Mechanism of Microbial Infections

8/19/2019 Mechanism of Microbial Infections

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Adapted from JF Zachary and MD McGavin

e . a o og c as s o e er nary sease , p. ‐

‐

Graduate Institute of Molecular and Comparative Pathobiology

School of Veterinary Medicine, NTU

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• Provide a mechanistic overview of the key

ste s involved in understandin the

pathogenesis of infectious diseases.

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• ynops s

• Portals of Entrys• Defense mechanism

• Genetic Resistant of Animals to Infectious

seases• Bacterial Diseases

• Viral Diseases

• Fungal Diseases• Protozoan Diseases

• Prion Diseases

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• In ectious agents o ow c rono ogy sequences

of events regulate by virulence determinates to infect target cells unique to specific organ system and cause disease (Fig. 4‐1).

• Entry (routes), ligand‐receptor interaction, colonization s readin cell dysfunction/death or clinical disease

• various infectious agents.

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Fig. 4‐1 Sequence of events in infection. The chronologic sequence of events used by infectious

microorganisms to co onize and invade mucosae and s in, spread to oca tissues and regiona

and systemic organ systems, and cause disease. (Courtesy Dr. J. F. Zachary, College of Veterinary

Medicine, University of Illinois.) 5


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• nges on, n a a on, cu aneous pene ra on,

ascending

infection

(Fig.

4‐

2).

(Fig.4‐3)

• mucus layer.

• cilia or microvilli, and/or mucosal epithelial cells.

• MALT via mucosa MØ or L.• MALT via D

•

• MALT via M cells and transcytosis

• Nerve ending and enter brain via retrograde axonal transport

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‐. .

microorganisms commonly enter the

body through ingestion (alimentary

ortal inhalation res irator

portal), cutaneous penetration (skin portal), and ascending infection

(lower urinary and reproductive

portals) and interact with epithelial

cells, macrophages, dendritic cells,

and lymphocytes of the mucosae or

skin. (Modified from Goering R,

Dockrell H, Roitt I, et al: Mims’

medical microbiology, ed 4, St. Louis,

2008, Mosby.)

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Fig. 4‐3 Mechanisms of Microbial

Pathway 1: Bacteria target the mucus

layer. Pathway 2: Bacteria target cilia

or microvilli and/or mucosal e ithelial

cells. Pathway 3: Bacteria target MALT

via mucosal macrophages (MØ)

and/or lymphocytes (L). Pathway 4:

Bacteria target MALT via dendritic

cells (D). Pathway 5: Bacteria target

MALT via transcytosis or intercellular

( unctional complexes) spread.

Pathway 6: Bacteria target MALT via

M cells and transcytosis. Pathway 7:

Bacter a target nerve en ngs n

mucosa and enter the brain via

retrograde axonal transport. our esy r. . . ac ary, o ege o

Veterinary Medicine, University of

Illinois.)

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• Locate at t e mucosa o t e a imentary an

respiratory system, is a protective mucus gel compose pre om nan y o muc n g ycopro e nssynthesized and secreted by goblet cells (Fig. 4‐4).

• Blocking from reaching target cells, • trapping for phagocytosis or bacteriostatic or

bacteriaocidal molecules

• Facilitate ha oc tosis b MØ D or M cells• Delivery

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• Mucus layer can be affected by

– function chan e of oblet cells

– factors produced by infectious agents,

– ,

– predisposing management stressor (dehydration,

s ipping, umi ity, venti ation, weat er c ange.

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• Infectious agents use three mechanism to

enetrate the mucus la er. – Penetrating motility

–

consumption as an energy source

– vas on o e mucus ayer n area aroun eyer s

patches and M cells, area devoid of mucus.

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• Biochemical difference in different locations

•

– Neutral

– Aci• Sulfated (Sulfomucins)

• Non‐sulfated (sialomucin)

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• g. ‐ an ‐ .

• Infectious agents entering the alimentary system.

• , , epithelium and epithelium containing M cell overlying Peyer’s patch.

• Mucus,

o og ca

an

p ys ca

arr er – Thickness and viscosity (830um in colon, 123um in jejunum), –

– Reservoirs for Ig A and lysozyme

– Free

radical

scarvenger – orma ora

• Microbial interaction with a barrier system: intestinal mucosa Fi . 4‐5

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Fig. 4‐4 Mucus

layer

of

alimentary

and

respiratory

mucosae.

A, Mucosa of the intestine (shown here) and

o t e con uct ve resp ratory a rways are covere y a mucus ayer not v s e n sect ons secrete y

goblet cells (G). The mucus covers the microvilli or cilia of these systems. H&E stain. B, The mucus layer has

an outer layer that traps microorganisms (infectious and noninfectious) and other particles and an inner

la er in which the cilia beat and which contains antimicrobial substances that diffuse into the outer la er.

Dendritic cells and mucosa‐associated macrophages and lymphocytes play central roles in preventing

infection of mucosa. (A courtesy Dr. J. F. Zachary, College of Veterinary Medicine, University of Illinois.)14


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Fig. 4‐5A Microbial

interactions

with

a barrier

system:

intestinal

mucosa. A, Mucosa that cover intestinal villi (V) and Peyer’s

to prevent the spread of infectious organisms into the underlying

lamina propria. H&E stain. B, Schematic diagram of the responses

of bacteria or viruses tra ed in the mucus la er 1 . Bacterial

proteins (virulence determinates) act to allow them to penetrate

the mucus layer and come into contact with the mucosal

epithelium (2). IgA secreted by mature plasma cells in the lamina

propria passes

through

mucosal

epithelial

cells

into

the

lumen

and

can act as an “opsonizing” defense mechanism thus preventing

infection. Bacteria then interact with mucosal epithelial cells,

dendritic cells (D), or M cells (3). They then encounter lymphoid

cells in the lamina propria or Peyer’s patches (4) and spread in

lymphocytes or as free virus in lymph from this location via efferent lymphatic vessels to regional lymph nodes (5). Note the absence of

a mucus layer over M cells and follicle‐associated epithelium. Also

see Fig. 4‐7 for an example of barrier system: respiratory mucosae.

cour esy r. . . ac ary, o ege o e er nary e c ne,

University of Illinois.)15


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Fig. 4‐5B Microbial interactions with a barrier

system: intestinal mucosa. A, Mucosa that cover

intestinal villi (V) and Peyer’s patches (P) and line

prevent the spread of infectious organisms into the underlying lamina propria. H&E stain. B,

Schematic diagram of the responses of bacteria

.

Bacterial proteins (virulence determinates) act to

allow them to penetrate the mucus layer and

come into contact with the mucosal epithelium (2).

propria passes through mucosal epithelial cells

into the lumen and can act as an “opsonizing”

defense mechanism thus preventing infection.

,

dendritic

cells

(D), or

M

cells

(3).

They

then

encounter lymphoid cells in the lamina propria or

Peyer’s patches (4) and spread in lymphocytes or

as free virus in l m h from this location via

efferent lymphatic vessels to regional lymph nodes

(5). Note the absence of a mucus layer over M

cells and follicle‐associated epithelium. Also see

Fi . 4‐7 for an exam le of barrier s stem:

respiratory mucosae. (A courtesy Dr. J. F. Zachary,

College of Veterinary Medicine, University of

Illinois.)

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• g. ‐ .

• Deposition of infectious agents in the respiratory system could be at nasal turbinates nasal har nx and or the conductive system bases on physical properties of the agents such as size, shape, weight, and electronic charge.

‐ , , . ,

fungi (5‐60um), protozoa (1 to 300 um)• Nasal cavity and turbinates trap 70‐80% of particles 3‐5 um

or greater, 60% of particle 2 um or greater; but cannot trap 1um


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g. ‐ epos on o n ec ous m croorgan sms. n ec ous m croorgan sms n a e roug

the nostrils are deposited on mucosa of the nasal turbinates, nasal pharynx, and/or the

conductive system of the respiratory tract. The site of deposition depends on the physical

, , , .

Goering R, Dockrell H, Roitt I, et al: Mims’

medical

microbiology, ed 4, St. Louis, 2008, Mosby.)18


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Fi . 4‐7 Mucociliar a aratus. A Cilia arrows of the bronchiole mucosal e ithelial cells

and the mucus layer (not visible) form the mucociliary apparatus of the conductive

component of the respiratory system. The mucus layer is not visible because it has been

removed during histologic processing of tissue. H&E stain. B, Diagram of the mucociliaryapparatus. The mucus layer is biphasic and consists of a luminal viscoelastic or gel layer

used to trap bacteria and a serous inner layer in which the cilia of ciliated mucosal epithelial

cells beat unidirectionally to move bacteria upward in the airways to be swallowed or

expectorated. G, Goblet cell. (Courtesy Dr. J. F. Zachary, College of Veterinary Medicine,

University of Illinois.)19


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• Biphasic, gel (luminar viscoelastic) and serous

inner la er.• Direction of moving, downward in nasal cavity

, .

• Unusual agents (Rhodococcus equi ) gains

access to alimentary system and cause disease.

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Immune Component in

the conductive system

• Mo and D cells and other components (Ig A)

• ’.

• Trojan horse (macrophages)

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Cutaneous penetration &

Ascending infection

• Injury then spreading (cutaneous ).

– Wound or insect bite

• Lower urinary system and reproductive system

– Coitus or contaminated AI materials

– injury

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• ost arr er system

– Skin

and

mucosa

of

several

systems – cc u ng unc on, • tight junction demosome and adherence junction

–

• Basement membrane and ECM

– Apical domain (Influenza), receptor‐mediated endocytosis

– Basolateral domain (Parvo), exocytosis (Fig. 4‐8)

• Innate and adaptive immune response• Monocyte‐Macrophage system

• Dendritic cells

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Fig. 4‐8 Domains of polarized epithelial cells in mucosal barriers. Infectious organisms use

the apical or basolateral domains of mucosal epithelial cells to enter and exist from these

cells. Apical or basolateral cell surface receptors may facilitate entry into the cell. (Courtesy Dr.

J. F. Zachary, College of Veterinary Medicine, University of Illinois. 24


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‐

• A network of phagocytic and immune cells (Fig.

4‐9).• Migration and surveillance

• Ki ing

Fig.

4‐

10• Traffickin Fi . 4‐11

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Fig. 4‐9 Tissue

locations

of

cells

of

the

monocyte

‐macrophage

system. (From Goering R,

Dockrell H, Roitt I, et al: Mims’ medical microbiology, ed 4, St. Louis, 2008, Mosby.) 26


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Fig. 4‐10 Phagocytosis and intracellular

destruction of microbes. Phagocytosis of a

particle (e.g., infectious microorganism)

involves binding to receptors on the leukocyte

membrane, engulfment, and fusion of lysosomes with phagocytic vacuoles. This

process is followed by destruction of ingested

particles within the phagolysosomes by

ysosoma enzymes and y reactive oxygen and

nitrogen species. The microbicidal products

generated from superoxide are hypochlorite ∙ ∙

an y roxy ra ca , an rom

nitric oxide (NO) it is peroxynitrite (OONO∙).

During phagocytosis, granule contents may be

.

MPO, Myeloperoxidase; iNOS, inducible NO

synthase. (From Kumar V, Abbas A, Fausto N,

disease, ed 8, Philadelphia, 2009, Saunders.)

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Fig. 4‐11 Leukocyte trafficking.

Infectious microorganisms often use

macrophages,

lymphocytes,

and/or

dendritic cells to spread themselves

to other organ systems as these cells

of their normal immunologic

surveillance activities. As an example,

lymphocytes move through the

circulation and enter lymph nodes via

specialized endothelial cells of

postcapillary venules (HEVs), leave

and pass through other nodes, finally entering the thoracic duct, which

empties into the circulation.

Lymphocytes enter white pulp of the

spleen, then pass into sinusoids of the

red pulp and leave via the splenic vein.

, , ,

al: Mims’

medical

microbiology, ed 4,

St. Louis, 2008, Mosby.)

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GENETIC RESISTANT of ANIMALS to

INFECTIOUS DISEASES• ene c res s ance o n ec ous seases s po ygene c

trait regulated mainly by the immune system and its

interaction with barrier s stem and environment factors such as weather conditions and nutritional status.

• ac ors nc u e : mmune ce s, s ruc ures , arr er system, functional process (adhesion, chemotaxis,

ha oc tosis ha osone‐l sosome fusion intracellular killing of microbes, and antigen process)

• PAMPs

receptor

recognize

pathogen‐

associated

mo ecu ar patterns

• MHC, BoLA

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INFECTIOUS DISEASES• Disor ers o arrier systems

– Epitheliogenesis imperfecta in horse pig and cattle• Loss of the peithelium in the skin, mucosa, tongue

• Alteration in sub‐basal plate, hemidesmosomes, laminin‐5

– y y • Defects of proteins in the outer and/or inner dynein arms of

cilia which ive them the motilit

• Retention of infectious agents in the respiratory system and causes pneumonia

• Disorders of innate immune response

• Disorders of the adaptive immune response

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INFECTIOUS DISEASES• sor ers o nnate mmune response

– Toll‐like receptors (TLRs) in the process of the phagocytosis (Fig. 4‐12)

• Pattern‐recognition receptors (PRRs) that recognized molecules on infectious agen s ca e s.

• IL‐1 involved in the initiation and sustain the innate immune response through

phagocytosis.

–

• Alteration in the leukocyte adhesion cascade, deficiency or dysfunction of integrinsand selectins and causing inability of neutrophils to adhere to endothelial cells in

the wall of blood vessels and mi rate into sites of bacterial infection.

– Granulocytopathy syndrome in dogs and cattle

• Reduced NADPH concentration and cause reduce concentration of hydrogen

peroxide in phagosome‐lysosome fusion. – Cyclic hematopoiesis in dogs

• Abnormality in stem cells in bone marrow results in periodic declines, every 10‐12

ds, in neutrophils concentrations followed by hyperplasia and a return to normal.

• Metabolic derangement in purine or pyrimidine metabolism may be the cause

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Fig. 4‐12 Toll‐like receptors in the process of phagocytosis. The process that results in phagocytosis is characterized by three interrelated steps:

adherence and diapedesis, tissue invasion by chemotaxis, and phagocytosis. A, Adherence, margination, diapedesis, and chemotaxis. The

primary phagocyte in the blood is the neutrophil, which usually moves freely within the vessel (1). At sites of inflammation, the neutrophil

progressively develops increased adherence to the endothelium, leading to accumulation along the vessel wall (margination or pavementing) (2). At sites of endothelial cell retraction the neutrophil exits the blood by means of diapedesis (3). Chemotaxis: In the tissues, the neutrophil detects

chemotactic factor gradients through surface receptors (1) and migrates towards higher concentrations of the factors (2). The high concentration

of chemotactic factors at the site of inflammation immobilizes the neutrophil (3). B, Specific receptors for recognition and attachment. C,

Phagocytosis. Opsonized microorganisms bind to the surface of a phagocyte through specific receptors (1). The microorganism is engulfed

, . , .

During this process the microorganism is exposed to products of the lysosomes, including a variety of enzymes and products of the hexose‐

monophosphate‐

shunt

(e.g.,

H2O2,

O2−

).

The

microorganism

is

killed

and

digested

(4).

Ab, Antibody;

AbR, antibody

receptor;

C3b, complement

component C3b; C3bR, complement C3b receptor; PAMP, pathogen‐associated molecular pattern; PRR, pattern recognition receptor. (From

McCance KL: Pathophysiology: the biologic basis for disease in adults and children, ed 6, St. Louis, 2010, Mosby.)32


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INFECTIOUS DISEASES• sor ers o e a ap ve mmune response – Agammaglobulinemia in young colts

‐

• Dysfunction of cytoplasmic tyrosine kinase resulting in blockage in the differentiation of B lymphocyte linages and a

– Severe combined immunodeficiency syndrome in dogs and arabian horse• X‐linked recessive mode

• Mutation within recombinase‐activating gene

‐

• Or incapable of completing signal transduction pathway due to defect in the surface receptor for interleukins

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• Pathogenecity

– Abilit to infect cells• Adhesion, multiplication, colonization, tissue invasion,

circumvention of animal defense mechanisms.

– Ability to produce toxins and damage cells and their ECM tissues such as colla en

• Toxins: cytolysis and invasion of vascularized ECM

tissues locall and s stemicall b exotoxins or endotoxins.

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Mechanisms adopted by infectious

microorganisms tp avoid phagocytosis

• Fig. 4‐13

•

• Opsonization prevented

• Contact with phagocyte prevented•

• Escape into the cytoplasm

• Resistant to killing

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Fig. 4‐13 Mechanisms adopted by infectious microorganisms to avoid phagocytosis. (From

Kumar V, Abbas A, Fausto N, et al: Robbins

&

Cotran pathologic

basis

of

disease, ed8, Philadelphia, 2009, Saunders.)

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• erence o ce mem rane

• Mucosa colonization

• Growth and replication

, ,

• Cell disruption, inflammation, injury or death• ‐.

• Co‐factors of pathogenecity

– Ph sical and environment issues weather access to food and water, management (shipping) or house stressor (ventilation, humidity or overcrowding)

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Fig. 4‐14 Virulence

determinates used by bacteria

to cause

disease. 38


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• Eg. Mucus ayer

• Motility – spirochetes

• Di estion and consum tion of mucus la er

– Clostridium

septicum,

– Consume oli osaccharides as carbon source: N‐acetylglucosamine, galactose, N‐acetylgalactosamine

• Random discover of mucosa lackin a mucus layer

– M cells

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,

,

• es on: gan ‐recep or n erac on g. ‐

• Invasion:

invasins – Sprea ing actors, ya uroni ase, co agenase, inase, lecithinase, phospholipase (Tab. 4‐2)

. ‐ , ‐

– Exodotoxins and lipoteichoic acid

–

• Other virulence determinates

– – Siderophores

– Biofilms intracellular bacterial communities

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Fig. 4‐15 Fimbrial (pilus) and afimbrial adhesins. These structures are used by infectious

microorganisms to attach and bind to protein receptors on membranes of target cells (especially mucosal epithelial cells) or to molecules of the mucus layer or vascularized

extracellular matrix (connective) tissues.

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Fig. 4‐16A Morphology and molecules of Gram‐positive and Gram‐negative bacteria.

o ecu es e exo ox ns, po e c o c ac , an en o ox ns popo ysacc ar e a orm

the structure of bacterial cell walls are often toxic. They act as virulence determinates that

damage cells and their extracellular matrices such as collagen. A, Morphology of a typical

. , ‐ . ‐

bacteria have a thin peptidoglycan layer and an outer membrane of LPS (right). (A and B from

Goering R, Dockrell H, Roitt I, et al: Mims’

medical

microbiology, ed 4, St. Louis, 2008, Mosby.)42


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Fig. 4‐16B Morphology and molecules of Gram‐positive and Gram‐negative bacteria. Molecules like exotoxins,

lipoteichoic acid, and endotoxins (lipopolysaccharide [LPS]) that form the structure of bacterial cell walls are often toxic.

. ,

typical bacterium. B, Gram‐positive bacteria have a thick layer of peptidoglycan (left). Gram‐negative bacteria have a thin

peptidoglycan layer and an outer membrane of LPS (right). (A and B from Goering R, Dockrell H, Roitt I, et al: Mims’

medical microbiology, ed 4, St. Louis, 2008, Mosby.) 43


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• ox ns – Exodotoxins and lipoteichoic acid (Fig. 4‐16, 17)

• Pore formation

• Inhibition of protein sysnthesis

• Hyperactivation

• Effects on nerve‐muscle transmission –

– Stimulation blocked

– Endotoxins (Fig. 4‐16, 17)• LPS activates a most every immune mec anism, as we as

clotting pathway

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Fig. 4‐17A Actions of bacterial


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Fig. 4 17A Actions of bacterial

toxins (virulence determinates) on

cells. A, The mode of action of

some exotoxins. Bacterial toxins act

in a variety of ways. Often the toxin

‐ ,

being concerned with entry into

cells while the other has inhibitory

activity against some vital function.

, ,

adenosine monophosphate; C,

Corynebacterium; Cl, Clostridium;

Staph, Staphylococcus; V, Vibrio. B,

.

Lipopolysaccharide (LPS) activates

almost every immune mechanism,

as well as the clotting pathway, and

,

powerful immune stimuli known.

DIC, Disseminated intravascular

coagulation; IFN, interferon; IL,

, ,polymorphonuclear leukocyte; TNF,

tumor necrosis factor. (A and B from

Goering R, Dockrell H, Roitt I, et al:

’ , ,

St. Louis, 2008, Mosby.)

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. ‐

.

,

of action of some exotoxins. Bacterial toxins act in a variety of ways. Often the toxin is a two‐chain molecule, one chain

being concerned with entry into cells while the other has inhibitory activity against some vital function. ACh, Acetylcholine;

cAMP, cyclic adenosine monophosphate; C, Corynebacterium; Cl, Clostridium; Staph, Staphylococcus; V, Vibrio. B, The

. ,

pathway, and as a result, LPS is one of the most powerful immune stimuli known. DIC, Disseminated intravascular

coagulation; IFN, interferon; IL, interleukin; M, macrophage; PMN, polymorphonuclear leukocyte; TNF, tumor necrosis factor. (A and B from Goering R, Dockrell H, Roitt I, et al: Mims’ medical microbiology, ed 4, St. Louis, 2008, Mosby.)

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• Ot er viru ence eterminates

– Secretion

systems• Bacterial organelles that secret or inject bacterial derived toxins into cytoplasm of host target cells (six types)

–

• Mediate the release of iron from intracelluar iron stores (heme, ferritin, transferrin, or lactoferrin molecules.

– Biofilms/intracellular bacterial communities• Form an exopolysaccharide matrix, on mucosal surface lining

• Bacteria embedded in biofilm are not susceptible to phagocytosis and are resistant to antibiotics

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Role of bacterial genes in susceptibility


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and/or resistance to disease• romosoma an or ac er op age

(plasmids of bacteria) –

• Ex. Rhodococcus equi –

• Capsular polysaccharides• Cholesterol oxidase

• Phospholipase C

• Lecithinase

– Plasmid virulence determinates• virulence‐associated rotein VAP

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and/or resistance to disease

– Enzymatic deactivation (b‐lactamases and extended‐spectrum (cephalosporin and monobactams)

– ‐ , , enterococci (VRE)

– Alteration of a metabolic pathway (sulfoamide‐resistant bact. (PABA‐‐‐folic acid),

– Reduced antibiotic accumulation in bact. Through membrane pump.

– Fig. 4‐18• Bacterial gene Transfer – Vertical gene transfer• Environment stress (antibiotics), (mutation rate 1x108)

– Horizontal gene transfer (Fig. 4‐19)

• • Transformation (via chromosomal DNA)

• Transduction (via bacteriophage)

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Fig. 4‐18 Mechanisms used by bacteria to establish resistance to antibiotics.

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Fig. 4‐19 Horizontal gene transfer. Mechanisms used by bacteria to transfer resistance to an

antibiotic to other bacteria.

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• Tab. 4‐3

•• Toxins

• Structural

injury• ,

• Alterations of cell cycle

• Dysfunction of electrolytes/fluid pumps

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Alimentary system


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Alimentary system

Enteric colibacillosis (Escherichia

coli )• Enterotoxigenic (ETEC)

– Nonstructural alteration in the function of cell membrane (ion and fluid transport system)

Enterohemorrhagic (EHEC) – Acute coagulative necrosis of the cells caused by

bacterial toxins and by acute inflammation and its

mediators and degradative enzyme

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• Enterocyte nvas on

– No in ETEC and EPEC

– Yes in EHEC• Structural alteration

– ETEC, no, toxin release cause functional change and secretary diarrhea

– , , ,

an

osmotic

diarrhea

(malabsorption)

and

less

significant

secretary

diarrhea – EHEC, yes, colon, enterocytes cell death, inflammation and hemorrhage, leads

.

• Gross and micro lesions

– ETEC, no

– EPEC and EHEC, yes, mucosa are rough and granular (enterocyte necrosis and

villus atrophy) with area of hemorrhage, acute inflammation and fibrin

exudation.

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Fig. 4‐20 Colonization

of

mucosa

in

enteric

colibacillosis.

Escherichia coli attach to microvilli, thus forming a uniform layer of

blue‐staining (hematoxylin) coccobacilli. Note the lack of epithelial

cell injury. H&E stain. (Courtesy Dr. J. F. Zachary, College of

Veterinary Medicine, University of Illinois.)

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• EHEC entero emorr age , co on, enterocytes ce eat , in ammation

and hemorrhage, leads to reduced absorption of colonic fluid and a

malabsorption diarrhea. – Ligand‐receptor interaction (colon specific)

– Secrets verotoxin that elicits an intense acute inflammatory response

– Lesions, emorr age co itis, resu t o com ination o in ammatory

enzymes and mediators and toxins. – LPS or endotoxin, multi le or s stemic effect, acute adrenal cortical

hemorrhage and necrosis

• Septicemic colibacillosis

e y esu ng om

• Endotoxic shock and cardiovascular collapse

• Enterotoxemic colibacillosis

• Edema disease, fibrinoid arteriopathy/arteriolopathy of the brain, ischemia, malacia.

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Fig. 7‐157 Fibrinous polyserositis, abdomen, pig. Strands and clumps of fibrin are scattered throughout serosal surfaces. A milk‐spotted liver is also resent. Courtes Dr. H. Gelber Colle e of Veterinar Medicine, Oregon State University.)

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Fig. 12‐25 Adrenocortical hemorrhage (Waterhouse‐Friderichsen

syn rome , a rena

g an ,

orse.

, use emorr age arrow a ect ng

the adrenal cortex is frequently seen in endotoxic shock. B, Subgrossphotomicrograph of diffuse hemo‐rrhage (arrow) affecting the adrenal cortex.

. , .

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Fig. 7‐126 Edema disease, head, pig. The skin of the eyelids, snout, and submandibular area are edematous as a result of production of

, capillaries. (Courtesy Dr. H. Gelberg, College of Veterinary Medicine,

Oregon State University.) 68


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. ‐

,

,

. mesentery is a result of an angiotoxin produced by Escherichia coli . (Courtesy Dr. W. Hascheck‐Hock and Dr. L. Borst, College o Veter nary Me c ne, Un vers ty o I no s.

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Proliferative Enteritis/Hemorrhagic bowel


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syndrome (Lawsonia intracellularis)• sease o p gs, orse an ams er – Porcine intestinal adenomatosis, proliferative ileitis, regional

ileitis,

garden

horse

disease – Necrotic enteritis, acute proliferative hemorrhagic enterophathy

• Ligand –receptor interaction in the ileum enterocyte, ileum

• How the bacterium penetrates into mucus layer? – Transient bacterial appendage as flagellum – Cofactor from anaerobic bacteria in mucus layer enhance the

colonization and replication

• (growth and replication) with proliferation of crypt enterocytes (hypertrophy and hyperplasia)

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Fig. 4‐21 Pathogenesis of proliferative enteritis in pigs. Lawsonia intracellularis infects cells of

the crypts located in the proliferative zone. 71

Proliferative Enteritis/Hemorrhagic bowel


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syndrome (Lawsonia intracellularis)• Un que eature o pro erat ve enter t s

• The bacterium is able to inhibit normal maturation of crypt cells, probably through

affect cell cycle, instead, dramatically increase the rate of crypt cell division,

– massive thickening of mucosal surface by proliferating crypt cells

– Normal villus structure is lost and replaced by a branching glandular pattern

– ‐

cells in thicken)

– Mitotic active is active

–

• Lesions of hemorrhage bowel syndrome: acute coagulative necrosis of the

proliferative crypt epithelium

– Ischemia or effect s of toxin (burn like injury)

– Cells can not survive 100um away from oxygen source

– Endotoxin

– Acute inflammation with hemorrhage and fibrinogenesis concurrently with

acute coagulative necrosis 72


73/122

Fig. 7‐153 Proliferative enteritis, ileum, pig. Note

,

Lawsonia‐induced epithelial hyperplasia. (Courtesy Dr. H. Gelberg, College of Veterinary Medicine, Oregon State University.)

73


74/122

Fig. 7‐155 Lawsonia enteritis, ileum, pig. A, Hemorrhagic bowel form. Note the prominent folds of hyperplastic mucosa and the concurrent hemorrhage forming a

luminal cast. B, Necroproliferative form. Note the prominent necrosis of the ilealmucosa and its diphtheritic membrane (cast) formed by cellular debris and inflammatory exudate. (A courtesy Dr. D.D. Harrington, School of Veterinary Medicine, Purdue University and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia. B courtesy of Dr. D. Driemeier, Federal University of Rio Grande do Sul, Brazil.)

74


75/122

Fi . 7‐154 Lawsonia enteritis, ileum, i . There is notable hyperplasia of enterocytes, resulting in distortion of normal architecture and “collision necrosis” of tightly packed

College of Veterinary Medicine, University of Illinois.)75


76/122

Fi . 7‐156 Proliferative enteritis ileum i . Curved Lawsonia spp. bacteria (arrow) are present in the apical cytoplasm of enterocytes. There is proliferation of crypt

‐. . . . , College of Veterinary Medicine, Oregon State University.)

76

Bovine Pneumonic


77/122

(Mannheimia(Pasteurella) haemolytica• ause n ury an ea coagu a ve necros s o a ce

populations in the respiratory system

• Lesions contribute b bacterial toxin leukotoxin acute inflammation and its mediator, and degradative enzymes

• Disease can be enhanced by environment stressors, and

• Host: cattle, sheep and goats• – Severe fibrinonecrotic (often hemorrhage) pneumonia

– Vasculitis

– Type I pneumocyte, a veo ar septa, capi ary en ot e ia ce s and vascular system

– Necrosis and apoptosis

77

Bovine Pneumonic


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Pasteurellosis/Mannheimiosis• ommensa , u cou e c ange e re a ons p

under the stressor, weaning, adverse weather

condition

chan e

in

diet

shi in• Colonization, first in conductive system, secondary the affect the O2‐CO2 exchange components (terminal

ronc o an a veo

– Neuraminidase, reduces the viscosity of mucus and cleaves the sialic acid reduced the net ne ative char e of cell membrane, attributes the contact of bacteria and cells

– Gravity and random Brownian movement also contribute

– gan ‐recep or n erac on, p an m r a a es n – Bacterial capsule (polysaccharides) inhibits phagocytosis of

the neutro hils and mucosal macro ha es

78

Bovine Pneumonic


79/122

Pasteurellosis/Mannheimiosis• ect t e ‐ exc ange components w c s more severe t en t e rst process

– Enormous replication after first stage settlers

– Large area of lung surface affected

– ‐ ‐

• The most important virulent determinates: Leukotoxin

– RTX toxin, cytotoxin cause death and apoptosis of neutrophils and macrophages

–

– High concentration, cell death due to pores formation in cell membrane

– Low concentration, apoptosis and activation of neutrophils and proinflammatory cytokine

production

– LPS+leukotoxin, activate complement system and proinflammatory cytokine production result

in vascular injury and severe acute inflammation.

– Vascular injury cause

• permeability changes

• with edema

• release of fibrinogen that polymerize to fibrin in alveolar space, interalveolar septa,

pneumonia).

• cause hemorrhage. 79

Bovine Pneumonic


80/122

Pasteurellosis/Mannheimiosis• Acute n ammat on, recru tment o arge num er o neutrop s rom c rcu at on

into affected lung tissue followed by activation of these cells via a respiratory burst

and release of degradative enzymes.

• The tissue is injury due to bystander effect.

• Bacterial components have the way to avoid injury by neutrophils.

– Polysaccharides (facilitate adherence colonization and likely invasion), inhibit

phagocytosis by neutrophils and disrupt complement mediated death of

bacteria – Outer membrane rotein chemotactic for neutro hils but when in contact

with neutrophils, they disrupt phagocytosis and intracellular killing of the

bacterium.

– LPS binds with cell membrane CD14 b2 inte rin and TLRs on alveolar

macrophage inducing

• the synthesis of proinflammatory cytokines

• Vascular injury80


81/122


82/122

Fig. 9‐71 Fibrinous bronchopneumonia (pleuropneumonia), pneumonic Mannheimiosis (Mannheimia haemolytica), right lung,

s eer. o e e cran oven ra pneumon a nvo v ng approx ma e y of the lung parenchyma. The lung is firm and swollen, and the pleura are covered with a thick layer of fibrin. (Courtesy Dr. A. López, Atlantic

.

82


83/122

Fig. 9‐72A Pneumonic Mannheimiosis (Mannheimia haemolytica), lung, steer. A, Cut surface. Interlobular septa (arrowheads) are notably distended by edema and fibrin. In the lung parenchyma are irregular areas of coagulativenecrosis (arrows) surrounded by a rim of inflammatory cells. B, Note a large irregular area of necrosis (N) of the

ulmonar arench ma. T icall these necrotic areas are surrounded b an outer dense la er of inflammator cells

(arrows). The interlobular septa are distended (arrowheads). Inset (bottom

right

corner) shows the typical elongated and basophilic appearance of degenerated neutrophils known as oat‐shaped cells. H&E stain. C, Note alveoli filled with fibrin (asterisks) and with neutrophils (N). The interlobular septa (IS) is distended with proteinaceous fluid. H&E stain. D,Mannheimia haemolytica produces leukotoxin (cytotoxic for ruminant leukocytes) and lipopolysaccharide. Note the accumulation of cells, chiefly neutrophils, in the alveoli. Also note the active hyperemia of acute inflammation of the a veo ar cap ar es. E sta n. , B, an courtesy Dr. . pez, t ant c eter nary o ege. D courtesy Dr. .F. Zac ary, College of Veterinary Medicine, University of Illinois.)

83


84/122

Fig. 9‐72A Pneumonic Mannheimiosis (Mannheimia haemolytica), lung, steer. A, Cut surface. Interlobular septa (arrowheads) are notably distended by edema and fibrin. In the lung parenchyma are irregular areas of coagulativenecrosis (arrows) surrounded by a rim of inflammatory cells. B, Note a large irregular area of necrosis (N) of the

ulmonar arench ma. T icall these necrotic areas are surrounded b an outer dense la er of inflammator cells

(arrows). The interlobular septa are distended (arrowheads). Inset (bottom

right

corner) shows the typical elongated and basophilic appearance of degenerated neutrophils known as oat‐shaped cells. H&E stain. C, Note alveoli filled with fibrin (asterisks) and with neutrophils (N). The interlobular septa (IS) is distended with proteinaceous fluid. H&E stain. D,Mannheimia haemolytica produces leukotoxin (cytotoxic for ruminant leukocytes) and lipopolysaccharide. Note the accumulation of cells, chiefly neutrophils, in the alveoli. Also note the active hyperemia of acute inflammation of the a veo ar cap ar es. E sta n. , B, an courtesy Dr. . pez, t ant c eter nary o ege. D courtesy Dr. .F. Zac ary, College of Veterinary Medicine, University of Illinois.)

84

Contagious bovine pleuropneumonia


85/122

(Mycoplasma mycoides var. Mycoides small colonies)• Pat ogenesis unc ear

– bacteria evades killing by phagosome‐lysosome fusion ?

– produce toxic molecules that injury and kill the cells?

– spread to blood vessels?

– causes vasculitis and thrombosis?

•

• Lesions: Fig. 4‐22

85

Contagious bovine pleuropneumonia


86/122

(Mycoplasma mycoides var. Mycoides small colonies)• Bacteria mem rane ipoprotein, a common

antigen of Mycoplasma mycoides var. Mycoides

may e nvo ve• Highly virulent strain could produce large

quantities of H2O2 that are cytotoxic for all cells

• H2O2 release appear to be correlated with adhesion of bacterium with cell membrane.

• Macro ha es ma s read bacterium via leukocyte trafficking systemically to lymph node and the joints

86


87/122

Fig. 4‐22A Contagious bovine pleuropneumonia. A, Thoracic cavity. The thoracic cavity is filled with a fibrinous pleural

e us on an t e v scera an par eta p eurae are covere y r n r nous p eur t s . so note t e areas o emorr age

affecting the pleurae and the subjacent lung. B, Transverse section of lung. Note the prominent interlobular septa filled with

fibrinous effusion and fibrin thrombi and additionally the area of hemorrhage (right half of the section). Infarcts with

pulmonary sequestra (not shown here) can occur in affected lung tissues likely arising from vascular injury leading to

n arct on.

, e

nter o u ar

septum

center s

e

w t

acute

n ammatory

ce s

m xe

w t

a

r nous e us on.

veo

are filled with highly proteinaceous edema fluid, fibrinous effusion, and acute inflammatory cells. There is extensive

necrosis of all tissues at the interface between alveoli and the interlobar septum (dark blue staining band). H&E stain. D,

Higher magnification of C. The dark blue color is attributable to necrosis of cells, including neutrophils leading to escape and

coagu at on o nuc e c ac s rom egenerate nuc e n t e n ammatory exu ate. veo are e w t e ema u an

acute inflammatory cells. H&E stain. (A and B courtesy Dr. D. Gregg, Plum Island Animal Disease Center and Noah’s Arkive,

College of Veterinary Medicine, The University of Georgia. C and D courtesy Dr. J. F. Zachary, College of Veterinary Medicine,

University of Illinois.) 87


88/122

Fig. 4‐22B Contagious bovine pleuropneumonia. A, Thoracic cavity. The thoracic cavity is filled with a fibrinous pleural

.




.

,

.




.





89/122


90/122

Fig. 4‐22D Contagious bovine pleuropneumonia. A, Thoracic cavity. The thoracic cavity is filled with a fibrinous pleural

e us on an e v scera an par e a p eurae are covere y r n r nous p eur s . so no e e areas o emorr age




n arc on.

, e

n er o u ar

sep um

cen er s

e

w

acu e

n amma ory

ce s

m xe

w

a

r nous e us on.

veo




coagu a on o nuc e c ac s rom egenera e nuc e n e n amma ory exu a e. veo are e w e ema u an





91/122

• arge quan es o e ema ox n an e a ox n are release into blood (bacterium proliferation in

circulation

– causing dysfunction and cell death of endothelial cells and barrier system,

– ox n ncrease e permea y o cap ary wa ,

– leading to edema, vasodilation, and hemorrhage in infected organ system.

• Toxin – disrupt the clotting cascade likely through massive

ac va on o an consump on o c o ng ac ors, – Un‐clotted blood at body orifices and within tissue and

or ans

91

炭疽


92/122

病

• pX01質體具有產生毒素基因，炭疽桿菌毒素在構

、、等同一類的AB毒素

• ，。

• 炭疽桿菌毒素可分為

– 保護抗原（protective antigen；簡稱PA）、

– ，屬於A，PA則屬於B。

92

炭疽


93/122

病

• PA+LF具有致死作用，

• – 可阻斷巨噬細胞的有絲分裂原活化蛋白激酶

（mitogen‐activated protein kinase），

– 干擾細胞內訊息傳遞，

– 可刺激巨噬細胞或淋巴球分泌α腫瘤致死因子（tumor necrosis factor‐α；簡稱TNF‐α）

– 及第1中介素（interleukin‐1）等細胞激素（cytokines），

– 。

93


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94

炭疽


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臨症狀與病變

• 人臨床症狀

• 人的感染可分

– 、

– 吸入型（即肺型）、 –

– 腦膜炎型。

95


96/122

Fig. 4‐23A Anthrax, ox. A, Because of the high fever, cadavers of cattle dying of anthrax decompose rapidly

with the usual result of excessive gas formation in the GI tract, abdominal distention and resultant “saw

orse

pos on

o

e

egs.

, e

sp een

s

en arge

an

oo y

sp enomega y,

oo y

sp een .

postmortem examination should not be performed on an animal suspected of dying from anthrax. Air‐dried

impression smears of blood from external orifices or from an ear vein can be stained and the bacterium

identified see Fi . 7‐135 . C, L m h nodes are also enlar ed and blood as a result of anthrax toxins that

destroy vascular endothelial cells (see Fig. 13‐53). Anthrax toxin can also cause severe injury to the intestines

(see Fig. 7‐135) and lungs. (A courtesy Dr. D. Driemeier, Federal University of Rio Grande do Sul, Brazil. B and

C courtesy Dr. J. King, College of Veterinary Medicine, Cornell University.) 96


97/122

Fig. 4‐23B Anthrax, ox. A, Because of the high fever, cadavers of cattle dying of anthrax decompose rapidly


” . , , .

postmortem examination should not be performed on an animal suspected of dying from anthrax. Air‐dried

impression smears of blood from external orifices or from an ear vein can be stained and the bacterium

identified (see Fig. 7‐135). C, Lymph nodes are also enlarged and bloody as a result of anthrax toxins that

destroy vascular endothelial cells (see Fig. 13‐53). Anthrax toxin can also cause severe injury to the intestines


C courtesy Dr. J. King, College of Veterinary Medicine, Cornell University.) 97


98/122

Fig. 4‐23C Anthrax, ox. A, Because of the high fever, cadavers of cattle dying of anthrax decompose rapidly


horse” position of the legs. B, The spleen is enlarged and bloody (splenomegaly, bloody spleen). A

postmortem examination should not be performed on an animal suspected of dying from anthrax. Air‐dried impression smears of blood from external orifices or from an ear vein can be stained and the bacterium

identified (see Fig. 7‐135). C, Lymph nodes are also enlarged and bloody as a result of anthrax toxins that

‐ . .


C courtesy Dr. J. King, College of Veterinary Medicine, Cornell University.)98


99/122

99


100/122

Fig. 7‐135A Necrohemorrhagic enteritis, intestine, alimentary anthrax, cow. A, Note the massive transmural hemorrhage and necrosis caused by anthrax toxin. B, Tissue impression. The light blue bacilli in the debris are Bacillus anthracis bacteria. Some bacilli have blunted ends (presumably spores). H&E stain. C, Tissue impression. Note the dark blue bacilli (Gram‐positive) in the debris. Gram stain. (A courtesy of Dr. D.

Driemeier, Federal University of Rio Grande do Sul, Brazil. B and C courtesy Drs. V. Valliand J.F. Zachar Colle e of Veterinar Medicine Universit of Illinois.100


101/122


102/122

• e acter um s a e to eva e t e ng mec an sms of neutrophils and macrophages (mechanism not

, , grow and replicate in macrophage and dendritic cells

• phagolysosome,

– ra id acidification of the ha osome

– LPS (a PAMP), a type IV secretion system

– Putative virulent determinates, cyclic b‐1,2 glucan, heat

shock proteins

– Encapulated smooth phenotype

102


103/122

• e ac er um sprea v a eu ocy es ra c ng systemically in macrophages, gain access to male

gland.

• placental trophoblast in placentomas and epithelium of reproductive tissues.• may infected fetal macrophages and spread into

fetus

• Pyogranulomatous reaction: chronic active reaction, macrophages and neutrophils

103

Fig. 4‐26A Brucellosis. Brucellosis is a disease in which the bacterium

initially targets lymphocytes and macrophages in mucosae‐associated

lymphoid tissues, regional lymph nodes, systemic lymph nodes, and

the s leen to re licate and row in number. It uses macro ha es to

spread to and through these tissues and then systemically to infect

cells and tissues in the placenta, sex organs of males and females, and

fetuses. Therefore brucellosis is initially and long term characterized

b h i ti l t l h d iti ith l


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b a chronic active o ranulomatous l m hadenitis with se uelae

that affect the reproductive systems. A, Boar, swollen testis. The testis

in enlarged due to chronic active pyogranulomatous inflammation.

Brucella spp. spread in macrophages via leukocyte trafficking from

l m hoid tissues s stemicall to the testis. B, The e idid mis can be

filled with pyogranulomatous exudate, which obstructs the flow of

spermatozoa and causes infertility. Infected animals can also serve as

carriers and spread the bacterium via sexual contact (also see Fig. 19‐

18 . C, Fetal cot ledons. Note the rou hened ranular ellow‐brown

surface of cotyledons (arrows) infected with the bacterium. This lesion

is caused by pyogranulomatous inflammation leading to severe

necrosis of the affected cotyledons. Normal cotyledons are dark red and have a smooth shiny surface. D, Fetal brucellosis, hepatomegaly

and fibrinous polyserositis. The bacterium is thought to be spread

from infected cotyledons to fetal organs via leukocytic trafficking in

fetal macrophage‐like cells. The bacterium causes extensive injury of

the vascular system and organs through inflammatory responses

induced in the fetus. (A courtesy Dr. C. Wallace, College of Veterinary Medicine, The University of Georgia; and Noah’s Arkive, College of

Veterinary Medicine, The University of Georgia. B courtesy Dr. K.

McEntee, Reproductive Pathology Collection, University of Illinois; and

Dr. J. King, College of Veterinary Medicine, Cornell University. C and D

courtesy Dr. K. McEntee, Reproductive Pathology Collection,

University

of

Illinois.) 104

Fig. 4‐26B Brucellosis. Brucellosis is a disease in which the

bacterium initially targets lymphocytes and macrophages in

mucosae‐associated lymphoid tissues, regional lymph nodes,

s stemic l m h nodes and the s leen to re licate and row in

number. It uses macrophages to spread to and through these tissues

and then systemically to infect cells and tissues in the placenta, sex

organs of males and females, and fetuses. Therefore brucellosis is

i iti ll d l t h t i d b h i ti


105/122

initiall and lon term characterized b a chronic active

pyogranulomatous lymphadenitis with sequelae that affect the

reproductive systems. A, Boar, swollen testis. The testis in enlarged

due to chronic active pyogranulomatous inflammation. Brucella spp.

s read in macro ha es via leukoc te traffickin from l m hoid

tissues systemically to the testis. B, The epididymis can be filled with

pyogranulomatous exudate, which obstructs the flow of

spermatozoa and causes infertility. Infected animals can also serve

as carriers and s read the bacterium via sexual contact also see Fi .

19‐18). C, Fetal cotyledons. Note the roughened granular yellow‐

brown surface of cotyledons (arrows) infected with the bacterium.

This lesion is caused by pyogranulomatous inflammation leading to

severe necrosis of the affected cot ledons. Normal cot ledons are

dark red and have a smooth shiny surface. D, Fetal brucellosis,

hepatomegaly and fibrinous polyserositis. The bacterium is thought

to be spread from infected cotyledons to fetal organs via leukocytic

traffickin in fetal macro ha e‐like cells. The bacterium causes

extensive injury of the vascular system and organs through inflammatory responses induced in the fetus. (A courtesy Dr. C.

Wallace, College of Veterinary Medicine, The University of Georgia;

and Noah’s Arkive, Colle e of Veterinar Medicine, The Universit of

Georgia. B courtesy Dr. K. McEntee, Reproductive Pathology

Collection, University of Illinois; and Dr. J. King, College of Veterinary

Medicine,

Cornell

University.

C and

D courtesy

Dr.

K.

McEntee,

Re roductive Patholo Collection, Universit of Illinois.

105


106/122

Fig. 4‐26C Brucellosis. Brucellosis is a disease in which the bacterium initially targets lymphocytes and macrophages in

mucosae‐associated lymphoid tissues, regional lymph nodes, systemic lymph nodes, and the spleen to replicate and grow in

number. It uses macrophages to spread to and through these tissues and then systemically to infect cells and tissues in the

placenta, sex organs of males and females, and fetuses. Therefore brucellosis is initially and long term characterized by a chronic active pyogranulomatous lymphadenitis with sequelae that affect the reproductive systems. A, Boar, swollen testis.

The testis in enlarged due to chronic active pyogranulomatous inflammation. Brucella spp. spread in macrophages via

leukocyte trafficking from lymphoid tissues systemically to the testis. B, The epididymis can be filled with pyogranulomatous

exudate, which obstructs the flow of spermatozoa and causes infertility. Infected animals can also serve as carriers and

spread the bacterium via sexual contact (also see Fig. 19‐18). C, Fetal cotyledons. Note the roughened granular yellow‐

brown surface of cotyledons (arrows) infected with the bacterium. This lesion is caused by pyogranulomatous inflammation

leading to severe necrosis of the affected cotyledons. Normal cotyledons are dark red and have a smooth shiny surface. D,

Fetal brucellosis, hepatomegaly and fibrinous polyserositis. The bacterium is thought to be spread from infected cotyledons

to fetal organs via leukocytic trafficking in fetal macrophage‐like cells. The bacterium causes extensive injury of the vascular

system and organs through inflammatory responses induced in the fetus. (A courtesy Dr. C. Wallace, College of Veterinary

Medicine, The University of Georgia; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia. B

courtesy Dr. K. McEntee, Reproductive Pathology Collection, University of Illinois; and Dr. J. King, College of Veterinary

Medicine, Cornell University. C and D courtesy Dr. K. McEntee, Reproductive Pathology Collection, University of Illinois.)106


107/122

Botulism and Tetanus

(Clostridium

botulinum and

C.

tetani)


108/122

(Clostridium botulinum and C. tetani )• o u sm, srup on o neuro rasm er ves c es

exocytosis at myoneural (flaccid paralysis)

. .,

• Tetanus, disruption of neurotransmitter vesicles ‐

junction

• These neurotoxin are roduced in anaerobic microenvironment, such as in necrotic tissue occurring in traumatic wounds, penetrating sole

o t e oo , gastric u cer in oa , • Gross and micro lesions are not observed

108


(Clostridium

botulinum and

C.

tetani )


109/122

( and )ranspor a on an r g n o e neuro ox n – Botulism, hematogenous, • Wound then circulation

• men ary a sorp on en c rcu a on• Neurotoxin in capillary then diffuse in the interstitial of lower peripheral nerve,

neural and muscular junction, enter the motor neuron through endocytoticvesicles

– Tetanus, retrograde axonal transportation• Wound, distal portion of neuron, endocytotic vesicles, transport into CNS,

then exocytosis into interstitial fluid of neural‐neural junction.• ree neuro ox n n e ce mem rane o n ory n erneuron o e sp na

cord, internalizes via endocytosis, act to disrupt the inhibitory neurotransimitters

• Mechanism of Disease: disru tion of neurotransmitter vesicles

exocytosis by disrupting synaptic fusion complex (Fig. 4‐27, 4‐28)

109


(Clostridium

botulinum and

C.

tetani )o u sm an e anus ox n ave eavy an g c a n a e ave


110/122

( and )o u sm an e anus ox n ave eavy an g c a n a e ave as typical A‐B toxin (diphtheria, cholera, pertussin, and shigellatoxin) compose of two units , a binding B domain that mediate

‐

domain (light chain) that serve as cleave protein within the target cells.

‐ , ‐ , neuron, cleave protein that form the synaptic fusion complex.

• This complex, formed by fusion of synaptic vesicles protein with ,

neurotransmitter vesicles into contact with neuronal cell membrane at the myoneural (botulism), and neural‐neural (tetanus)junction,

(acetylcholine) and inhibitory neurotansmitters (glycin and r‐aminobutyric acid (GABA), respectively.

110


(Clostridium

botulinum and

C.

tetani )y oma n o e anus ox n on y n s o n ory


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( )y ‐ oma n o e anus ox n on y n s o n ory interneurons and not other types of motor neuron (different type of glycosylphosphatidylinositol‐anchored proteins may be

.• Disruption of the synpatic fusion complex prevents the neurotransmitted vesicles from fusing with the membrane, which in

.

• Protein that form the synaptic fusion complex (SNARE proteins)

include – neurotansm tter ves c e prote n • such as vesicle‐associated membrane protein (VAMPs),

• synaptobrevin,

– presynap c p asma mem rane pro e n • Syntaxin

• Synatosomal‐associated protein (SNAP‐25)

111

ff f b l d


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• Different types of C. botulinum produce

different toxin (A‐G), and these t es tar et

and cleaves specific types of SNARE proteins.

blood‐brain barrier, therefore, neural‐neural junction functions in the CNS remain intact.

• Severe clinical si ns but no ross and micro

lesions

112

• s an acronym er ve rom


113/122

• s an acronym er ve rom (Soluble NSF Attachment Protein) REceptor" that

with more than 60 members (found in yeast and mammalian cells

• The primary role of SNARE proteins is to mediate

vesicle fusion through full fusion exocytosis or kiss‐and‐run fusion exocytosis. That is, the exocytosis of cellular transport vesicles with the

compartment (such as a lysosome).

113


114/122

Fig. 4‐27 Mechanism of

myoneural junction

dysfunction in botulism.

Note that botulinum toxin

reac es t e myoneura

junction via the circulatory

system. (Courtesy Dr. J. F.

,

Veterinary Medicine,

University of Illinois.)

114


115/122

Fig. 4‐28 Mechanism of

neural‐neural junction

dysfunction in tetanus. Note

that tetanus toxin reaches the

neural‐neural junction via retrograde axonal transport.

The selectivity of tetanus


116/122

The selectivity of tetanus

toxin for inhibitory

interneurons is likely

mediated by the expression of different

glycosylphosphatidylinositol‐

anc ore prote n s on

different types of neurons.

The B‐domain of tetanus

the type of

glycosylphosphatidylinositol‐

on inhibitory interneurons.

(Courtesy Dr. J. F. Zachary,

Medicine, University of

Illinois.) 116


117/122

Listeriosis

(Listeria

monocytogenes)• n que oca on: ra n s em es ons per vascu ar


118/122

n que oca on: ra n s em, es ons, per vascu armicroabscesses with active hyperemic and/or

pattern.

• , the oral cavity.

• Bacterium colonization enter nerve ending, retrograde axonal transport in cranial nerve (i.e., trigeminal cranial nerves that

terminate in t e rain stem pons, me u ar oblongata, and proximal cervical spinal cord)

118

Listeriosis

(Listeria

monocytogenes)n er ng ce s roug en ocy os s an en ocy c ves c es o non‐


119/122

g g y yphagocytic cells.

• Bacterial internalization, the entry process, is mediated by

n erna ns ype an a u ze os ce recep or ‐ca er n, a transmembrane glycoprotein.

• Initially, does not cause inflammation due to BBB is intact. Neuron s perm ss ve an a ow acter um pro erat on n t e cytop asm.

• Listeriolysin, a virulent determinates, inhibit immune response.

• Enou h number of bacterium after c to lasm roliferation read to infect other cells, affect cytoskeleton, polymerization and depolymerization of host cell actin filaments

• Surface rotein actA ro el them into another cells via actin

polymerization, pseudopod formation, invagination of adjacent cells, double membrane of endocytotic phagocytic vesicles.

• Random rocess not cell s ecific

119


120/122

Fig. 4‐29 Mechanism of infection in listeriosis. Listeria monocytogenes propels itself via actin

polymerization (Listeria actin‐based motility) within a membrane pseudopod into cell

membranes of adjacent neural cells forming invaginations of the membrane that ultimately

result in double‐membrane endocytotic phagocytic vesicles.120

Listeriosis

(Listeria

monocytogenes)• Dou e mem rane o en ocytot c p agocyt c ves c es, yse y enzymes o t e


121/122

following, then bacterium is release into cytoplasm of newly infected cells.

– Listeriolysin O

– Phospholipase C – lecithinase

• , , ,

varied types of nerve cells, like neuron and microglial cells.

• Infection of and injury to endothelial cells of capillaries initiates the inflammation, ,

ensues.

• Bacterium infects endothelial cells with active expression of adhesion molecules as

, ,

binding, both components of acute inflammation

– P and E selectin

– Interce u ar a es on mo ecu es ICAM‐1

– Vascular‐cell adhesion molecule (VCAM‐1)121


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Fig. 14‐88A Listeriosis, medulla, cow. A, Microabscesses. Note the areas of faint blue discoloration in this subgrossmagnification of the medulla (arrows). The less well‐defined blue areas are aggregates of neutrophils (microabscesses), and the blue linear lesions are perivascular cuffs. Listeria monocytogenes, the causative agent, uses retrograde axonal transport via the cranial nerves to enter the CNS and localize in the medulla (brainstem) and proximal cervical spinal cord. The lesion is rarely visible on gross observation. H&E stain. B, Early microabscesses (arrows) and inflammation are the result of inflammatory mediators that have injured axons (arrowheads) and will lead to Wallerian degeneration, seen here at the stage of swollen eosinophilic axons. H&E stain. C, Listeria monocytogenes, which is Gram‐positive (blue coccobacilli), can sometimes be detected in microabscesses in a histologic section stained with a Gram stain. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) 122

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Mechanism of Microbial Infections