(The pat ~ ogenesis of Systemic Chlamydjial Inf'ections:

rrheoret cal Considerations of Host Cell Energy Depletion

and Its etabolic Consequences

cell's existing energy output at the netexpense of depriving host cell biosyn-the tic pathways. This obligatory deple-tion in host cell ATP due to intracellularchlarnydial infection has been demon-strated by Gill and Stewart. Theseinvestigators used an in vitro cell cul-tule model in which they demonstratedthat a decline in host cell ATP1evelswas accompanied by a concomitantincrease in ADP levels. Two additionalstudies, one by Horoschak and Moulderand another by Bose arid Liebhaber,have demonstrated that a high multi-plicity of infection of host cells withchlamydiae quickly brings host celldivision to a halt, whereas lower multi-plicities slow, but do not immediatelyS(op, the division of host cells. In addi-tion, it has been noted that infection ofciliated respiratory cells by Chlamydiapneumoniae paralyzes the cilia. Both

acids. ChJamydiae are known to possessfragments of the gJycolytic, p(:ntos~phosphate, and citric acid path'.vaysand appear to be capable of convertingglucose-6-phosphate (but not glucose)to pyruvate and pentose. Ho\vl~ver,chlamydiae seem to lack enzyttlesneeded for the net generation of adeno-sine triphosphate (ATP). Thus, chlamy-dial development is dependent on activemitochondrial and nuclear fun(:tion ofthe host cell. For this reason, chlamydiaeare considered obligatory intral:ellular

parasites.

Chlamydia and Host CellMitochondriaThe requirement of an exogenous sourceof ATP and the presence of a SI>ecificATP transport system in chlamydiaehave provided supporting evidence forthe energy parasite concept Hatch andcolleagues have demonstrated thatthis ATP transport system is an ATP-adenosine diphosphate (ADP) ~xchangemechanism similar to that four1d in milo-chondria by Duee and Vignais. Moreover,electron microscopic studies have shownthat repJicating chlamydiae are alwaysfound in close proximity to mitochon-dria. Therefore, it has been suggestedthat chlamydiae behave in the rever.semanner of mitochondria in that mito-chondria import ADP from the host cellcytoplasm and export ATP, whilechlamydiae import ATP and export ADT.

Chlamydia and Host Cell EnergyChlamydial dependence onho:;t cellenergy must necessarily deplete the host

In This Issue

Charles w. Stra ton, M.D.William M. Mit hell, M.D., PhD.Departments of p thology and MedicineVanderbilt Unive ity School of MedicineNashville, Tennes ee 37232

IntroductionThe recent obse ation that Chlamydiapneumoniae ca infect human endothe-lial cells in vivo has led to speculationthat such chroni infections might playa role in the pa ogenesis of atheroscle-rosis. Regardles of any role in athero-

: sclerosis, the fa t that this pathogencan chronically nfect endotheIiaI cells.monocytes, sm oth muscle cells, andperhaps other c lls raises a number oft11eoreticaI cons derations related tochlamydial ene gy requirements andtheir subsequen effects on the host cell.The following iscussion addresseshost-cell energ depletion and its pos-sible metabolic onsequences as thesemetabolic cons qu~nces could beimportant in th pathogenesis ofsystemic chlam dial infections.

Chlamydial equirementsfrom Eukary tic Host CellsChlamydiae are prokaryocytes thatdevelop in euk otic cells and utilizepart of the host ell metabolism. Beckerand Asher have noted that the tra,\sitic,nof elementary b ies (EBs) to reticulatebodies (REs) fo C. trachomatis requiresthe presence of unctioning mitochon-dria in the infec ed cell as well as theproduction by t e host cell of nucleo-side triphospha es which are neededfor chlamydial iosynthesis of nucleic

The Pathogenesis of SystemicChlamydial Infections:Theoretical Considerationsof Host Cell Energy Depletion-and Its Metabolic Consequences ..33Charles ~~ Stratton. William M. Mitchell

Advances in Our Understanding ofthe Pathogenesis of InfectiousMeningitis 38Nariner K. '.fidha

331069-411X/91/SO.00+ 11.50AIDlEX 16(S)33-40.1~97 Q 1998 Elscvier Scie:lce Inc.

phenomenon are likely to be energy

related. The effe t of chlamydia-relatedenergy deprivati n on hQst cell biosyn-theticpathways as been noted in vivoas well. For exam l.e. Koul and co1leagueshave shown in e perimental mastitis in

goats that chlam dial infection results

in dy...function o acinar cells of udder,teat sinus epithel urn, hepatocytes, and

renal tubules up o 34 days after expel;-mental infe::tion.

l\IIitochondrial l Generation of Energy in Eucaryotic Cells

As chlamydiae c energy parasites of

eucaryotic cells, t is useful to review

the mito::hondri31 function of these host

cells as ceilular rtergy is provided by

these' organelles. The mechanism for

the mitochondli I generation of energy

is a function of tfue cellular ultrastruc-

ture. Each intrac~llular mitochondrion

has two distinct ~embranes, an inner

and an outer me4tbrane, that define

functiQnal space ~ .An intermembrane space is defined y the cuter and inner

mitochondrial m mbranes. The inner

mitod1ondrial m mbrane defines an

internr space, o~ compartment, known

as the. mitochondrial matrix. It is the

mitoohondrial mlltrix which contains

the ~cialized Pl.ot~ins of the electron

transport chain ~ esPiratory chain) and '-the e.nzymes of e citric acid cycle

(Kre.hs cycle) re ponsible for the gener-

atioro of ATP. -fh inner membrane has a

very large surfa J e area due to its char-

acteristic infold, known as cristae. This

inner membrane contains the electron

transport carrier~ (primarily cyto-

chromes). It al ~ contains a high con-

centration of c iolipin, a phospholipid

believed to decr ase the permeability

of this bilayer t small ions. The outer

mitochondrial s ~ ace has direct access

with the cytolso via the outer mem-

brane which co tains major integral

proteins called -orins. Porins can form

channels within e outer membrane

through which ,*olecules that are less

than 10,000 M~ «10 KOa) can freely

Figure 1. Mitochondrial energy production

(FAD). The three N~H and FADH2molecules created by the citric acidcycle as well as the NADH generatedby glycolysis are oxidized -a processwhich transfers electron pairs to accep-tor molecules on the inner mitochondri-al membrane, eventually leading to thereduction of oxygen and the formationof water.

The oxidation ofNADHor FADH2releases a hydride ion (HJ, which isquickly converted to a proton (Hj andtwo high-energy electrons (2 e-). Thesetwo high-energy electrons reduce"mole-cular oxygen to water during mito-chondrial respiration. This transfer ofelectrons from NADH or FAD~ tooxygen is catalyzed by a series of elec-tron carriers that are associated withmultiprotein complexes. These com-plexes include NADH dehydrogenase,cytochrome oxidase, and ATP synthetase(ATPase). The high-energy electrons aretransferred to ubiquinone by a flavinand several iron-sulfur prosthetic groupsattached to the multiprotein complexes.The hydrophobic ubiquinone thenmoves laterally in the inner membraneand transfers the electrons to the b-c

pass from the cytosol.The production of ATP within the

mitochondria is powered by a mecha-

nism called chemiosmotic coupling(Figure I). This process begins with the

conversion of glucose to pyruvate in the

cytoplasm by the glycolytic path\vay(Embden-Meyerhoff pathway). The netreaction produces two reduced nicoti-namide adenine dinucleotide (NADH)molecules that serve as the principalelectron donors for the reduction ofoxygen. The two NADH molecules aswell as pyruvate enter the mitochondrial

matrix. Pyruvate is converted to acetyl-coenzyme A which is the key substratefor the citric acid cycle. The metabo-lism of pyruvate in the mitochondria isassisted by two cofactors. biotin andlipoic acid. Fatty acids also enter the

mitochondrial matrix where they areoxidized to acetyl-coenzyme A. Both

pyruvate and fatty acids thus fuel thecitric acid cycle. During the citricacid cycle, acetyl-coenzyme A is oxi-dized to two molecules ofCO2 which is

released from the cell; the electronsreleased by this reaction are transferredto NAD and flavin adenine dinucleotide

NOTE:: No respon~ibility is assurned by the Publisher for any injury and/or damage to persons or propel1y as a matter of products liability. negligence or otherwise. or from any use oroperation ~f any meth~. products. instructions or ideas cont:lined in the malerial herein. No suggesled test or procedure should be carried out unless. in the reader's judg~t. itS risk ujustified. Because of rapid advances in the medical sci:nces. we recommend that the independcnt verification of diagnoses and drug doses should be madc:. Discu$sions. views. and

reconlr.",ndat:()ns ~ 10i n",dica! procedures. choice of drugs, and drug dosages are the responsibilily of Ihe authors.

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Antimicrobics and Infectious Dise:15es Newsletler 16(S) 199134 Q 1998 Eiscvier Science Inc.l069-4'7X197/S0.00 + 17.50

IMITOCHONDRIA

Gycine + a.ccinyl CoA

~r~

~~~Delta-Aminolewlinic Acid

(ALA)

CYTOSOL

L~ De-l

ALA + ALA ~ Porphobilinogeil

~~

Hydroxymet hylbilane

~~ ~ ~neous

lJroporphyrinogen /I.kOPOrPhyrinogenIII I

( U~yrin09..' IIl ~xyt ~

Co;Jroporphyrinogen / CoproporphyrinogenIII/ I

ICoproporphyrinogen In

( COP'O-yrincgen III 1 ,I 0-.. ) ~

Hardonoporphyrinogen( Coproporp/lyrinogen III 1 Il o.;dOs. -J ..

p(ot oporphyrif)ogen

l prolcP=noge: J +

Protoporphyrin

)+l-bne

Il Fe"cc!lelalase

Fi,\,ure 2. Biosynthesis of heme

multiprotei complex. Cytochrome c isanother sol ble electron carrier that. inturn. transfe s electrons between multi-protein corn lexes III and IV.

As the hi i.1~energy electron pairlstransferred t each of these three multi-protein corn lexes, the protons produced

pass freely rom the mitochondrialmatrix to th intermembrane space via

channeis in complexes I. III. and IV.1'hus, the tt nsfer of electrons from

NADH do n the electron transportchain cause protons to be pumped outof the mitoc ondrial matrix and into theintermembr ne space. These protonsthen reenter the matrix through a speci-tic channel in complex V. This protongradient ac oss the inner membrane

results in th proton motive force whichdrives ATP ynthesis.

ATP syn esis is carried out in sub-mitochond al elementary particleswhich use e electron pair from NADHof FADH2 t re:duce oxygen and convert

ADP plus p osphate to ATP. ATP syn-thetase is re ersible, and without the

large proton motive force. it could theo-reLically hy rolyze ATP and use the freeenergy deri ed from this hydrolysis tomove proto s out of the mitochondrialmatrix. Eec use of the large protonmotive forc , protons move down theirelectroche .cal gradient through ATP

syntheta-se; .s proton movement drivesATP synthe is.

Il1hibito of the passage of high-

energyelec ons to O2 (e.g., cyanide ion)block ATP s nthesis. The converse isalso true: in "bition of ATP synthesisblocks elec on transfer in the mitochon-dria. In gen ral, electron transfer andATP synthe is are obligatorily coupled;

neither reac on occurs without the other.However, u der certain conditions, mito-

chondrial o idation can be uncoupledfrom phosp orylation. For example.certain che icals (e.g., 2-4 dinitrophe-nol) and ion phores (e.g., oligomycin)can uncoupl this mitochondrial reaction.

Mechanis s for Chlamydia to

Derive En rgy from the Host Cell

The transfo ation of chlamydial ele-

mentary b ies (EEs) to reticulate bod-ies (REs) is known to initially involve

the activati n of intrinsic chlamydial

ATPase thal are contained within theEEs. lhis ase is oligomycin sensi-tive and ma nesium ion dependent and,

by detir:itio , is considered an F-type

affected by depletion of host cell energy.Gajdos has demonstrated that the meta-bolic consequenc~ of the interruptionof ATP biosynthesis is a secondary por-.phyria. A review of the biosynthesis ofheme is warranted (Figure 2). Hemesynthesis is a series of irreversible bio-chemical reactions, some of which occurin the cell nlitochondria and some in the

cytoplasm. The intramitochondrial reac-

tions are mainly oxidation-reductionwhile those in the cytosol are condensa-

tion and decarboxylation. Porphyrino-gens, porphyrins, and porphyria are allrelated to heme synthesis. The biosyn~thesis of heme occurs in all human cells

and involves a relatively small number ofstarting materials which are condensed

to form porphyrinogens; the porphyrinsare formed from the porphyrinogens by

non-enzymatic o,.idation. As porphyrino-gens progress through the heme biosyn-thesis pathway, the numbers of carboxyl

side groups on the corresponding por-phyrins decreases, as does the water

solubility of the compounds.Heme is a Fe2+ complex in which the

ferrous ion is held within the organicligand, tetrapyrrolic macrocycle. Theheme-containing tetrapyrrolic macro-cyclic pigments are known as porphy-rinogens and playa major role in cellu-

lar biochemistry. A number of critical

cellular functions such as electron trans-

port, reduction of oxygen, and hydroxy-

ATPase. This chlamydial F-type ATPaseshares both sequential and structuralhomology with mitochondrial ATP syn-thase and, like mitochondrial ATP syn-thase, catalyzes the condensation ofADP and inorganic phosphorus (Pi) toform ATP.

Chlamydial ATPase in esserice maybe competing with host cell mitochon-drial ATPase. This, of course, wouldreduce the ATP produced by the mito-chondria. A net reduction of ATP in thehost cell mitochondria would result inan concomitant lowering of the electrontransfer in the host cell mitochondriabecause electron transfer and ATP syn-thesis are obligatorily coupled; neitherreaction occurs without the other. Theestablishment of a large electrochemicalproton gradient across the inner mito-chondrial membrane by chlamydialinfection could halt normal electron"transport and might even cause a reverseelectron flow in some sections of thehost cell respiratory chain. The reduc-tion of electron transfer in the.host cellmitochondria, in turn, could lower thetranslocation and reduction of extra-matrix mitochondrial fenic iron tointramatrix ferrous iron. If this occurred,the energy depletion would interferewith the biosynthesis of heme.

The Biosynthesis of HemeThe biosynthesis of heme is an energy-dcpendent process which is adversely

35Anlimicrobics all\J Infectious Dise=s Newsle«er 16(5) 1997 O 1998 Eisevi~ Science Inc. 1069-417x,'}7/SO.00 + 17.50

1.

destroying O-and H2O2. In the extra-cellular milieu, ceruloplasmin, a copper-

containing plasma protein, mimics thedismutase activity of superoxide dis-mutase and protects the extracellular

milieu from autobxidation. Thus, the

accumulation of porphyrinogens/por-phyrins in human tissues and body

fluids produces a condition of chronicsystem overload of oxidative stress with

long tenn effects particularly noted for

neural, hepatic, and renal tissue.

The first step of heme biosynthesis is

the rate-limiting step and begins in the

mitochondria where delta-arninolevulinic

acid (d-ALA) is.condensed from glycine

and succinyl coenzyme,A by the mito-

chondrial enzyme a-ALA synthase in

the presence of pyridoxal 5'-phosphate.

d-ALA diffuses into the cell cytoplasm

after its fonnation where two d-ALAmolecules are then condensed by the

enzyme d-ALAdehydratase to fonn the

monopyrrole porphobilinogen (PBG).Tllis enzyme, d-ALA dehydratase, isinhibited by lead .and heme. The next

step of heme biosynthesis involves the

enzyme PBG deaininase which catalyzes

the synthesis of the linear molecule of

tetrapyrrole hydroxy.methyJbilane fromfour molecules of PBG. This reaction Iscritical as its product, hydroxymethyl-

bilane, can be converted to the asym-metric uroporphyrinogen-m by the

action of uroporphyrinogen-III cosyl1-

thase, or it can undergo.spontaneous

non-enzymatic conversion to the sym-

met(ic uroporphyrinogen-I. The iso-metric porphyrinogens fonned from

uroporphyrinogen-I are metabolic

products with no known physiologic

function. These also undergo non-

enzymatic oxidation to porphyrins.

The enzyme PBG deaminase may

have a partial deficiency which resultsin acute intennittent porphyria which

is inherited as a Mendelian autosomal

dominant trait. Because of the partial

enzyme block in the third step of the

pathway of heme biosynthesis, there is

increased activity of the initial and rate-

controlling enzyme d-ALA synthase

which is under negative feedback con-

trol by heme. During clinical attacks

and sometimes also during remission,

there is overproduction of the porphyrin

precursors a-ALA and PBG which are

fonned prior to the enzyme defect then

lation are medialted by a family of

heme-based cytqchromes includingcatalase, peroxid~se. and superoxidedismutase. Mor~over, the oxygen-carrying propertiFs of hemoglobin and .

myoglobin are b*sed on heme. Manycellular enzymesl such as cytochrome

P-450 and tryprolphan pyrrolase

contain heme. :

The porphyri~s are consequences of

any impairment ~f the formation of por-phyrinogens or i~ their transformationto heme. Porphy~ns are formed from

porphyrinogens ~y non-enzymatic oxi-dation. Each of t~e various genetic por-

phyrias is linked ItO a deficiency in theheme biosynthesis pathway. As a conse-

quence of the en*yme defects, there is

increased activity of the initial and rate-

controlling enzy~e of this biosyntheticpathway which rdsults in overproductionand increased extretion of porphyrino~gen precursors amd porphyrinogens. Theporphyrias are often considered phar-

macogenetic disorders as many phar-macological agemts including a numberof anticonvulsants such as carbama-

zepfue, phenytoin, phenobarbitone, andpremidone are potent inducers of hemebios¥nthesis and consequently can pre-

cipi"tate biochemical and clinical exa{:-erbations in patients who have the

, unoerlying genetic defect.

When porphyrinogens accumulatesecondary to enzymatic defects in theheme biosynt.,esis pathway, they are

oxidized to photQsensitizing porphyrins.Porphyrins are c1assified as photody-

namic agents beQause they generally

require oxygen to exert their damagingbiologic effects. Porphyrins may be

converted from ground state to excited

state molecules after absorption of radi-

ation. Excited state porphyrins transfer

energy to oxygen molecules and pro-duce reactive oxrgen species such as

singlet oxygen, sluperoxide anion, superoxide radical, hyjjroxyl radical, andhydrogen peroxitIe. Reactive oxygenspecies have been noted to disrupt

membrane lipids, cytochrome P-450,

and DNA structure. If these reactive

oxygen species are released into theextracellular spa~e, as seen in acute

pol1Jhyria, autoo~idation of surroundingtissue may result~ Two cytoplasmic

enzymes. sIJpero"ide dismutase andcatalase. protect ~ellular contentsagainst reactive tj>xygen species by

are excreted in excess in the urine.The enzyme uroporphyrinogen-m

cosynthase takes the linear molecule oftetrapyrrole hydroxymethylbilane andcloses the porphyrin ring. In the absenceof the uroporphyrinogen-III cosynthase

enzyme, hydroxymethylbilane sponta-neously cyclizes to form the I isomer ofuroporphyrinogen. The enzy~atic defectin congenital erythroporetic porphyriais found in the uroporphyrinogen-IIIcosynthase enzyme. Uroporphyrinogen-III is converted to 7, 6, 5-carboxyl

porphyrinogen-III by uroporphyrinogendecarboxylase. Both hepatoerythropor-etic porphyria and porphyria c.utaneatarda have a defect in this enzyme.

A critical step in the biosynthesis ofheme is the later mitochondrial stagesin which the last three enzymes of heme

synthesis, coproporphyrinogen oxidase,protoporphyrinogen oxidase, and ferro-chelatase drive the concurrent transloca-tion and reduction of extra-mitochondrialferric iron to ferrous ion in the mito-chondrion (Figure 3). At the same time,coproporphyrinogen-III must also enterthe mitochondrion in order to be oxi-dized to protoporphyrinogen into whichthe ferrous ion is inserted to form heme.Coproporphyrinogen oxidase convertscoproporphyrinogen-III to protopor-

phyrinogen. Hereditary coproporphyriais an autosomal dominant disorder inwhich the genetic defect is a partialdeficiency of coproporphyrinogen oxi-dase. Protoporphyrinogen in turn is oxi-dized to protoporphyrin by the enzymeproroporphyrinogen oxidase. Theseoxidative steps take place in the mito-chondrial matrix membrane as copro-porphyrinogen-111 moves from thecytosol back into the matrix. The finalstep of heme biosynthesis, like the ini-tial, occurs in the mitochondrial matrixwhere protoporphyrin is chelated withferrous iron to form heme. The enzyme .

ferrochetalase catalyzes this last reaction.

Chlamydia and SecondaryPorphyria: A Theoretical

PossibilityAs mentioned, ferric/ferrous transloca--tion is a critical step in the biosynthesisof heme as it catalyses the oxidativeentry of coproporphyrinogen into themitochondria matrix as protoporphyrin.When coproporhyrinogen is unable toreturn to the nvtochondrial matrix, itaccumulates first in the cytosol and then

36 1069-4 1 VX197/S0.00 + 17.50 O 1998 Elsevier Science Inc. Anlimicrobics and In{eclious Diseases Newsleller 16(5) 1997

r I ~YTa30l

Coproporphyrinogen

),"7

Figure 3.Biosynthesis ofheme: energy-requiring step

Fe3+

~a:x~ ~

1.{

co ro or h rino en

proloporphyrinogenoxidase

Fe2+

~ "

U~

I"I-EME MITOCHONDRIA

~Negat ive Feedbackon ALA syntha se

Jin the extracellular ITtilieu. Within themitochondrial matrix, the final steps inthe biosynthesis of heme are halted.Because the accumulation of hemewithin the mitochondrial matrix nor-ma!ly exerts a negative feedback onheme biosynthesis, the reduction ofheme caused by the inability ofcopro-porphyrinogen to return to the mitccho-ndrial matrix results in the increasedproduction of heme precursers such asa-.~A and PBG, the first and secondproducts in heme biosynthesis. 1nus,porphyrin precursers such as d-ALAand PBG begin to accumulate in themitochondrial matrix, then in the cytol-sol, and then in the extracellular miliell.

Depletion of host cell energy by theintracellular infection with Chlamydiaspecies might cause additional energy-related complications. As fewer elec-trons are available to move through theelectron transport chain of the host cellmitochondrial matrix membrane, thecitric acid cycle produces rrlore succinyl-CoA which. in turn, promotes increasedsynthesis of d-ALA. The net result is anincreased amount of heme precursorsand hej.,.:e porphyrins. The rJresence ofporphyrins in the mitochondrial matrixmay damage the cell as these moleculesare unstable and form free radicals. 1behigh energy electrons generated bythese free radicals could be .'captured"by ubiquinone and cytochrome c whichare present in the mitochondrial matrix

membrane. This. of course. wouldeffectively uncouple electron transportfrom ATP synthesis and "short circuit"the proton-motive force: ATP synthesiswould then be reduced. LessATP. inturn, means increased porphyrins, anda destructive cycle is begun.

The clinical result of the intracellularand extracellular accumulation of por-phyrins, if extensive. ,,'ould be an tissue/

organ specific secondary porphyriawhich might produce the classical man-ifestations of porphyria. including neu-ropsychiatric symptoms and signs. Asth~ chlamydial-infected host cells lyse.as can happen in the normal life cycleof Chlamydia. the intracellular porphy-rins are released and result in porphyria.Moreover. if chlamydiae were to infecthepatic cells. the use of any pharmaco-logic agents that are metabolized in theliver will increase the need for cyto-chIome P-450 which is a heme-basedenzyme. Hence. the biosynthesis ofheme in the liver is increased. If hepaticcells were infected with Chlamydiaspecies, the decreased energy in thehost cell would not allow heme bio-synthesis to go to completion, andporphyrins in the liver/entero-hepaticcirculation would increase. It alsomight be predicted that any host cellinfected with Chlamydia species couldha\'e an increased amount of intracellu-tar porphyrins that would be releasedwhen antimicrobial agelits kill the

microorganism. The theoretical meta-

bolic disorder described clearly would

be of paramount importance in dealingwith cb.ronic systemic chlamydia! infec-

tions as might be seen with intravascu-

lar infections caused by Chlamydia

pneumoniae.

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