Bacterial Pathogenesis

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Bacterial Pathogenesis Infectious disease -
cycle of biological interactions. Most
interventions in preventing infectious disease do
not directly involve the physician. By
understanding the complete process of bacterial
pathogenesis, you will be better equipped to aid
in intervention and prevention at the numerous
steps other than by administering antibiotics or
vaccines.
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Bacterial Pathogenesis There is order to the
universe! Your favorite movie Clichés Learn
the basic story lines and key points The 100 x
100 grid
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A. Definitions and concepts 1. Disease -
damage caused by presence of microorganisms or
their products (can be inapparent or without
observable symptoms at a point in time). 2.
Colonization - presence of microorganisms without
disease at that point. This term applies to
surfaces only, i.e., the blood cannot be
colonized and host cells with intracellular
infection are not colonized.
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3. Infection - an important but sometimes
ambiguous term! a. When referring to a patient,
"infection" always means disease (opposite of
colonization). For example, if a person has
Staphylococcus aureus in their nose, but has no
symptoms, they are colonized. As soon as
symptoms appear (e.g., an inflamed hair follicle
with pus and pain), they have an infection. b.
When referring to a specific site in the body,
infection can mean the simple presence of
microbes without referring to disease or not. In
the example immediately above, we could say that
the staphylococci had "infected" the nares before
they actually caused disease.
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c. Because of this semantic issue, we will make
sure that the term is clarified on exams. If you
are ever in doubt of what it means during
discussions of patients or diseases, you should
ask. We will make every attempt to define the
term with modifiers such as "asymptomatic",
"inapparent", etc., when appropriate.
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4. Carrier state - colonization with a
pathogen 5. Pathogen - any organism that has
the potential to cause disease 6. Overt
(strict, primary) vs. Opportunistic
pathogens a. overt pathogens have a high
probability of causing disease in an otherwise
healthy host b. opportunistic pathogens have a
low probability and usually require a debilitated
or compromised host
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B. Normal flora 1. Definition - frequently
found on or within the body of healthy
persons 2. They can cause disease under the
right conditions (endogenous infection/disease)
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3. Some tissues, organs are dense with normal
flora, others are normally sterile a.
colonized sites i. alimentary/intestinal
tract ii. upper respiratory tract iii.
distal genitourinary tract iv. skin b.
normally sterile sites i. blood ii.
CSF iii. interstitial fluid and spaces iv.
lymph
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4. Normal flora and disease a. breach of
tissues/barriers b. endocarditis with oral
streptococci c. peritonitis after bowel
trauma 5. Protective effects of normal
flora a. priming immune system i.
specific/adaptive - antibodies against
nonpathogens that cross-react with
pathogens ii. innate - integrity of gut and
production of cytokines b. exclusion of
pathogens from colonized surfaces c.
production of nutrients - vitamin
K d. Probiotics
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6. Considerations of normal flora in
medicine a. Manipulations (by YOU) that enable
normal flora to cause disease (surgery,
chemotherapy, antibiotic use) b. presence of
bacteria doesn't always mean disease is ongoing
or that antibiotics need to be prescribed
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C. Functions/stages of pathogens/disease 1. enco
unter 2. entry 3. spread (/-) 4. multiplicatio
n 5. evasion of host defenses 6. damage 7. outc
ome a. transmission to new host (/-) b.
recovery or not check out www.mgm.ufl.edu/gulig/
mmid/pathogenesis/index.htm
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1. Encounter a. Exogenous vs. endogenous
infection and normal flora b. sources food,
water, air, body fluids (sex, etc.), insects,
animals, fomites (things) c. Is there a
reservoir in other animals or in the
environment? d. Can we eliminate the source or
reservoir?
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2. Entry - where in/on the body we initially
contact the bacteria a. surface of skin b.
mucosal membrane open to outside i.
ingestion ii. inhalation iii. sex c.
direct inoculation (trauma, bite, injection,
surgery)
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d. virulence function adherence i. mucosal
surface with moving fluid, bacteria must stick or
be washed away ii. specific ligand-receptor
interactions - not glue iii. virulence
factors ? structures pili/fimbriae,
fibrillae ? surface proteins ?
extracellular matrix polysaccharide and
lipoteichoic acid of oral streptococci
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3. Spread - movement from surface through
tissues and body a. not all bacteria spread to
cause disease b. bacteria cannot penetrate
intact skin c. mucosal surface is usually
first barrier
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d. virulence functions i. cellular invasion -
invading into host cells intracellular ?
professional phagocytes (macrophages and PMN) by
phagocytosis ? non-phagocytes bacterial
mediated endocytosis resulting in a
phagosome/endosome (can involve type III secreted
proteins - injected into host cell affecting
actin polymerization) ? some bacteria escape
the phagosome into the cytoplasm
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ii. tissue invasion - through tissues, either
through cell or between cells ? degrade
extracellular matrix ? disrupt tight
junctions e. use of host cells to move through
blood or lymph (intracellular pathogens)
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4. Multiplication a. We dont encounter
enough bacteria to cause damage and disease
without their increase in number in your
body b. variety of nutritional environments in
the body i. intestinal lumen, blood,
urine ii. intracellular bacteria- cytoplasm
vs. phagolysosome
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c. inoculum size and disease ? threshold for
bacterial inoculum to replicate to high enough
numbers to cause disease d. incubation period
? how long it takes the inoculum to result in
clinical damage e. acquisition of Fe from
transferrin, lactoferrin, or other Fe-binding
proteins (e.g. siderophores as virulence factors)
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5. Evasion of host defenses ? consider where
the bacteria are and which defenses they will
encounter a. Complement - beyond mucosal
surface i. functions ?opsonization -
C3b ?lysis of gram-negatives - C5-9 (Membrane
Attack Complex MAC) ?inflammation - C3a,
C5a
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ii. virulence mechanisms for evasion of
complement ?do not bind and/or activate
complement - polysaccharide capsules ? cause
inhibition of activation and amplification
cascade - bind factor H (M protein of
streptococci) ?keep activation away from
membrane - smooth LPS ?degrade complement -
secrete proteases
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b. Phagocytes - beyond mucosal surface i.
EXTRACELLULAR vs. INTRACELLULAR pathogens
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ii. extracellular antiphagocytic functions
?inhibit recruitment - inhibit complement,
cytokines ?kill the phagocytes toxins
?prevent phagocytosis - prevent opsonization,
prevent binding (carbohydrate capsules)
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iii. intracellular pathogen functions
?inhibit phagosome-lysosome fusion ?escape
phago(lyso)some into cytoplasm ?inhibit
oxidative burst ?resist antimicrobial
functions
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c. Antibodies i. antigenic mimicry
microbial surface components look like host
?polysialic acid capsule of Neisseria
meningitidis ii. antigenic cloaking - bind
host proteins to bacterial surface ?protein A
of Staphylococcus aureus binds IgG
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iii. antigenic variation - change antigenic
composition ?pili of Neisseria
gonorrhoeae iv. antigenic variety - numerous
serological types among strains in the world
(each strain is antigenically stable) ?M
protein of Streptococcus pyogenes v. degrade
antibodies ?IgAse of Haemophilus influenzae
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d. Cell-mediated immunity ?alter host response
from cell-mediated (Th1) to antibody (Th2)
response - Mycobacterium leprae
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6. Damage a. cytotoxicity (kill host cells)
necrosis vs. apoptosis programmed cell
death) i. from outside toxins ii. from
inside - intracellular growth iii. apoptosis -
type III secreted (injected) proteins b.
pharmacology/physiology (alter host cell
function) - toxins
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c. host immune/inflammatory response (host
causes damage to itself) i. nonspecific
inflammation, abscess, cytokines ii. specific
immune response - antibodies (Rheumatic
fever - Streptococcus pyogenes) -
cell-mediated (Reiters syndrome - bacterial heat
shock proteins)
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d. Toxins i. Endotoxin vs. Exotoxin ii.
Endotoxin (LPS) from gram-negatives only
?damage is caused by host through macrophages
producing cytokines (TNF-a, IL1, IL-6)
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iii. Exotoxins (proteins) ?several have A-B
motif Aactive portion, Bbinding portion
?lytic (lyse host cells - creating pores or
lipase activity) ?cytotoxic (kill cells by
altering functions, e.g., protein synthesis)
?pharmacological (alter host cell function, e.g.,
cAMP levels)
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?extracellular enzymes (degrade extracellular
matrix, e.g., protease, lipase, hyaluronidase)
?superantigens (stimulate host T cell responses
in antigen-independent manner (binding to Vß of T
cell receptor) resulting in cytokine cascade -
similar to endotoxin) ?type III secreted
proteins (injected into host cell) - induce
apoptosis, affect actin polymerization, etc.
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7. Outcome a. What happens to patient i.
without treatment? ii. with treatment? b.
Does the organism move to a new host
(contagious)?
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7. Outcome transmission to new host? a.
completes the cycle to lead to new encounter -
step 1 b. not all pathogens spread to new
human host (e.g., Legionella pneumophila) c.
not all pathogens are contagious - humans may be
dead end hosts
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d. most bacterial pathogens are contagious -
some examples of how i. fecal-oral ii.
sexually transmitted iii. droplet spread
(respiration) iv. skin-skin v. fomite vi.
vertical - in utero, at birth
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Relationship of pathogenesis and immunity