Download Microbial Infection

Microbiology: Host-Parasite Relationships (Jackson)
PART 1: INFECTION AND TRANSMISSION
Portals of Entry:
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Skin: primary barrier to infection but some pathogens can traverse it
Arthropod vectors inject pathogens into humans
Strep and staph bind to fibronectin in wounds and indwelling devices
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Lungs:
Up to 10,000 microorganisms are introduced into the lungs per day
Pathogens need to overcome ciliary action:
o Adapt Strong Adhesins:
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Rhinovirus uses capsid protein for attachment to ICAM-1-type molecule

Mycoplasma pneumonia attaches to neuramic acid on host respiratory epithelium
o Paralyze Ciliary Action:
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Bordetella pertussis produces tracheal cytotoxin

Influzena virus infection causes ciliated cell dysfunction
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Gastrointestinal Tract:
Intestinal pathogens express receptor-specific adhesions
o Receptor specificity dictates colonization site and pathogenesis
o Adhesions typically located on the tip of bacterial pili to overcome cell-cell repulsion
Some microbes enter through antigen sampling cells of Peyer’s patches
Resident microflora are the best defense for GI tract:
o Disruption can lead to opportunistic infections
o Antibiotic-associated enterocolitis is caused by overgrowth of resident opportunist
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Urogenital Tract:
Vaginal Pathogens: must colonize mucosa or take advantage of localized injuries
Urethral Pathogens: primary defense is flushing action of urine; mucus lining of the bladder and sIgA also
provide defense against UTIs
o Female more susceptible to UTIs because of shorter urethra
o UTI pathogens (E.coli) have adhesins that permit ascending infections

Adhesins specialized for urinary epithelium
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Inflammatory response to UTI causes pathology
Mechanisms of Transmission:

Different Mechanisms of Transmission:
Respiratory
Fecal-oral
Sexual contact
Vector-borne (malaria), person-person, or animal-person (rabies)
Vertebrate reservoir (plague)

Routes of Infection (see picture pg. 4):
Some pathogens transiently infect at a primary layer and rapidly shed (influenza and Shigella)
Some pathogens invade deeper tissues and may be shed from secondary site (Varicella)

Vertical vs. Horizontal Transmission:
Vertical: from parent to offspring, via placenta, sperm, ovum, blood or milk
Horizontal: from person to person

Infectious Dose (ID50):
ID can vary: can range from very small (ie. only 10 cells) to very large (ie. 10,000,000 cells)
Route of Infection Important:
o Aerosol is the most effective means of person-to-person transmission
o Successful infections depend on receptors and localized defenses
o (Ex) Rhinovirus Route of Entry:

A single rhinovirus particle in the nasal cavity causes successful infection

200 rhinovirus particles are required for infection if inoculation occurs in the pharynx

Stability of Organism in Environment: another factor involved in transmission
Respiratory and sexually transmitted pathogens are unstable: need person-to-person contact
Spore producing organisms: spores can persist in the environment for years

Microbe Replication Rates: another factor involved in transmission
Can take minutes (E.coli) or days (Mycobacteria spp.) to double
Genetic Determinants of Infection:
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Susceptibility to Infection is Influenced by Genetic Determinants in the Host:
Host Specificity:
o Some pathogens only infect humans or closely related primates (measles, Shigella)
o Others are capable of infecting a wide range of hosts (rabies)
Intraspecies Genetic Determinants Dictate Susceptibility:
o Individuals heterozygous for sickle cell trait are less susceptible to malaria

Sickle cell trait due to aa substitution in Hb (HbS)

Result is Plasmodium falciparum parasite (causes malaria) is unable to utilize the altered Hb
o Individuals homozygous for sickle cell trait are susceptible to other infections (due to functional
asplenia)

Susceptible to infection with encapsulated bacteria, which are usually filtered by the spleen
o Positive selection for sickle cell trait occurs amongst populations in endemic areas

Unique Sets of Microbial Genes Encode Virulence Factors:
Virulence Factor Genes for Various Bacteria:
o Adhesins (uropathogenic E.coli)
o Invasion attributes (Shigella spp.)
o Antigenic drift of M protein (S.pyogenes)
o Environmentally responsive regulon (cholera toxin production)
o Antigenic variation of pili (Neisseria)
PART 2: MICROBIAL DEFENSES AND PERSISTENT INFECTIONS
Microbial Defenses:

Mechanisms Bacteria and Protozoa Use to Resist Complement Mediated Killing:
Capsule (S.pneumoniae)
Long LPS O antigen (Salmonella typhi)
Coating with inverted Ab (S.aureus and S.pyogenes)
Membrane-bound enzymes can degrade complement

Mechanisms Bacteria and Protozoa Use to Resist Phagocytosis:
Release toxins that kill phagocytes (S.aureus and S.pyogenes)
Catalase to resist oxidative killing (S.aureus)
Prevent phagosome fusion with lysosome (Mycobacterium tuberculosis); still taken up by phagocyte
Escape from phagolysosome and live in cytoplasm (Trypanosoma cruzi); still taken up by phagocyte
Defenses against cytokines:
o Secretion of IL-2 receptors that prevent T cell activation during malaria (Plasmodia spp.)
o Secretion of enzymes that cleave IL-2 and IFN-gamma (Pseudomonas aeruginosa)
Persistence:
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Persistent Infections:
Highly adapted parasites can live in host for long periods (years)
o Shed of persistent microbes into the environment may be:

Continuous (ie. shed of Hepatitis B virus into the blood)
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Intermittent (ie. tubercle bacillus)
Viruses are well adapted to persistent infections (can silently infect host)
o Herpesvirus may latently infect DRG becoming re-activated later
o Herpesvirus may be shed in saliva secretions and infect others
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Strategies Microbes Use to Evade Host Immune Response:
Concealment of Antigens:
o Some viruses interfere with the display of Ags on the surface of infected cells (HIV)
o Skin or secretory duct colonizers readily shed, making them less susceptible to circulating lymphocytes
o Molecular Mimcry (CMV, strep pyogenes):

Bacteria and protozoa synthesize molecules that cross react with human proteins

Basis for autoimmune disease following infection
o Pathogens can coat themselves with host proteins

S.aureus covers itself with Fc receptors to bind Ig molecules
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Viruses can secrete Fc receptors to bind Igs on the surface of infected cells
o Induction of tolerance or anergy
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CMV avoids inducing an immune response by infecting during embryonic life
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Coccidiodes immitis induces anergy by producing large quantities of Ag
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Antigenic Variation:
o Variation of surface components during infection (confounds immune response to pathogen)
o Influenza Virus:

Antigenic Drift: repeated point mutations in hemagglutinin and neuaminidase genes
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Antigenic Shift: recombination of different strains to form a new strain, leading to pandemics
o Parasites may carry repertoire of unexpressed surface protein genes (Neisseria and the African
Trypanosomes)
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Movement of gene 3’ to promoter permits its expression (cassette mechanism)

Sequential recombination permits the expression of different Ags during the life cycle
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Antigenic switching may lead to relapses during infection
Immunosuppression:
o Can be caused by infection of T cells, B cells and macrophages by viruses
o Bacterial toxins disrupt normal immune response

Some toxins lyse lymphocytes, cleave Ig, and inactivate complement
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Staph and strep superantigens disrupt normal immune response
o Herpesvirus encodes a cytokine homologue that interferes with the immune system
PART 3: PATHOLOGIC CONSEQUENCES OF INFECTION
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Bacterial Exotoxins: hydrolytic enzymes that degrade DNA or CT, promoting spread
Cytolysins: disrupt cell membrane and cause it to lyse
Cytotoxins: classic bacterial toxins with AB subunit structure
o B subunit binds receptor on a cell (gets A into the cell)
o A subunit is an enzyme that does something to your cell

Most transfer ADP-ribose group from NAD to a substrate
o Effects:
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Inhibit protein synthesis (diphtheria toxin)
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Increases cytosolic cAMP levels (cholera toxin)
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Disrupt nerve transmission (tetanus and botulinum toxin)
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Bacterial Endotoxins: Gram (-) LPS
Effects: induces fever and vascular collapse (shock); primarily due to action of cytokines (IL-1 and TNF)
Note: staph and strep superantigens induce similar physiological responses
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Damage Response:
You do not want the host response to be too weak or too strong (results in extensive microbial-induced cell
damage at both of these extremes)
Want a response of moderate intensity to have minimal host damage