whether all meningococci or only distinct

phenotypess are able to invade cells of the mucosal epithelium, a logical first step in the onset

too meningococcal disease.

Inn chapter 2, we describe the development of a new experimental infection model,

monolayerss of primary nasopharyngeal epithelial cells. Infection experiments indicated that

meningococcall phenotypes like those found in the bloodstream or liquor do not interact with

thee nasopharyngeal epithelium. Invasion of these epithelial cells however did occur following

concurrentt phase variation of multiple surface antigens. Comparison of invasive

meningococcii selected on epithelial cells originating from different anatomical sites indicated

thatt meningococcal class 5 proteins (Opa and Ope) may promote tissue tropism.

Inn chapter 3, we investigated the interaction of Ope and a distinct Opa protein with

certainn epithelial cells in more detail. We could show that both bacterial proteins bound to

epitheliall cell surface proteoglycan receptors, but only Opc-expressing bacteria could exploit

thiss newly identified meningococcal host cell receptor to gain access to the cell interior.

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Inn chapter 4 we describe the discovery that human neutrophil defensins, present in neutrophil

granulee extract stimulate meningococcal invasion of epithelial cells, irrespective of the Mc

phenotype. .

Inn chapter 5 we could show that the invasion stimulating effect of neutrophil defensins

iss associated with the formation of defensin rich intermembrane contact sites between

bacterial-- and host cell membranes and involves a novel mechanism of bacterial invasion of

mammaliann cells.

Finally,, in chapter 6, the implications of our findings are discussed, in the context of

theirr relevance for colonization and development of meningococcal disease.

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References s

11 Aase, A., E.A- Hoybe, J. Kolberg, E. Rosenqvist, and T.E. Michaelsen. 1998. Most antibodies to PorB

doo not bind to viable meningococci, but bind strongly to ethanol-killed bacteria. In Abstracts of the

Eleventhh International Pathogenic Neisseria Conference (Nassif,X., Quentin-Millet,M.J., Taha,M.K., eds)

Paris,, Edition E.D.K., p.284.

2.. Abraham, S.N., A.B. Jonsson, and S. Normark . 1998. Fimbriae-mediated host-pathogen cross-talk.

Curr.Opin.Microbiol.. 1:75-81.

3.. Achtman, M. 1995. Epidemic spread and antigenic variability of Neisseria meningitidis.

Trends.Microbiol.. 3:186-192.

4.. Achtman, M., B. Kusecek, G. Morelli , K. Eickmann, J.F. Wang, B. Crowe, R.A. Wall , M. Hassan-

King ,, P.S. Moore, and W. Zollinger. 1992. A comparison of the variable antigens expressed by clone

IV-11 and subgroup II I of Neisseria meningitidis serogroup A. J.Infect.Dis. 165:53-68.

5.. Achtman, M., M. Neibert, B.A. Crowe, W. Strittmatter , B. Kusecek, E. Weyse, M.J. Walsh, B.

Slawig,, G. Morelli , and A. Moll . 1988. Purification and characterization of eight class 5 outer membrane

proteinn variants from a clone of Neisseria meningitidis serogroup A. J.Exp.Med. 168:507-525.

6.. Achtman, M., R.A. Wall , M. Bopp, B. Kusecek, G. Morelli , E. Saken, and M. Hassan-King. 1991.

Variationn in class 5 protein expression by serogroup A meningococci during a meningitis epidemic.

J.Infect.Dis.. 164:375-382.

7.. Aho, EX., J.W. Botten, RJ. Hall , M.K . Larson, and J.K. Ness. 1997. Characterization of a class II

pilinn expression locus from Neisseria meningitidis: evidence for increased diversity among pilin genes in

pathogenicc Neisseria species. Infect.Immun. 65:2613-2620.

8.. Aho, E.L., J.A. Dempsey, M.M . Hobbs, D.G. Klapper, and J.G. Cannon. 1991. Characterization of the

opaa (class 5) gene family of Neisseria meningitidis. Mol.MicrobioI. 5:1429-1437.

9.. Andersen, B.M. 1978. Mortality in meningococcal infections. ScandJ.Infect.Dis. 10:277-282.

10.. Andersen, B.M. and O. Solberg. 1988. Endotoxin liberation associated with growth, encapsulation and

virulencee of Neisseria meningitidis. ScandJ.Infect.Dis. 20:21-31.

11.. Apicella, M.A . 1976. Serogrouping of Neisseria gonorhoeae: identification of four immunologically

distinctt acidic polysaccharides. J.Infect.Dis. 134:377-383.

12.. Apicella, M.A. and N.C. Gagliardi. 1979. Antigenic heterogeneity of the non-serogroup antigen

structuree of Neisseria gonorhoeae lipopolysaccharides. Infect.Immun. 26:870-874.

13.. Apicella, M.A., R.E. Mandrell , M. Shero, M.E. Wilson, J.M. Griffiss, G.F. Brooks, C. Lammei, J.F.

Breen,, and P.A. Rice. 1990. Modification by sialic acid of Neisseria gonorhoeae lipooligosaccharide

epitopee expression in human urethral exudates: an immunoelectron microscopic analysis. J.Infect.Dis.

162:506-512. .

14.. Barlow, A.K., J.E. Heckels, and LN. Clarke. 1989. The class 1 outer membrane protein of Neisseria

meningitidis:meningitidis: gene sequence and structural and immunological similarities to gonococcal porins.

Mol.MicrobioI.. 3:131-139.

15.. Bauer, K., A. Schmid, W. Boos, R. Benz, and J. Tommassen. 1988. Pore formation by pho-controlled

outer-membranee proteins of various Enterobacteriaceae in lipid bilayers. Eur.J.Biochem. 174:199-205.

24 4

Page 20: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

GeneralGeneral introduction

16.. Benz, R. and K. Bauer. 1988. Permeation of hydrophilic molecules through the outer membrane of

gram-negativee bacteria. Review on bacterial porins. Eur.J.Biochem. 176 :1-19.

17.. Bhat, K.S., C.P. Gibbs, O. Barrera, S.G. Morrison , F. Jahnig, A. Stern, E.M. Kupsch, T.F. Meyer,

andd J. Swanson. 1991. The opacity proteins of Neisseria gonorhoeae strain MS 11 are encoded by a

familyy of 11 complete genes [published erratum appears in Mol Microbiol 1992 Apr,6(8): 1073-6].

Mol.Microbiol.. 5:1889-1901.

18.. Bhattacharjee, A.K., HJ . Jennings, and C.P. Kenny. 1978. Structural elucidation of the 3-deoxy-D-

manno-octulosonicc acid containing meningococcal 29-e capsular polysaccharide antigen using carbon-13

nuclearr magnetic resonance. Biochemistry 17:645-651.

19.. Bhattacharjee, A.K., HJ . Jennings, C.P. Kenny, A. Martin , and I.C. Smith. 1976. Structural

determinationn of the polysaccharide antigens of Neisseria meningitidis serogroups Y, W-I35, and BOl.

CanJ.Biochem.. 54:1-8.

20.. Biswas, G.D., T. Sox, E. Blackman, and P.F. Sparling. 1977. Factors affecting genetic transformation

off Neisseria gonorhoeae. J.Bacterid. 129:983-992.

21.. Biswas, G.D., S.A. Thompson, and P.F. Sparling. 1989. Gene transfer in Neisseria gonorhoeae.

Clin.Microbiol.Rev.. 2 Suppl:S24-8:S24-S28

22.. Bjerknes, R., H.K. Guttormsen, CO. Solberg, and L.M . Wetzler. 1995. Neisserial porins inhibit

humann neutrophil actin polymerization, degranulation, opsonin receptor expression, and phagocytosis but

primee the neutrophils to increase their oxidative burst. Infect.Immun. 63:160-167.

23.. Bjune, G., E.A. Hoiby, J.K. Gronnesby, O. Arnesen, J.H. Fredriksen, A. Halstensen, E. Holten, A.K.

Lindbak ,, H. Nokleby, and E. Rosenqvist. 1991. Effect of outer membrane vesicle vaccine against group

BB meningococcal disease in Norway [see comments]. Lancet 338 :1093-1096.

24.. Blake, M.S. and E.C. Gotschlich. 1983. Gonococcal membrane proteins: speculation on their role in

pathogenesis.. Prog.Allergy 33:298-313:298-313.

25.. Bradley, D.E. 1980. A function of Pseudomonas aeruginosa PAO polar pili : twitching motility.

Can.J.Microbiol.. 26:146-154.

26.. Brandtzaeg, P., K. Bryn, P. Kierulf , R. Ovstebo, E. Namork, B. Aase, and E. Jantzen. 1992.

Meningococcall endotoxin in lethal septic shock plasma studied by gas chromatography, mass-

spectrometry,, ultracentrifugation, and electron microscopy. J.Clin.Invest. 89:816-823.

27.. Brandtzaeg, P., R. Ovstebo, and P. Kierulf . 1995. Bacteremia and compartmentalization of LPS in

meningococcall disease. Prog.Clin.Biol.Res. 392:219-33:219-233.

28.. Broome, C.V. 1986a. The carrier state: Neisseria meningitidis. Antimicrob.Agents Chemother. 18A:25-

34. .

29.. Broome, C.V. 1986b. The carrier state: Neisseria meningitidis. J.Antimicrob.Chemother. 18 Suppl A:25-

34:25-34. .

30.. Bundle, D.R., HJ. Jennings, and C.P. Kenny. 1974. Studies on the group-specific polysaccharide of

NeisseriaNeisseria meningitidis serogroup X and an improved procedure for its isolation. J.Biol.Chem. 249:4797-

4801. .

25 5

Page 21: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

ChapterChapter 1

31.. Bygraves, J.A., R. Urwin , A J. Fox, SJ. Gray, J.E. Russell, I.M . Feavers, and M.C. Maiden. 1999.

Populationn genetic and evolutionary approaches to analysis of Neisseria meningitidis isolates belonging to

thee ET-5 complex. J.Bacteriol. 181:5551-5556.

32.. Carbonetti, N., V. Simnad, C. Elkins, and P.F. Sparling. 1990. Construction of isogenic gonococci

withh variable porin structure: effects on susceptibility to human serum and antibiotics. Mol.Microbiol.

4:1009-1018. .

33.. Cartwright , K.A., J.M. Stuart, D.M. Jones, and N.D. Noah. 1987. The Stonehouse survey:

nasopharyngeall carriage of meningococci and Neisseria lactamica. Epidemiol.Infect. 99:591 -601.

34.. Catlin, B.W. I960. Transformation of Neisseria meningitidis by deoxyribonucleates from cells and from

culturee slime. J.Bacteriol. 79:579-590.

35.. Caugant, D.A. 1998. Population genetics and molecular epidemiology of Neisseria meningitidis. APMIS

106:505-525. .

36.. Caugant, D.A., K. Bovre, P. Gaustad, K. Bryn, E. Holten, E.A. Hoiby, and L.O. Froholm. 1986.

Multilocuss genotypes determined by enzyme electrophoresis of Neisseria meningitidis isolated from

patientss with systemic disease and from healthy carriers. J.Gen.Microbiol. 132:641-652.

37.. Caugant, D.A., E.A. Hoiby, P. Magnus, O. Scheel, T. Hoel, G. Bjune, E. Wedege, J. Eng, and L.O.

Froholm.. 1994. Asymptomatic carriage of Neisseria meningitidis in a randomly sampled population.

J.Clin.Microbiol.. 32:323-330.

38.. Caugant, D.A., B.E. Kristiansen, L.O. Froholm, K. Bovre, and R.K. Selander. 1988. Clonal diversity

off Neisseria meningitidis from a population of asymptomatic carriers. Infect.Immun. 56:2060-2068.

39.. Claassen, I., J. Meylis, P. van der Ley, C. Peeters, H. Brons, J. Robert, D. Borsboom, A. van der

Ark ,, I. van Straaten , P. Roholl, B. Kuipers, and J. Poolman. 1996. Production, characterization and

controll of a Neisseria meningitidis hexavalent class 1 outer membrane protein containing vesicle vaccine.

Vaccinee 14:1001-1008.

40.. Connell, T.D., W.J. Black, T.H. Kawula, D.S. Barritt , J.A. Dempsey, K.J. Kverneland, A.

Stephenson,, B.S. Schepart, G.L. Murphy , and J.G. Cannon. 1988. Recombination among protein II

geness of Neisseria gonorhoeae generates new coding sequences and increases structural variability in the

proteinn II family . Mol.Microbiol. 2:227-236.

41.. Cowan, S.W., T. Schirmer, G. Rummel, M. Steiert, R. Ghosh, R.A. Pauptit, J.N. Jansonius, and J.P.

Rosenbusch.. 1992. Crystal structures explain functional properties of two E. coli porins. Nature 358:727-

733. .

42.. Craven, D.E., M.S. Peppier, CE. Frasen, L.F. Mocca, P.P. McGrath , and G. Washington. 1980.

Adherencee of isolates of Neisseria meningitidis from patients and carriers to human buccal epithelial cells.

J.Infect.Dis.. 142:556-568.

43.. Crowe, B.A., R.A. Wall , B. Kusecek, B. Neumann, T. Olyhoek, H. Abdillahi , M. Hassan-King, B.M.

Greenwood,, J.T. Poolman, and M. Achtman. 1989. Clonal and variable properties of Neisseria

meningitidismeningitidis isolated from cases and carriers during and after an epidemic in The Gambia, West Africa.

J.Infect.Dis.. 159:686-700.

44.. de Vries, F.P., R. Cole, J. Dankert, M. Frosch, and J.P. van Putten. 1998. Neisseria meningitidis

producingg the Ope adhesin binds epithelial cell proteoglycan receptors. Mol.Microbiol. 27:1203-1212.

26 6

Page 22: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

GeneralGeneral introduction

45.. de Vries, F.P., A. van der Ende, J.P. van Putten, and J. Dankert. 1996. Invasion of primary

nasopharyngeall epithelial cells by Neisseria meningitidis is controlled by phase variation of multiple

surfacee antigens. Infect.Immun. 64:2998-3006.

46.. Deghmane, A.E., S. Petit, A. Topilko, Y. Pereira, D. Giorgini , M. Larribe , and M.K . Taha. 2000.

Intimatee adhesion of Neisseria meningitidis to human epithelial cells is under the control of the crgA

gene,, a novel LysR-type transcriptional regulator. EMBO J.2000.Mar.l.,19.(5.):1068.-1078. 19:1068-

1078. .

47.. Derrick , J.P., R. Urwin , J. Suker, I.M . Feavers, and M.C. Maiden. 1999. Structural and evolutionary

inferencee from molecular variation in Neisseria porins. Infect.Immun. 67:2406-2413.

48.. DeVoe, I.W. 1982. The meningococcus and mechanisms of pathogenicity. Microbiol.Rev. 46:162-190.

49.. DeVoe, I.W. and J.E. Gilchrist . 1975. Pili on meningococci from primary cultures of nasopharyngeal

carrierss and cerebrospinal fluid of patients with acute disease. J.Exp.Med. 141:297-305.

50.. Edwards, M., R.L. McDade, G. Schoolnik, J.B. Rothbard, and E.C. Gotschlich. 1984. Antigenic

analysiss of gonococcal pili using monoclonal antibodies. J.Exp.Med. 160 :1782-1791.

51.. Estabrook, M.M. , J.M. Griffiss, and G.A. Jarvis. 1997. Sialylation of Neisseria meningitidis

lipooligosaccharidee inhibits serum bactericidal activity by masking lacto-N-neotetraose. InfecLlmmun.

65:4436-4444. .

52.. Feavers, I.M. , A.B. Heath, J.A. Bygraves, and M.C. Maiden. 1992. Role of horizontal genetic

exchangee in the antigenic variation of the class 1 outer membrane protein of Neisseria meningitidis.

Mol.Microbiol.. 6:489-495.

53.. Feavers, I.M . and M.C. Maiden. 1998. A gonococcal porA pseudogene: implications for understanding

thee evolution and pathogenicity of Neisseria gonorhoeae. Mol.Microbiol. 30:647-656.

54.. Finne, J., D. Bitter-Suermann, C. Goridis, and U. Finne. 1987. An IgG monoclonal antibody to group

BB meningococci cross-reacts with developmentally regulated polysialic acid units of glycoproteins in

neurall and extraneural tissues. J.Immunol. 138:4402-4407.

55.. Finne, J., M. Leinonen, and P.H. Makela. 1983. Antigenic similarities between brain components and

bacteriaa causing meningitis. Implications for vaccine development and pathogenesis. Lancet 2:355-357.

56.. Forest, K.T., S.A. Dunham, M. Koomey, and J.A. Tainer. 1999. Crystallographic structure reveals

phosphorylatedd pilin from Neisseria : phosphoserine sites modify type IV pilus surface chemistry and

fibrefibre morphology. MoLMicrobiol. 31:743-752.

57.. Frasch, C.E., W.D. Zollinger, and J.T. Poolman. 1985. Serotype antigens of Neisseria meningitidis and

aa proposed scheme for designation of serotypes. Rev.Infect.Dis. 7:504-510.

58.. Frosch, M. and T.F. Meyer. 1992. Transformation-mediated exchange of virulence determinants by co-

cultivationn of pathogenic Neisseria e. FEMS Microbiol.Lett. 79:345-349.

59.. Gibbs, C.P., B.Y. Reimann, E. Schultz, A. Kaufmann, R. Haas, and T.F. Meyer. 1989. Reassortment

off pilin genes in Neisseria gonorhoeae occurs by two distinct mechanisms. Nature 338:651-652.

60.. Goldschneider, I., E.C. Gotschlich, and M.S. Artenstein. 1969. Human immunity to the

meningococcus.. I. The role of humoral antibodies. J.Exp.Med. 129:1307-1326.

61.. Goodman, S.D. and J J. Scocca. 1988. Identification and arrangement of the DNA sequence recognized

inn specific transformation of Neisseria gonorhoeae. Proc.Natl.Acad.Sci.U.S.A. 85:6982-6986.

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ChapterChapter 1

62.. Gotschlich, E.C. 1983. Thoughts on the evolution of strategies used by bacteria for evasion of host

defenses.. Rev.Infect.Dis. 5 SuppI 4:S778-83:S778-S783

63.. Gotschlich, E.C., T.Y. Liu , and M.S. Artenstein. 1969. Human immunity to the meningococcus. 3.

Preparationn and immunochemical properties of the group A, group B, and group C meningococcal

polysaccharides.. J.Exp.Med. 129:1349-1365.

64.. Griffiss, J.M., H. Schneider, R.E. Mandrell , R. Yamasaki, G.A. Jarvis, J.J. Kim , B.W. Gibson, R.

Hamadeh,, and M.A. Apicella . 1988. Lipooligosaccharides: the principal glycolipids of the neisseria!

outerr membrane. Rev.Infect.Dis. 10 Suppl 2:S287-95:S287-S295

65.. Gubish, E.R.J., K.C. Chen, and T.M. Buchanan. 1982. Attachment of gonococcal pili to lectin-resistant

cloness of Chinese hamster ovary cells. Infect.Immun. 37:189-194.

66.. Gunn, J.S. and D.C. Stein. 1996. Use of a non-selective transformation technique to construct a multiply

restriction/modification-deficientt mutant of Neisseria gonorhoeae. Mol.Gen.Genet. 251:509-517.

67.. Haas, R. and T.F. Meyer, 1986. The repertoire of silent pilus genes in Neisseria gonorhoeae: evidence

forr gene conversion. Cell 44:107-115.

68.. Haas, R., H. Schwarz, and T.F. Meyer. 1987. Release of soluble pilin antigen coupled with gene

conversionn in Neisseria gonorhoeae. Proc.Natl.Acad.Sci.U.S.A. 84:9079-9083.

69.. Hagblom, P., E. Segal, E. Billyard , and M. So. 1985. Intragenic recombination leads to pilus antigenic

variationn in Neisseria gonorhoeae. Nature 315:156-158.

70.. Haines, K.A., J. Reibman, X.Y. Tang, M. Blake, and G. Weissmann. 1991. Effects of protein I of

NeisseriaNeisseria gonorhoeae on neutrophil activation: generation of diacylglycerol from phosphatidylcholine via

aa specific phospholipase C is associated with exocytosis. J.Cell Biol. 114:433-442.

711 Haines, K.A., L. Yeh, M.S. Blake, P. Cristello, H. Korchak, and G. Weissmann. 1988. Protein I, a

translocatablee ion channel from Neisseria gonorhoeae, selectively inhibits exocytosis from human

neutrophilss without inhibiting 02- generation. J.Biol.Chem. 263:945-951.

72.. Hakomori , S. 1981. Blood group ABH and Ii antigens of human erythrocytes: chemistry, polymorphism,

andd their developmental change. Semin.Hematol. 18:39-62.

73.. Halter, R., J. Pohlner, and T.F. Meyer. 1989. Mosaic-like organization of IgA protease genes in

NeisseriaNeisseria gonorhoeae generated by horizontal genetic exchange in vivo. EMBO J. 8:2737-2744.

74.. Hamadeh, R.M., M.M . Estabrook, P. Zhou, G.A. Jarvis, and J.M. Griffiss. 1995. Anti-Gal binds to

pilii of Neisseria meningitidis: the immunoglobulin A isotype blocks complement-mediated killing.

Infect.Immun.. 63:4900-4906.

75.. Hammerschmidt, S., C. Birkholz , U. Zahringer, B.D. Robertson, J. van Putten, O. Ebeling, and M.

Frosch.. 1994. Contribution of genes from the capsule gene complex (cps) to lipooligosaccharide

biosynthesiss and serum resistance in Neisseria meningitidis. Mol.Microbiol. 11:885-896.

76.. Hammerschmidt, S., R. Hilse, J.P. van Putten, R. Gerardy-Schahn, A. Unkmeir, and M. Frosch.

1996.. Modulation of cell surface sialic acid expression in Neisseria meningitidis via a transposable

geneticc element. EMBO J. 15:192-198.

77.. Hammerschmidt, S., A. Muller , H. Sillmann, M. Muhlenhoff, R. Borrow, A. Fox, J. van Putten,

W.D.. Zollinger, R. Gerardy-Schahn, and M. Frosch. 1996. Capsule phase variation in Neisseria

28 8

Page 24: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

GeneralGeneral introduction

meningitidismeningitidis serogroup B by slipped-strand mispairing in the polysialyltransferase gene (siaD): correlation

withh bacteria] invasion and the outbreak of meningococcal disease. Mol.Microbiol. 20:1211-1220.

78.. Hart , C.A. and T.R. Rogers. 1993. Meningococcal disease. J.Med.Microbiol. 39:3-25.

79.. Hedlund, M., M. Svensson, A. Nilsson, R.D. Duan, and C. Svanborg. 1996. Role of the ceramide-

signalingg pathway in cytokine responses to P-fimbriated Escherichia coli. J.Exp.Med. 183:1037-1044.

80.. Henderson, B., S. Poole, and M. Wilson. 1996. Bacterial modulins: a novel class of virulence factors

whichh cause host tissue pathology by inducing cytokine synthesis. Microbiol.Rev. 60:316-341.

81.. Henricbsen, J. 1983. Twitching motility. Annu.Rev.Microbiol. 37:81-93:81-93.

82.. Jarvis, G.A. and N.A. Vedros. 1987. Sialic acid of group B Neisseria meningitidis regulates alternative

complementt pathway activation. Infect.Immun. 55:174-180.

83.. Jennings, H.J., K.G. Johnson, and L. Kenne. 1983. The structure of an R-type oligosaccharide core

obtainedd from some lipopolysaccharides of Neisseria meningitidis. Carbohydr.Res. 121:233-41:233-241.

84.. Jennings, H.J.R.K.G.K.CP. 1979. Structural elucidation of the capsular polysaccharide antigen of

NeisseriaNeisseria meningitidis serogroup Z using l3C-nuclear magnetic resonance. Can.J.Biochem. 57:2902-2907.

85.. Jennings, M.P., M. Bisercic, K.L . Dunn, M. Virji , A. Martin , K.E. Wilks, J.C. Richards, and E.R.

Moxon.. 1995. Cloning and molecular analysis of the Isil (rfaF) gene of Neisseria meningitidis which

encodess a heptosyl-2-transferase involved in LPS biosynthesis: evaluation of surface exposed

carbohydratess in LPS mediated toxicity for human endothelial cells. Microb.Pathog. 19:391-407.

86.. Jennings, M.P., Y.N. Srikhanta, E.R. Moxon, M. Kramer , J.T. Poolman, B. Kuipers, and P. van der

Ley.. 1999. The genetic basis of the phase variation repertoire of lipopolysaccharide immunotypes in

NeisseriaNeisseria meningitidis. Microbiology. 145:3013-3021.

87.. John, CM. , J.M. Griffiss, M.A. Apicella, R.E. Mandrell , and B.W. Gibson. 1991. The structural basis

forr pyocin resistance in Neisseria gonorhoeae lipooligosaccharides. J.Biol.Chem. 266:19303-19311.

88.. Jones, D.M., R. Borrow, AJ. Fox, S. Gray, K.A. Cartwright , and J.T. Poolman. 1992. The

lipooligosaccharidee immunotype as a virulence determinant in Neisseria meningitidis. Microb.Pathog.

13:219-224. .

89.. Jonsson, A.B., D. liver , P. Falk, J. Pepose, and S. Normark . 1994. Sequence changes in the pilus

subunitt lead to tropism variation of Neisseria gonorhoeae to human tissue. Mol.Microbiol. 13:403-416.

90.. Jonsson, A.B., G. Nyberg, and S. Normark . 1991. Phase variation of gonococcal pili by frameshift

mutationn in pilC, a novel gene for pilus assembly. EMBO J. 10:477-488.

91.. Jonsson, A.B., J. Pfeifer, and S. Normark . 1992. Neisseria gonorhoeae PilC expression provides a

selectivee mechanism for structural diversity of pili . Proc.Natl.Acad.Sci.U.S.A. 89:3204-3208.

92.. Jonsson, A.B., M. Rahman, and S. Normark . 1995. Pilus biogenesis gene, pilC, of Neisseria

gonorhoeae:gonorhoeae: pilCl and pilC2 are each part of a larger duplication of the gonococcal genome and share

upstreamm and downstream homologous sequences with opa and pil loci. Microbiology. 141:2367-2377.

93.. Kahler, CM. , L.E. Martin , G.C Shih, M.M . Rahman, R.W. Carlson, and D.S. Stephens. 1998. The

(alpha2-->8)-linkedd polysialic acid capsule and lipooligosaccharide structure both contribute to the ability

off serogroup B Neisseria meningitidis to resist the bactericidal activity of normal human serum,

Infect.Immun.. 66:5939-5947.

29 9

Page 25: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

ChapterChapter I

94.. Kahler, CM . and D.S. Stephens. 1998. Genetic basis for biosynthesis, structure, and function of

meningococcall lipooligosaccharide (endotoxin). Crit.Rev.Microbiol. 24:281-334.

95.. Kallstrom , H., M.S. Islam, P.O. Berggren, and A.B. Jonsson. 1998. Cell signaling by the type IV pili

off pathogenic Neisseria. J.Biol.Chem. 273:21777-21782.

96.. Kallstrom , H., M.K . Liszewski, J.P. Atkinson, and A.B. Jonsson. 1997. Membrane cofactor protein

(MCPP or CD46) is a cellular pilus receptor for pathogenic Neisseria . Mol.Microbiol. 25:639-647.

97.. Kawula, T.H., E.L. Aho, D.S. Barritt , D.G. Klapper, and J.G. Cannon. 1988. Reversible phase

variationn of expression of Neisseria meningitidis class 5 outer membrane proteins and their relationship to

gonococcall proteins II . Infect.Immun. 56:380-386.

98.. Kim , J.J., R.E. Mandrell , and J.M. Griffiss. 1989. Neisseria lactamica and Neisseria meningitidis share

lipooligosaccharidee epitopes but lack common capsular and class 1, 2, and 3 protein epitopes.

Infect.Immun.. 57:602-608.

999 Kim , J.J., R.E. Mandrell , Z. Hu, M.A. Westerink, J.T. Poolman, and J.M. Griffis s 1988

Electromorphicc characterization and description of conserved epitopes of the lipooligosaccharides of

groupp A Neisseria meningitidis. Infect.Immun. 56:2631-2638.

100.. Kim , J.J., D. Zhou, R.E. Mandrell , and J.M. Griffiss. 1992. Effect of exogenous sialylation of the

lipooligosaccharidee of Neisseria gonorhoeae on opsonophagocytosis. Infect.Immun. 60:4439-4442.

101.. Koomey, M., S. Bergstrom, M. Blake, and J. Swanson. 1991. Pilin expression and processing in pilus

mutantss of Neisseria gonorhoeae: critical role of Gly-1 in assembly. Mol.Microbiol. 5:279-287.

102.. Koomey, M., E.C. Gotschlich, K. Robbins, S. Bergstrom, and J. Swanson. 1987. Effects of recA

mutationss on pilus antigenic variation and phase transitions in Neisseria gonorhoeae. Genetics 117:391-

398. .

103.. Kulshin, V.A., U. Zahringer, B. Lindner , C.E. Frasch, CM . Tsai, B.A. Dmitriev , and E.T. Rietschel

.. 1992. Structural characterization of the lipid A component of pathogenic Neisseria meningitidis.

J.Bacteriol.. 174:1793-1800.

104.. Kupsch, E.M., B. Knepper, T. Kuroki , I. Heuer, and T.F. Meyer. 1993. Variable opacity (Opa) outer

membranee proteins account for the cell tropisms displayed by Neisseria gonorhoeae for human leukocytes

andd epithelial cells. EMBO J. 12:641-650.

105.. Lambden, P.R., J.N. Robertson, and P.J. Watt. 1980. Biological properties of two distinct pilus types

producedd by isogenic variants of Neisseria gonorhoeae P9. J.Bacteriol. 141:393-396.

106.. Lambden, P.R., J.N. Robertson, and PJ. Watt, 1981. The preparation and properties of alpha and beta

pilii from variants of Neisseria gonorhoeae P9. J.Gen.Microbiol. 124:109-117.

107.. Lambert , H.P, 1991. Infections of the central nervous system., B.C. Decker, Philadelphia.

108.. Lynch, E.C., M.S. Blake, E.C Gotschlich, and A. Mauro. 1984. Studies of porins spontaniously

transferredd from whole cells and reconstituted from purified proteins of Neisseria gonorhoeae and

NeisseriaNeisseria meningitidis. Biophys.J. 45:104-107.

109.. Maiden, M. C and B.G. Spratt. 1999. Meningococcal conjugate vaccines: new opportunities and new

challenges.. Lancet 354:615-616.

30 0

Page 26: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

GeneralGeneral introduction

110.. Maiden, M.C., J. Suker, A J. McKenna, J.A. Bygraves, and I.M . Feavers. 1991. Comparison of the

classs 1 outer membrane proteins of eight serological reference strains of Neisseria meningitidis.

Mol.Microbiol.. 5:727-736.

111.. Mandrell , R.E., J.M. Grifflss, and B.A. Macher. 1988. Lipooligosaccharides (LOS) of Neisseria

gonorhoeaegonorhoeae and Neisseria meningitidis have components that are immunochemically similar to precursors

off human blood group antigens. Carbohydrate sequence specificity of the mouse monoclonal antibodies

thatt recognize crossreacting antigens on LOS and human erythrocytes [published erratum appears in J

Expp Med 1988 Oct 1,168(4): 1517], J.Exp.Med. 168:107-126.

112.. Mandrell . R.E., J.J. Kim , CM . John, B.W. Gibson, J.V. Sugai, M.A. Apicella, J.M. Griffiss, and R.

Yamasaki.. 1991. Endogenous sialylation of the lipooligosaccharides of Neisseria meningitidis.

J.Bacteriol.. 173:2823-2832.

113.. Mandrell , R.E., A J. Lesse, J.V. Sugai, M. Shero, J.M. Griffiss, J.A. Cole, N.J. Parsons, H. Smith,

S.A.. Morse, and M.A. Apicella. 1990. In vitro and in vivo modification of Neisseria gonorhoeae

lipooligosaccharidee epitope structure by sialylation. J.Exp.Med. 171:1649-1664.

114.. Mandrell , R.E. and W.D. Zollinger. 1977. Lipopolysaccharide serotyping of Neisseria meningitidis by

hemagglutinationn inhibition. Infect.Immun. 16:471-475.

115.. Marceau, M., J.L. Beretti, and X. Nassif. 1995. High adhesiveness of encapsulated Neisseria

meningitidismeningitidis to epithelial cells is associated with the formation of bundles of pili . Mol.Microbiol. 17:855-

863. .

116.. Masson, L. and B.E. Holbein. 1985. Influence of nutrient limitation and low pH on serogroup B

NeisseriaNeisseria meningitidis capsular polysaccharide levels: correlation with virulence for mice. Infect.Immun.

47:465-471. .

117.. McGee, Z.A. and D.S. Stephens. 1984. Common pathways of invasion of mucosal barriers by Neisseria

gonorhoeaegonorhoeae and Neisseria meningitidis. Surv.Synth.Pathol.Res. 3:1-10.

118.. McGuinness, B., A.K. Barlow, I.N. Clarke, J.E. Farley, A. Anilionis, J.T. Poolman, and J.E.

Heckels.. 1990. Deduced amino acid sequences of class 1 protein (PorA) from three strains of Neisseria

meningitidis.meningitidis. Synthetic peptides define the epitopes responsible for serosubtype specificity. J.Exp.Med.

171:1871-1882. .

119.. McNeil, G. and M. Virji , 1997. Phenotypic variants of meningococci and their potential in phagocytic

interactions:: the influence of opacity proteins, pili , PilC and surface sialic acids. Microb.Pathog. 22:295-

304. .

120.. McNeil, G., M. Virji , and E.R. Moxon. 1994. Interactions of Neisseria meningitidis with human

monocytes.. Microb.Pathog. 16:153-163.

121.. Merker , P., J. Tommassen, B. Kusecek, M. Virji , D. Sesardic, and M. Achtman. 1997. Two-

dimensionall structure of the Ope invasin from Neisseria meningitidis. Mol.Microbiol. 23:281-293.

122.. Milagres, L.G., M.C. Gorla, C.T. Sacchi, and M.M . Rodrigues. 1998. Specificity of bactericidal

antibodyy response to serogroup B meningococcal strains in Brazilian children after immunization with an

outerr membrane vaccine. Infect.Immun. 66:4755-4761.

31 1

Page 27: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

ChapterChapter 1

123.. Minetti , C.SJ.C.M.a.B.M.S. 1998. Meningococcal PorA class 1 protein exist in nature as a

heterotrimericc porin with PorB protein., p. 15, Nassif X., Quentin-Millet, M.J., and Taha, M.K. (ed.),

Abstractss of the Eleventh International pathogenic Neisseria conference, Edition E.D.K., Paris.

124.. Mizuno, T., M.Y. Chou, and M. Inouye. 1983. A comparative study on the genes for three porins of the

Escherichiaa coli outer membrane. DNA sequence of the osmoregulated ompC gene. J.Biol.Chem.

258:6932-6940. .

125.. Morello, J.A. and M. Bohnhoff. 1989. Serovars and serum resistance of Neisseria gonorhoeae from

disseminatedd and uncomplicated infections. J.Infect.Dis. 160:1012-1017.

126.. Murphy , G.L., T.D. Connell, D.S. Barritt , M. Koomey, and J.G. Cannon. 1989. Phase variation of

gonococcall protein II: regulation of gene expression by slipped-strand mispairing of a repetitive DNA

sequence.. Cell 56:539-547.

127.. Nairn, C.A., J.A. Cole, P.V. Patel, NJ. Parsons, J.E. Fox, and H. Smith. 1988. Cytidine 5-

monophospho-N-acetylneuraminicc acid or a related compound is the low Mr factor from human red blood

cellss which induces gonococcal resistance to killing by human serum. J.Gen.Microbiol. 134:3295-3306.

128.. Nassif, X., J.L. Beretti, J. Lowy, P. Stenberg, P. O'Gaora, J. Pfeifer, S. Normark , and M. So. 1994.

Roless of pilin and PilC in adhesion of Neisseria meningitidis to human epithelial and endothelial cells.

Proc.Natl.Acad.Sci.U.S.A.. 91 :3769-3773.

129.. Nassif, X., M. Marceau, C. Pujol, B. Pron, J.L. Beretti, and M.K . Taha. 1997. Type-4 pili and

meningococcall adhesiveness. Gene 192:149-153.

130.. Nicolson, I.J., A.C. Perry, J.E. Heckels, and J.R. Saunders. 1987. Genetic analysis of variant pilin

geness from Neisseria gonorhoeae P9 cloned in Escherichia coli: physical and immunological properties of

encodedd pilins. J.Gen.Microbiol. 133:553-561.

131.. Olyhoek, A.J., J. Sarkari , M. Bopp, G. Morelli , and M. Achtman. 1991. Cloning and expression in

Escherichiaa coli of ope, the gene for an unusual class 5 outer membrane protein from Neisseria

meningitidismeningitidis (meningococci/surface antigen). Microb.Pathog. 11:249-257.

132.. Parge, H.E., K.T . Forest, M.J. Hickey, D.A. Christensen, E.D. Getzoff, and J.A. Tainer. 1995.

Structuree of the fibre-forming protein pilin at 2.6 A resolution. Nature 378:32-38.

133.. Parsons, N.J., J.R. Andrade, P.V. Patel, J.A. Cole, and H. Smith. 1989. Sialylation of

lipopolysaccharidee and loss of absorption of bactericidal antibody during conversion of gonococci to

serumm resistance by cytidine 5'-monophospho-N-acetyl neuraminic acid. Microb.Pathog. 7:63-72.

134.. Parsons, N.J., J.A. Cole, and H. Smith. 1990. Resistance to human serum of gonococci in urethral

exudatess is reduced by neuraminidase. Proc.R.Soc.Lond.B.Biol.Sci. 241:3-5.

135.. Patrick, C.C., G.T. Furuta, M. Edwards, M. Estabrook, M.S. Blake, and C.J. Baker. 1993. Variation

inn phenotypic expression of the Opa outer membrane protein and lipooligosaccharide of Neisseria

meningitidismeningitidis serogroup C causing periorbital cellulitis and bacteremia. Clin.Infect.Dis. 16:523-527.

136.. Pavliak, V., J.R. Brisson, F. Michon, D. Uhrin , and H.J. Jennings. 1993. Structure of the sialylated L3

lipopolysaccharidee of Neisseria meningitidis. J.Biol.Chem. 268:14146-14152.

137.. Peeters, C.C., H.C. Rumke, L.C. Sundermann, Rouppe van der Voort EM, J. Meulenbelt, M.

Schuller,, A.J. Kuipers, P. van der Ley, and J.T. Poolman. 1996. Phase I clinical trial with a hexavalent

PorAA containing meningococcal outer membrane vesicle vaccine. Vaccine 14:1009-1015.

32 2

Page 28: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

GeneralGeneral introduction

138.. Peltola, H. 1983. Meningococcal disease: still with us. Rev.Infect.Dis. 5:71-91.

139.. Perry, M.B., V. Daoust. K.G Johnson, B.B. Diena, and F.E. Ashton. 1978. Gonococcal R-type

lipopolysaccharide.,, p. 101-107. In G.F. Brooks et al.(ed.), Immunobiology of Neisseria gonorhoeae,

Americann Society for Microbiology, Wahington, DC.

140.. Perry, M.B., B. B Diena, and F.E. Ashton. 2000. Lipopolysaccharide of Neisseria gonorhoeae, p.285-

301.. In R.B. Roberts (ed.), The gonococcus, Wiley, New York.

141.. Poolman, J.T., F.B. Wientjes, C.T.P. Hopman, and H.C. Zanen. 1985. Influence of the length of

lipopolysaccharidee melecules on the surface exposure of class 1 and class 2 outer membrane proteins of

NeisseriaNeisseria meningitidis 2996 (B:2b:P1.2), p.562-570. In G.K. Schoolnik et al.(ed.), The Pathogenic

Neisseriae,Neisseriae, American Society for Microbiology, Wahington, D.C.

142.. Porat, N., M.A. Apicella, and M.S. Blake. 1995a. A lipooligosaccharide-binding site on HepG2 cells

similarr to the gonococcal opacity-associated surface protein Opa. Infect.Immun. 63:2164-2172.

143.. Porat, N., M.A. Apicella, and M.S. Blake. 1995b. Neisseria gonorhoeae utilizes and enhances the

biosynthesiss of the asialoglycoprotein receptor expressed on the surface of the hepatic HepG2 cell line.

Infect.Immun.. 63:1498-1506.

144.. Potts, W.J. and J.R. Saunders. 1988. Nucleotide sequence of the structural gene for class I pilin from

NeisseriaNeisseria meningitidis: homologies with the pilE locus of Neisseria gonorhoeae. Mol.Microbiol. 2:647-

653. .

145.. Pron, B., M.K . Taha, C. Rambaud, J.C. Fournet, N. Pattey, J.P. Monnet, M. Musilek, J.L. Beretti,

andd X. Nassif. 1997. Interaction of Neisseria meningitidis with the components of the blood-brain barrier

correlatess with an increased expression of PilC. J.Infect.Dis. 176:1285-1292.

146.. Quagliarello, V. and W.M. Scheld. 1992. Bacterial meningitis: pathogenesis, pathophysiology, and

progress.. N.EnglJ.Med. 327:864-872.

147.. Rahman, M., H. Kallstrom , S. Normark , and A.B. Jonsson. 1997. PilC of pathogenic Neisseria is

associatedd with the bacterial cell surface. Mol.Microbiol. 25:11-25.

148.. Rahman, M.M. , D.S. Stephens, CM . Kahler, J. Glushka, and R.W. Carlson. 1998. The

lipooligosaccharidee (LOS) of Neisseria meningitidis serogroup B strain NMB contains L2, L3, and novel

oligosaccharides,, and lacks the lipid-A 4'-phosphate substituent. Carbohydr.Res. 307:311-324.

149.. Ram, S., D.P. McQuillen, S. Gulati , C. Elkins, M.K . Pangburn, and P.A. Rice. 1998. Binding of

complementt factor H to loop 5 of porin protein 1A: a molecular mechanism of serum resistance of

nonsiaiylatedd Neisseria gonorhoeae. J.Exp.Med. 188:671-680.

150.. Ram, S., A.K. Sharma, S.D. Simpson, S. Gulati , D.P. McQuillen, M.K . Pangburn, and P.A. Rice.

1998.. A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria

gonorhoeae.gonorhoeae. J.Exp.Med. 187:743-752.

151.. Rest, R.F. and J.V. Frangipane. 1992. Growth of Neisseria gonorhoeae in CMP-N-acetylneuraminic

acidd inhibits nonopsonic (opacity-associated outer membrane protein-mediated) interactions with human

neutrophils.. Infect.Immun. 60:989-997.

152.. Robertson, B.D., M. Frosch, and J.P. van Putten. 1993. The role of galE in the biosynthesis and

functionn of gonococcal lipopolysaccharide. Mol.Microbiol. 8:891-901.

33 3

Page 29: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

ChapterChapter 1

153.. Robertson, J.N., P. Vincent, and M.E. Ward. 1977. The preparation and properties of gonococcal pili .

J.Gen.Microbiol.. 102:169-177.

154.. Rothbard, J.B., R. Fernandez, L. Wang, N.N. Teng, and G.K. Schoolnik. 1985. Antibodies to peptides

correspondingg to a conserved sequence of gonococcal pilins block bacterial adhesion.

Proc.Natl.Acad.Sci.U.S.A.. 82:915-919.

155.. Rudel, T., D. Facius, R. Barton, I . Scheuerpflug, E. Nonnenmacher, and T.F. Meyer. 1995. Role of

pilii and the phase-variable PilC protein in natural competence for transformation of Neisseria

gonorhoeae.gonorhoeae. Proc.Natl.Acad.Sci.U.S.A. 92:7986-7990.

156.. Rudel, T., I. Scheurerpflug, and T.F. Meyer. 1995. Neisseria PilC protein identified as type-4 pilus tip-

locatedd adhesin. Nature 373:357-359.

157.. Rudel, T., A. Schmid, R. Benz, H.A. Kolb, F. Lang, and T.F. Meyer. 1996a. Modulation of Neisseria

porinn (PorB) by cytosolic ATP/GTP of target cells: parallels between pathogen accommodation and

mitochondriall endosymbiosis. Cell 85:391-402.

158.. Rudel, T., A. Schmid, R. Benz, H.A. Kolb, F. Lang, and T.F. Meyer. 1996b. Modulation of Neisseria

porinn (PorB) by cytosolic ATP/GTP of target cells: parallels between pathogen accommodation and

mitochondriall endosymbiosis. Cell 85:391-402.

159.. Rudel, T., J.P. van Putten, C.P. Gibbs, R. Haas, and T.F. Meyer, 1992. Interaction of two variable

proteinss (PilE and PilC) required for pilus-mediated adherence of Neisseria gonorhoeae to human

epitheliall cells. Mol.Microbiol. 6:3439-3450.

160.. Ryll , R.R., T. Rudel, I . Scheuerpflug, R. Barten, and T.F. Meyer. 1997. PilC of Neisseria meningitidis

iss involved in class II pilus formation and restores pilus assembly, natural transformation competence and

adherencee to epithelial cells in PilC-deficient gonococci. Mol.Microbiol. 23:879-892.

161.. Sarkari , J., N. Pandit, E.R. Moxon, and M. Achtman. 1994. Variable expression of the Ope outer

membranee protein in Neisseria meningitidis is caused by size variation of a promoter containing poly-

cytidine.. Mol.Microbiol. 13:207-217.

162.. Saukkonen, K., H. Abdillahi , J.T. Poolman, and M. Leinonen. 1987. Protective efficacy of

monoclonall antibodies to class 1 and class 3 outer membrane proteins of Neisseria meningitidis

B:15:P1.166 in infant rat infection model: new prospects for vaccine development. Microb.Pathog. 3:261-

267. .

163.. Saukkonen, K., M. Leinonen, H. Abdillahi , and J.T. Poolman. 1989. Comparative evaluation of

potentiall components for group B meningococcal vaccine by passive protection in the infant rat and in

vitroo bactericidal assay. Vaccine 7:325-328.

164.. Schneider, H., C.A. Hammack, M.A. Apicella, and J.M. Griffiss. 1988. Instability of expression of

lipooligosaccharidess and their epitopes in Neisseria gonorhoeae. Infect.Immun. 56:942-946.

165.. Schoolnik, G.K., R. Fernandez, J.Y. Tai, J. Rothbard, and E.C. Gotschlich. 1984. Gonococcal pili .

Primaryy structure and receptor binding domain. J.Exp.Med. 159 :1351-1370.

166.. Schoolnik, G.K., J.Y. Tai, and E.C. Gotschlich. 1983. A pilus peptide vaccine for the prevention of

gonorrhea.. Prog.Allergy 33:314-31 :314-331.

167.. Schwan, E.T., B.D. Robertson, H. Brade, and J.P. van Putten. 1995. Gonococcal rfaF mutants express

Rd22 chemotype LPS and do not enter epithelial host cells. Mol.Microbiol. 15:267-275.

34 4

Page 30: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

GeneralGeneral introduction

168.. Segal, E., E. Billyard , M. So, S. Storzbach, and T.F. Meyer. 1985. Role of chromosomal rearrangement

inn N. gonorrhoeae pilus phase variation. Cell 40:293-300.

169.. Seifert, H.S., R.S. Ajioka , C. Marchal, P.F. Sparling, and M. So. 1988. DNA transformation leads to

pilinn antigenic variation in Neisseria gonorhoeae. Nature 336:392-395.

170.. Song, W., L. Ma, R. Chen, and D.C. Stein. 2000. Role of lipooligosaccharide in Opa-independent

invasionn of Neisseria gonorhoeae into human epithelial cells. J.Exp.Med.2000.Mar.20.,191.(6.):949.-60.

191:949-960. .

171.. Sparling, P.F. 1966. Genetic transformation of Neisseria gonorhoeae to streptomycin resistance.

J.Bacteriol.. 92:1364-1371.

172.. Spitalnik, S.L., J.F. Schwartz, J.L. Magnani, D.D. Roberts, P.F. Spitalnik, CI . Civin, and V.

Ginsburg.. 1985. Anti-My-28, an antigranulocyte mouse monoclonal antibody, binds to a sugar sequence

inn lacto-N-neotetraose. Blood 66:319-326.

173.. Spratt, B.G., L.D. Bowler, Q.Y. Zhang, J. Zhou, and J.M. Smith. 1992. Role of interspecies transfer of

chromosomall genes in the evolution of penicillin resistance in pathogenic and commensal Neisseria

speciess . J.Mol.Evol. 34:115-125.

174.. Stephens, D.S. 1989. Gonococcal and meningococcal pathogenesis as defined by human cell, cell culture,

andd organ culture assays. Clin.Microbiol.Rev. 2 Suppl:S104-ll:S104-Sl 11

175.. Stephens, D.S. and M.M . Farley. 1991. Pathogenic events during infection of the human nasopharynx

withh Neisseria meningitidis and Haemophilus influenzae. Rev.Infect.Dis. 13:22-33.

176.. Stephens, D.S. and Z.A. McGee. 1981. Attachment of Neisseria meningitidis to human mucosal

surfaces:: influence of pili and type of receptor cell. J.Infect.Dis. 143:525-532.

177.. Stern, A., M. Brown, P. Nickel, and T.F. Meyer. 1986. Opacity genes in Neisseria gonorhoeae: control

off phase and antigenic variation. Cell 47:61-71.

178.. Stern, A. and T.F. Meyer. 1987. Common mechanism controlling phase and antigenic variation in

pathogenicc Neisseria e. Mol.Microbiol. 1:5-12.

179.. Stern, A., P. Nickel, T.F. Meyer, and M. So. 1984. Opacity determinants of Neisseria gonorhoeae: gene

expressionn and chromosomal linkage to the gonococcal pilus gene. Cell 37:447-456.

180.. Stimson, E., M. Virji , S. Barker, M. Panico, I. Blench, J. Saunders, G. Payne, E.R. Moxon, A. Dell,

andd H.R. Morris . 1996. Discovery of a novel protein modification: alpha-glycerophosphate is a

substituentt of meningococcal pilin. Biochem.J. 316:29-33.

181.. Svanborg, C, M. Hedlund, H. Connell, W. Agace, R.D. Duan, A. Nilsson, and B. Wullt . 1996.

Bacteriall adherence and mucosal cytokine responses. Receptors and transmembrane signaling.

Ann.N.Y.Acad.Sci.. 797:177-90:177-190.

182.. Swanson, J. 1978. Studies on gonococcus infection. XII . Colony color and opacity variants of gonococci.

Infect.Immun.. 19:320-331.

183.. Swanson, J., S. Bergstrom, K. Robbins, O. Barrera, D. Corwin, and J.M. Koomey. 1986. Gene

conversionn involving the pilin structural gene correlates with pilus+ in equilibrium with pilus- changes in

NeisseriaNeisseria gonorhoeae. Cell 47:267-276.

184.. Swartley, J.S., A.A. Marfin , S. Edupuganti, L.J. Liu , P. Cieslak, B. Perkins, J.D. Wenger, and D.S.

Stephens.. 1997. Capsule switching of Neisseria meningitidis. Proc.Natl.Acad.Sci.U.S.A. 94:271-276.

35 5

Page 31: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

ChapterChapter 1

185.. Taha, M.K. , D. Giorgini , and X. Nassif. 1996. The pilA regulatory gene modulates the pilus-mediated

adhesionn of Neisseria meningitidis by controlling the transcription of pilCl. Mol.Microbiol. 19:1073-

1084. .

186.. Taha, M.K. , P.C. Morand, Y. Pereira, E. Eugene, D. Giorgini , M. Larribe , and X. Nassif. 1998.

Pilus-mediatedd adhesion of Neisseria meningitidis: the essential role of cell contact-dependent

transcriptionall upregulation of the PilCl protein. Mol.Microbiol. 28:1153-1163.

187.. Tinsley, C.R. and J.E. Heckels. 1986. Variation in the expression of pili and outer membrane protein by

NeisseriaNeisseria meningitidis during the course of meningococcal infection. J.Gen.Microbiol. 132:2483-2490.

188.. Tommassen, J., P. Vermeij , M. Struyve, R. Benz, and J.T. Poolman. 1990. Isolation of Neisseria

meningitidismeningitidis mutants deficient in class 1 (porA) and class 3 (porB) outer membrane proteins.

Infect.Immun.. 58:1355-1359.

189.. Trust, T.J., R.M. Gillespie, A.R. Bhatti, and L.A. White. 1983. Differences in the adhesive properties

off Neisseria meningitidis for human buccal epithelial cells and erythrocytes. Infect.Immun. 41:106-113.

190.. Tsai, CM. , R. Boykins, and C.E. Frasch. 1983. Heterogeneity and variation among Neisseria

meningitidismeningitidis lipopolysaccharides. J.Bacterid. 155:498-504.

191.. Tsai, CM . and C I . Civin. 1991. Eight lipooligosaccharides of Neisseria meningitidis react with a

monoclonall antibody which binds lacto-N-neotetraose (Gal beta l-4GlcNAc beta l-3Gal beta l-4Glc).

Infect.Immun.. 59:3604-3609.

192.. Tsai, CM. , L.F. Mocca, and C.E. Frasch. 1987. Immunotype epitopes of Neisseria meningitidis

lipooligosaccharidee types 1 through 8. Infect.Immun. 55:1652-1656.

193.. Ulmer, J.B., C.J. Burke, C Shi, A. Friedman, J.J. Donnelly, and M.A. Liu . 1992. Pore formation and

mitogenicityy in blood cells by the class 2 protein of Neisseria meningitidis. J.Biol.Chem. 267:19266-

19271. .

194.. van der Ende, A., CT . Hopman, S. Zaat, B.B. Essink, B. Berkhout, and J. Dankert. 1995. Variable

expressionn of class 1 outer membrane protein in Neisseria meningitidis is caused by variation in the

spacingg between the -10 and -35 regions of the promoter. J.Bacteriol. 177:2475-2480.

195.. van der Ley, P., J.E. Heckels, M. Virji , P. Hoogerhout, and J.T. Poolman. 1991. Topology of outer

membranee porins in pathogenic Neisseria spp. Infect.Immun. 59 :2963-2971.

196.. van der Ley, P., J. van der Biezen, and J.T. Poolman. 1995. Construction of Neisseria meningitidis

strainss carrying multiple chromosomal copies of the porA gene for use in the production of a multivalent

outerr membrane vesicle vaccine. Vaccine 13:401-407.

197.. van Putten, J.P., T.D. Duensing, and J. Carlson. 1998. Gonococcal invasion of epithelial cells driven

byy P.1A, a bacterial ion channel with GTP binding properties. J.Exp.Med. 188:941-952.

198.. van Putten, J.P., H.U. Grassme, B.D. Robertson, and E.T. Schwan. 1995. Function of

lipopolysaccharidee in the invasion of Neisseria gonorhoeae into human mucosal cells. Prog.Clin.Biol.Res.

392:49-58:49-58. .

199.. Verheul, A.F., H. Snippe, and J.T. Poolman. 1993. Meningococcal lipopolysaccharides: virulence

factorr and potential vaccine component. Microbiol.Rev. 57:34-49.

36 6

Page 32: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

GeneralGeneral introduction

200.. Virji , M., C. Alexandrescu, DJ. Ferguson, J.R. Saunders, and E.R. Moxon. 1992. Variations in the

expressionn of pili : the effect on adherence of Neisseria meningitidis to human epithelial and endothelial

cells.. Mol.Microbiol. 6:1271-1279.

201.. Virji , M., J.E. Heckels, WJ. Potts, C.A. Hart , and J.R. Saunders. 1989. Identification of epitopes

recognizedd by monoclonal antibodies SMI and SM2 which react with all pili of Neisseria gonorhoeae but

whichh differentiate between two structural classes of pili expressed by Neisseria meningitidis and the

distributionn of their encoding sequences in the genomes of Neisseria spp. J.Gen.Microbiol. 135:3239-

3251. .

202.. Virji , M., K. Makepeace, DJ. Ferguson, M. Achtman, and E.R. Moxon. 1993. Meningococcal Opa

andd Ope proteins: their role in colonization and invasion of human epithelial and endothelial cells.

Mol.Microbiol.. 10:499-510.

203.. Virji , M., K. Makepeace, DJ. Ferguson, M. Achtman, J. Sarkari , and E.R. Moxon. 1992. Expression

off the Ope protein correlates with invasion of epithelial and endothelial cells by Neisseria meningitidis.

Mol.Microbiol.. 6:2785-2795.

204.. Virji , M., K. Makepeace, I . Peak, G. Payne, J.R. Saunders, DJ. Ferguson, and E.R. Moxon. 1995.

Functionall implications of the expression of PilC proteins in meningococci. Mol.Microbiol. 16:1087-

1097. .

205.. Vogel, U., H. Claus, G. Heinze, and M. Frosch. 1999. Role of lipopolysaccharide sialylation in serum

resistancee of serogroup B and C meningococcal disease isolates. Infect.Immun. 67:954-957.

206.. Vogel, U. and M. Frosch. 1999. Mechanisms of neisserial serum resistance. Mol.Microbiol. 32:1133-

1139. .

207.. Vogel, U., A. Weinberger, R. Frank, A. Muller , J. Kohl, J.P. Atkinson, and M. Frosch. 1997.

Complementt factor C3 deposition and serum resistance in isogenic capsule and lipooligosaccharide sialic

acidd mutants of serogroup B Neisseria meningitidis. Infect.Immun. 65 :4022-4029.

208.. Waage, A., A. Halstensen, and T. Espevik. 1987. Association between tumour necrosis factor in serum

andd fatal outcome in patients with meningococcal disease. Lancet 1:355-357.

209.. Waage, A., A. Halstensen, R. Shalaby, P. Brandtzaeg, P. Kierulf , and T. Espevik. 1989. Local

productionn of tumor necrosis factor alpha, interleukin 1, and interleukin 6 in meningococcal meningitis.

Relationn to the inflammatory response. J.Exp.Med. 170:1859-1867.

210.. Ward, MJ. , P.R. Lambden, and J.E. Heckels. 1992. Sequence analysis and relationships between

meningococcall class 3 serotype proteins and other porins from pathogenic and non-pathogenic Neisseria

species.. FEMS Microbiol.Lett. 73:283-289.

211.. Weiser, J.N., J.B. Goldberg, N. Pan, L. Wilson, and M. Virji . 1998. The phosphorylcholine epitope

undergoess phase variation on a 43-kilodalton protein in Pseudomonas aeruginosa and on pili of Neisseria

meningitidismeningitidis and Neisseria gonorhoeae. Infect.Immun. 66:4263-4267.

212.. Woods, J.P. and J.G. Cannon. 1990. Variation in expression of class 1 and class 5 outer membrane

proteinss during nasopharyngeal carriage of Neisseria meningitidis. Infect.Immun. 58:569-572.

213.. Wyle, F.A., M.S. Artenstein, B.L. Brandt, E.C. Tramont, D.L, Kasper, P.L. Altieri , S.L. Herman,

andd J.P. Lowenthal. 1972. Immunologic response of man to group B meningococcal polysaccharide

vaccines.. J.Infect.Dis. 126:514-521.

37 7

Page 33: UvA-DARE (Digital Academic Repository) …...NeisseriaNeisseria meningitidis: host-parasite relationship and course of infection NeisseriaNeisseria meningitidis NeisseriaNeisseria

ChapterChapter I

214.. Young, J.D., M. Blake, A. Mauro, and Z.A. Cohn. 1983. Properties of the major outer membrane

proteinn from Neisseria gonorhoeae incorporated into model lipid membranes. Proc.Natl.Acad.Sci.U.S.A.

80:3831-3835. .

215.. Zhang, J.P. and S. Normark . 1996. Induction of gene expression in Escherichia coli after pilus-mediated

adherencee [see comments]. Science 273:1234-1236.

216.. Zhu, P., G. Morelli , and M. Achtman. 1999. The opcA and (psi)opcB regions in Neisseria : genes,

pseudogenes,, deletions, insertion elements and DNA islands. Mol.Microbiol. 33:635-650.

217.. Zollinger, W.D. and R.E. Mandrell . 1977. Outer-membrane protein and lipopolysaccharide serotyping

off Neisseria meningitidis by inhibition of a solid-phase radioimmunoassay. Infect.Immun. 18:424-433.

218.. Zollinger, W.D. and R.E. Mandrell . 1980. Type-specific antigens of group A Neisseria meningitidis:

lipopolysaccharidee and heat-modifiable outer membrane proteins. Infect.Immun. 28:451-458.

38 8