Download 슬라이드 1

Mechanism of Bacterial Pathogenesis
미생물학교실
권 형 주
학습목표
1.
2.
3.
4.
5.
6.
감염체의 침입경로를 4가지 이상 열거하고 설명한다.
병원체의 전파경로를 3가지 이상 열거하고 설명한다.
세균의 병원성인자를 설명한다.
내독소와 외독소의 차이점을 비교한다.
숙주의 비특이적 방어기전을 3가지 이상 열거하고 설명한다.
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 disease
o Pathogenicity
: The ability of an infectious agent to cause dusease
o Virulence
: The quantitative ability of an agent to cause disease
: Virulence involves invasion and toxigenicity
o Virulence factor
: enhance the ability of bacteria to cause diseases
o Signs and symptoms of a disease
: systemic responses
: Bacterial strain and inoculum size
- different for different bacteria
o 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
Bacterial Port of Entry
Route
Ingestion
Examples
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
Body surfaces as sites
of microbial infection
Colonization, Adhesion, Invasion
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
Microbe
Staphylococcus aureus
Staphylococcus sp.
Streptococcus, group A
Streptococcus pneumoniae
Escherichia coli
Other Enterobacteriaceae
Neisseria gonorrhoeae
Treponema pallidum
Chlamydia sp.
Mycoplasma pneumoniae
Vibrio cholerae
LTA : lipoteichoic acid
Adhesin
LTA
Slime
LTA-M protein complex
Protein
Type 1 fimbriae
Colonization factor antigen
fimbriae
P fimbriae
Type 1 fimbriae
Fimbriae
P 1, P 2, P 3
Cell surface lectin
Protein P1
Type 4 pili
Receptor
Unknown
Unknown
Fibronectin
N-acetylhexosamine-gal
D-Mannose
GM ganglioside 1
P blood group glycolipid
D-Mannose
GD1 ganglioside
Fibronectin
N-acetylglucosamine
Sialic acid
Fucose and mannose
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
: Many 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
1) Integral part of the cell wall of G(-) bacteria.
Released on bacterial death and in part during growth
2) Produced by both G(+) and G(-) baceria
2) Found only in G(-) bacteria
3) Polypeptides with a MW of 10,000-900,000
3) LPS complexes. Lipid A portion probably
responsible for toxicity
4) Relatively stable; withstand heating at above 60oC for
hours without loss of toxicity
4) Relatively unstable; toxicity often destroyed
rapidly by heating at above 60oC)
5) Highly antigenic; stimulate formation of
high-titer antitoxin. Antitoxin neutralizes toxin
5) Weakly immunogenic
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 mg quantities or less
8) Usually bind to specific receptors on cells
9) Usually do not produce fever in the host
6) Not converted to toxoids
10) Frequently controlled by extrachromosomal genes
(eg, plasmids)
7) Moderately toxic; fatal for animals in 10-100 mg quantities
8) Specific receptors not found on cells (????)
9) Usually produce fever in the host by release of IL-1
and other mediators
10) Synthesis directed by chromosomal genes
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
: diarrhea
o Escherichia coli O157:H7
o Clostridium perfringens o Vibrio chorea
o Staphylococcus aureus
o Yersinia enterocolitica
o Shigella dysenteriae
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 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 bacteria
Mechanisms 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