Mechanism of Bacterial Pathogenesis

미생물학교실

권 형 주

학습목표

1. 감염체의 침입경로를 4 가지 이상 열거하고 설명한다 .2. 병원체의 전파경로를 3 가지 이상 열거하고 설명한다 .3. 세균의 병원성인자를 설명한다 .4. 내독소와 외독소의 차이점을 비교한다 .5. 숙주의 비특이적 방어기전을 3 가지 이상 열거하고 설명한다 .6. 다음 용어를 설명한다 . 1) Infection 2) Virulence 3) Pathogen 4) Pathogenicity 5) Pathogenicity island 6) Biofilms

o Normal flora : many of which serve important functions for their hosts. : aid in the digestion of food, produce vitamins (e.g., vitamin K). : can protect the host from colonization with pathogenic microbes. : gastrointestinal (GI) tract, mouth, skin, upper respiratory tract

o Virulent bacteria : promote their growth in the host at the expense of the host's tissue or organ function. : Disease results from the damage or loss of tissue or organ function or the development of host inflammatory responses.

o Opportunistic bacteria : take advantage of preexisting conditions that enhance the susceptibility of the patient, such as immunosuppression, to grow and cause more serious disease. : Pseudomonas aeruginosa infects burn victims and the lungs of patients with cystic fibrosis. : patients with the acquired immune deficiency syndrome (AIDS) are very susceptible to infection by intracellularly growing bacteria, such as the mycobacteria.

o Infection : Multiplication of an infectious agent within the body : Multiplication of pathogenic bacteria (even if the person is asymptomatic) is deemed an infection (not in normal flora)o Pathogen : A microorganism capable of causing diseaseo Pathogenicity : The ability of an infectious agent to cause duseaseo Virulence : The quantitative ability of an agent to cause disease : Virulence involves invasion and toxigenicityo Virulence factor : enhance the ability of bacteria to cause diseaseso Signs and symptoms of a disease : systemic responses : Bacterial strain and inoculum size - different for different bacteriao Pathogenicity island : components of virulence factors are often encoded together - large chromosomal region - coordinated expression of several genes ex) o SPI-2 pathgenicity island (Salmonella) - acidic pH (phagocytic vesicle) : toxic proteins o N-acyl homoserine lactone (AHL) - Pseudomonas: Biofilm formation - Polysaccharide production

Bacterial Virulence Mechanisms

• Adherence • Invasion • By-products of growth (gas, acid) • Toxins • Degradative enzymes • Cytotoxic proteins • Endotoxin • Superantigen • Induction of excess inflammation • Evasion of phagocytic and immune clearance • Capsule • Resistance to antibiotics • Intracellular growth

How infectious diseases are transmitted

- Direct transmission methods- Indirect transmission

- Animal human : Yersinia pestis (plaque) - rodent, rodent fleas : Bacillus anthracis (anthrax) - raw hair from infected animals- Environment human : ingestion - Clostridium perfringens (gastroenteritis) - C. botulinum (botulism) : Wounds(soil) - C. pefringens (gas gangrene) - C. Tetani (tetanus)- Food contamination : E. coli- Seafood, drinking water : Vibro cholerae- Human human : Mycobacterium tuberculosis (tuberculosis) - Cough and production of aerosols : Staphylococcus aureus - on hands

- Emerging and reemerging infectious disease

Entry into the Human Body

Route Examples

Ingestion Salmonella sp., Shigella sp., Yersinia enterocolitica, enterotoxigenic Escherichia coli, Vibrio sp., Campylobacter sp., Clostridium botulinum, Bacillus cereus, Listeria sp., Brucella sp.

Inhalation Mycobacterium sp., Nocardia sp., Mycoplasma pneumoniae, Legionella sp., Bordetella, Chlamydia psittaci, Chlamydia pneumoniae, Streptococcus sp.

Trauma Clostridium tetani

Needlestick Staphylococcus aureus, Pseudomonas sp.

Arthropod bite Rickettsia, Ehrlichia, Coxiella, Francisella, and Borrelia spp., Yersinia pestis

Sexual transmission

Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum

Bacterial Port of Entry Body surfaces as sites of microbial infection

Colonization, Adhesion, Invasion

Microbe Adhesin ReceptorStaphylococcus aureus LTA UnknownStaphylococcus sp. Slime UnknownStreptococcus, group A LTA-M protein complex FibronectinStreptococcus pneumoniae Protein N-acetylhexosamine-galEscherichia coli Type 1 fimbriae D-Mannose Colonization factor antigen

fimbriaeGM ganglioside 1

P fimbriae P blood group glycolipidOther Enterobacteriaceae Type 1 fimbriae D-MannoseNeisseria gonorrhoeae Fimbriae GD1 ganglioside

Treponema pallidum P1, P2, P3 Fibronectin

Chlamydia sp. Cell surface lectin N-acetylglucosamineMycoplasma pneumoniae Protein P1 Sialic acidVibrio cholerae Type 4 pili Fucose and mannose

LTA : lipoteichoic acid

Colonization

o Legionella : Lung, cannot tolerate high Temp. (35 oC)o defect natural defence mechanism, new portal of entry - cystic fibrosis : reduction of ciliary mucoepithelial function, altered mucosal secretions - S. aureus, P. aeruginosa, colonization in lungs

Bacterial biofilms

o aggregate of interactive bacteria attached to a solid surface (artificial valves, catheters)

- sticky web of polysaccharide

- binds the cell together, to the surface

: Pseudomonas aeruginosa – airway infection in cystic fibrosis patients

: Staphylococcus epidermidis, Staphylococcus aureus

- infection of central nervous catheters, eye infections (contact lenses)

: Dental plaque

o Biofilm matrix : protect the bacteria from host defenses and antibiotics

Pathogenic Actions of Bacteria

o TISSUE DESTRUCTION

: By-products of bacterial growth - production of acids, gas (fermentation) - substances that are toxic to tissue : M any bacteria release degradative enzymes - break down tissue - providing food for the growth of the organisms - promoting the spread of the bacteria, especially if blood vessels are involved. : Clostridium perfringens - normal flora of the GI tract - opportunistic pathogens - infection in oxygen-depleted tissues and cause gas gangrene. - produce enzymes (e.g., phospholipase C, collagenase , protease, hyaluronidase ) - several toxins, - acid and gas from bacterial metabolism, which destroy the tissue.

: Staphylococci - hyaluronidase , fibrinolysin, and lipases. - streptolysins S and O, hyaluronidase , DNAases, and streptokinases - facilitate the development of infection and spread into the tissue

o TOXINS

Toxins - bacterial products that directly harm tissue or trigger destructive biologic activities. - degradative enzymes : cause lysis of cells, - specific receptor-binding proteins : initiate toxic reactions in a specific target tissue. - cell wall components : systemic response (e.g., fever) by promoting the inappropriate release of cytokines. Exotoxins Endotoxins

1) Excreted by living cell; high conc. in liquid medium

2) Produced by both G(+) and G(-) baceria

3) Polypeptides with a MW of 10,000-900,000

4) Relatively unstable; toxicity often destroyed rapidly by heating at above 60oC)

5) Highly antigenic; stimulate formation of high-titer antitoxin. Antitoxin neutralizes toxin

6) Converted to antigenic, nontoxic toxoids by formalin, acid, heat etc. Toxoids are used to immunize (eg, tetanus toxoid)7) Highly toxic; fatal to animals in g quantities or less8) Usually bind to specific receptors on cells9) Usually do not produce fever in the host

10) Frequently controlled by extrachromosomal genes (eg, plasmids)

1) Integral part of the cell wall of G(-) bacteria. Released on bacterial death and in part during growth

2) Found only in G(-) bacteria

3) LPS complexes. Lipid A portion probably responsible for toxicity4) Relatively stable; withstand heating at above 60oC for hours without loss of toxicity

5) Weakly immunogenic

6) Not converted to toxoids

7) Moderately toxic; fatal for animals in 10-100 g quantities8) Specific receptors not found on cells (????)9) Usually produce fever in the host by release of IL-1 and other mediators10) Synthesis directed by chromosomal genes

o EXOTOXINS

- Exotoxins : proteins - produced by gram-positive or gram-negative bacteria : cytolytic enzymes : receptor-binding proteins : alter a function or kill the cell. : In many cases, the toxin gene is encoded on a plasmid - tetanus toxin of C. tetani, - LT(heat-labile) and ST (heat-stable)toxins of enterotoxigenic E. coli : lysogenic phage (Corynebacterium diphtheriae and C. botulinum. : cytolytic enzyme, α-toxin (phospholipase C) produced by C. perfringens, - breaks down sphingomyelin and other membrane phospholipids, resulting in cell lysis

o Enterotoxins

: protein toxin released by a microorganism in the intestine: chromosomally encoded exotoxins: often heat stable, low MW, water soluble : cytotoxic and kill cells by altering the apical membrane permeability of the mucosal (epithelial) cells of the intestine wall: increased cAMP, increased calcium ion conc. intracellularlly : diarrheao Escherichia coli O157:H7 o Clostridium perfringens o Vibrio choreao Staphylococcus aureus o Yersinia enterocolitica o Shigella dysenteriae

o Mode of action of dimeric A-B exotoxins

o Superantigen

- TCR-MHC interaction without specific antigen

- Cytokine storm : IL-1, TNF, IL-12

- Life-threatening autoimmune-like responses

: Toxic shock syndrome toxin of S. aureus

: Staphylococcal enterotoxins

: Erythrogenic A or C of S. pyrogenes

o ENDOTOXIN AND OTHER CELL WALL COMPONENTS

o Lipopolysaccharide (LPS) : endotoxin. : gram-negative bacteria : Firmly bound to the cell surface : released only when the cells are lysed : powerful activator of acute-phase and inflammatory reactions : The lipid A portion of LPS is responsible for endotoxin activity. - Endotoxin is not the same as exotoxin - only gram-negative bacteria make endotoxin

o Endotoxin-like pyrogenic acute-phase responses- Peptidoglycan -Teichoic -lipoteichoic acids, are released, and these stimulate.

Endotoxin-Mediated Toxicity

• Fever • Leukopenia, followed by leukocytosis • Activation of complement • Thrombocytopenia • Disseminated intravascular coagulation • Decreased peripheral circulation and perfusion to major organs • Shock • Death

Immunity to bacteriaMechanisms of immunity are related to bacterial surface structure: Four main types of bacterial cell wall ; - Gram-positive bacteria, -Gram-negative bacteria - Mycobacteria, -Spirochaetes: Outer lipid bilayer of G(-) bacteria - Lyse membrane: complement cytotoxic cells: Other types of bacteria - Phagocytosis: Outer surface of the bacterium - Fimbriae, fragellae covered by a protective capsule phagocytes, complement 작용 방해 Targets for the antibody response

Mechanism of immunity are related to bacterial mechanisms of pathogenicity

Patterns of pathogenicity-Toxicity without invasiveness : Corynebacterium diphtheriae, Vibrio cholerae Pathogenicity depends on toxin production Neutralizing antibody-Invasiveness without toxicity : Pathogenicity does not depends on single toxin Immunity requires killing-Most bacteria are intermediate between these extremes

Mechanism for escaping host defense

Pathogenic bacteria may avoid the effects of antibody

- Neisseria gonorrhoeae

Pathogenic bacteria can avoid the detrimental effects of complement