Transcript 07 M301 Mech of Patho 2011 - Cal State LA

Mechanism of
Pathogenicity
Host vs Parasite:
Advantage Parasite
Pathogenicity and Virulence
 Pathogenicity - ability of MO to cause
disease
 Virulence - degree of pathogenicity;
disease-evoking power of MO
 Measurement - MO’s virulence tested
experimentally in animals or in lab
 LD50 (Lethal Dose) - number MO (or amount
toxin) needed kill 50% inoculated hosts (test
population)
 ID50 (Infectious Dose) - number MO needed to
cause disease in 50% test population
Infection, Virulence,
Disease
 Lower the LD50 or ID50, the more virulent
the MO
 Likelihood disease results from infection:
 Increasing numbers of MO
 Decreasing resistance of host
Host Disease Factors
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Susceptible (overall health)
Gender (female, male)
Nutritional status (balanced, diet)
Weather and climate (seasons, hot, cold, moisture)
Fatigue (lack of rest, sleep)
Age (very young, old)
Habits (active/inactive, over/under weight)
Life style (physical, mental, social, spiritual)
Pre-existing illness (inherited, chronic, infection)
Emotional disturbance (stress, anger)
Chemotherapy (legal, illegal drugs)
Disease By MO
 Must gain entrance to host
 Portal of entry - avenue by which
MO enters host
 Include:
 Mucous membrane
 Skin
 Parenteral route
Entry Mucous Membrane:
RT, GI Tract
 Respiratory Tract – easiest, most frequent;
via aerosols, direct mucous membrane
contact (i.e., influenza, pneumonia, TB,
measles, smallpox)
 Gastrointestinal Tract – ingested via food,
water, dirty hands; entry fecal-oral route:
 Survive HCl (stomach), bile and digestive
enzymes (small intestine)
 Exit in feces (i.e. polio, infectious hepatitis,
typhoid fever, bacillary dysentery, amoebic
dysentery, cholera)
Entry Mucous Membrane:
GU Tract, Eye
 Genitourinary Tract – Via close contact:
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Treponema pallidum (syphilis)
Neisseria gonorrhoeae (gonorrhea)
Trichomonas vaginalis (trichomoniasis)
Herpes simplex virus type II (genital herpes)
 Conjunctiva of the eye – Via direct
contact:
 Haemophilus aegyptius - contagious
conjunctivitis, “pinkeye”
 Chlamydia trachomatis – trachoma, may lead to
blindness
Entry: Skin and Parenteral
 Skin – few MO gain entry through hair
follicles and sweat ducts
 Necator americanus (hookworm)
 Schistosoma sp. (schistosomiasis) actually bore
through skin
 Parenteral route – MO directly deposited
into tissues when skin or mucous membrane
barriers penetrated or injured
 Tetanus
 Subcutaneous mycoses (fungal infections)
Multiple Portal of Entry
 Many MOs have preferred portal of entry and
only cause disease through that route:
 Salmonella typhi only cause disease when it comes
in through the GI tract
 Some MOs initiate disease from variety of
portals of entry (flea/tick bite, ingestion,
aerosol, contact infected animal):
 Yersinia pestis – bubonic plague
 Francisella tularensis – tularemia, rabbit fever
MO Attachment
 MO must attach or
adhere to host tissues
 Attachment via surface
projections called
adhesin, colonization
factor, ligand (often
glyco or lipoprotein) on
MO which bind
specifically to receptor
(carbohydrate,lipid,
protein) on host cell
Pili (Fimriae)
 Bacterial adhesin may be fimbrial or
afimbrial in nature
 E. coli has ligand on pili which attach
it to intestinal epithelial cell
Ligand
 Neisseria gonorrhoeae has ligand on pili
that attach to epithelial cells in GU tract
 Streptococcus mutans adheres to surfaces
of tooth enamel via extracellular
polysaccharide that it secretes
 Streptococcus pyogenes binds to
fibronectin on surface of epithelial cells
via M protein and lipoteichoic acid in its
cell wall
Virus Ligand
 Sendai virus
glycoprotein project
from surface of virus
envelope to attach to
cell receptor
 Rhinovirus proteins
(VP1, VP2, VP3) form a
“canyon” buried in
surface of the virus
for attachment to cell
receptor (ICAM-1)
MO Resistance of Host
Defense
 MO produce substances that allow it to
disseminate
 Capsule - interfere cells function in
phagocytosis of MO
 M protein -Streptococcus pyogenes resist
phagocytosis
 IgA protease - produced by some MO,
cleave IgA (important in host preventing
MO attachment)
MO Resistance
 Antigenic variation - to escape host immune
defense recognition
 Resistant to complement-mediated bacteriolysis
– sterically hinder attachment of complement
components
 Survive inside phagocytic cells - prevent
phagosome-lysosome fusion or resistant to
lysosomal enzymes
 Escape the phagosome - before phagosomelysosome fusion
 Downregulate MHC class I expression - avoid
immune recognition
 Downregulate CD4 expression of T lymphocytes
– interfere with immune response
Bacteria Blocking
Phagosome - Lysosome
Fusion
Bacteria Escape Before
Phagosome – Lysosome
Fusion
MO Resistance
 Immunologically privileged site (macrophage) protected from immune defense
 Shed antigen or decrease expression antigen prevent immune recognition
 Immunosuppress the host – hinder immune
defense
 Siderophore - acquire iron (nutrition factor)
needed by host
 Hypothermic factor - decrease host temperature
 Leukocidan - kill WBCs, hinder immune defense
MO Resistance
 Coagulase - fibrin clot to
wall off MO, protect
from host defense
 Protein A (S. aureus),
Protein G (S. pyogenes) bind the Fc portion of
IgG, hinder PMN
opsonization
 Apoptosis (program cell
death) substance target host macrophage
 Flagella - allow MO to
move away from
phagocytes
MO Resistance: Preventing
uptake of bacteria
 Secrete molecules
that block uptake of
MO by phagocyte (by
depolymerizing actin)
 Substance delivered
directly to phagocyte
via bacteria Type III
secretion system
MO Dissemination
 Kinase - break down fibrin clots (in host
inflammatory reaction) that prevent MO
from spreading
 Hemolysin - destroy RBCs, tissue cells; many
act as porin to alter membrane permeability
 Hyaluronidase - dissolves hyaluronic acid
which hold cells together
 DNAse - salvage nucleotides; also help MO
to spread by breakdown of viscous nucleic
acid which hinder movement
MO Dissemination
 Collagenase - break down collagen which forms
framework of muscle
 Lipase - break down cell lipids
 Necrotizing factor - kill host cells
 Apoptosis (program death) substance –destroy
tissue, cell
 Actin - recruited for intracellular movement
MO Disease: Direct Damage
 Attachment, penetration and multiplication
may cause direct damage
 Penetration may involve:
 Outer membrane proteins
 Type III secretion systems deliver substances
induce uptake of bacteria in nonphagocytic cells
 Note: previously Type III secretion system also
deliver substances that block uptake of MO by
phagocytic cells
Bacteria Secretion System
 Type II and Type III export proteins through
inner and outer membranes
of MOs
 Type II - general
secretory pathway,
secretes substances
outside the bacteria;
similar pathway found in
Gram(+)
 Type III - act as molecular
syringe to inject
substances, including
toxins, directly into target
cells; found in Gram (-)
bacteria (Salmonella,
Shigella, EPEC)
MO Direct Damage:
Toxins
 Toxins can also cause direct damage
 Poisonous substances produced by MO
 May be entirely responsible for its
pathogenicity
 Toxigenicity: capacity to produce a toxin
 Toxemia: refers to symptoms caused by
toxins in the blood
 Two types: Exotoxin and Endotoxin
MO Exotoxins
 Most, but not all, produced by Gram(+)
 Secreted via Type II secretion system
 Soluble in body fluids and transported
rapidly throughout body
 Protein whose gene may be bacterial,
carried on plasmid, or encoded in lysogenic
bacteriophage
Botulinum Exotoxin
 Among the most lethal toxins known to
humans
 One mg botulinum toxin kill 1 million guinea
pigs
 Cause of the disease and disease specific
 Host produce antitoxins (antibodies) which
provide immunity against effects of toxin
 Inactivated by heat, formaldehyde, iodine
or other substances to produce toxoids
when injected no longer cause disease, but
stimulate body to produce protective
antitoxin antibodies (vaccine)
Exotoxin
Structure
 Many have an
A (toxic effect) /
B (binding)
structure
Botulinum Neurotoxin: Flaccid
Paralysis
 Clostridium botulinum
 Toxin not released until death of MO
 Acts at neuromuscular junction to prevent
transmission of nerve impulse leading to
flaccid paralysis and death from
respiratory failure
Tetanus Neurotoxin: Spastic
Paralysis
 Clostridium tetani
 Causes excitation of CNS leading to
spasmodic contractions and death from
respiratory failure
 Also called “lockjaw”
Diphtheria Cytotoxin
 Corynebacterium diphtheriae
 Inhibits protein synthesis in eukaryotic
cells and can cause death in patient
Enterotoxin
 Staphylococcal enterotoxin Staphylococcus aureus; induces vomiting
and diarrhea by preventing absorption
of water in intestine
 Others – Escherichia, Salmonella,
Vibrio, Shigella causes enteritis,
cholera, dysentery
Vibrio
Enterotoxin
 Vibrio cholerae
 Alters water and electrolyte
balance in intestine leading
to very severe, life
threatening, watery diarrhea
MO Endotoxins
 On outer membrane of most Gram(-)
 Lipid A toxic part of LPS
(lipopolysaccharide)
 Exert effects when bacteria die and LPS
released
 All produce same signs and symptoms, i.e.
not disease specific
 Symptoms include fever (pyrogenic
response), weakness, generalized aches
and pains, and sometimes shock
 Antibodies against endotoxin do not
protect host from their effects
 Only large doses are lethal; leads to
“septic shock”
Endotoxins: Pyrogenic
Response
Exotoxin versus Endotoxin
Exotoxins versus Endotoxins
MO Indirect Damage:
Hypersensitivity
 Occur due to
immunopathologic
mechanisms
 Immediate
hypersensitivity
reactions (due to
IgE antibodies)
MO Immunopathogenesis
 Cross-reacting or auto antibody form:
 Bind to host tissue, activate complement resulting in damage
to tissue
 Immune complexes are antigen-antibody complexes
that form in bloodstream:
 Can trigger severe inflammatory reactions resulting in
damage to host tissues
 May get trapped in capillaries and trigger complement
cascade with resulting tissue damage
Portal of Exit
 MO needs to have portal of exit
 Usually related to part of body infected
 Most common are: respiratory tract and
gastrointestinal tract
 May also exit: genital tract, urine, skin,
biting insect, or contaminated needle
Summary: Mechanism of
Pathogenicity
Class Assignment
 Textbook Reading: Chapter 2 B.
Pathogenesis of Infection
 Key Terms
 Learning Assessment Questions