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Microbiology: Host-Parasite Relationships (Jackson) PART 1: INFECTION AND TRANSMISSION Portals of Entry: 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 Lungs: Up to 10,000 microorganisms are introduced into the lungs per day Pathogens need to overcome ciliary action: o Adapt Strong Adhesins: 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: Bordetella pertussis produces tracheal cytotoxin Influzena virus infection causes ciliated cell dysfunction 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 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 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: 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: 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) 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 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 Viruses can secrete Fc receptors to bind Igs on the surface of infected cells o Induction of tolerance or anergy CMV avoids inducing an immune response by infecting during embryonic life Coccidiodes immitis induces anergy by producing large quantities of Ag - 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 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) Movement of gene 3’ to promoter permits its expression (cassette mechanism) Sequential recombination permits the expression of different Ags during the life cycle 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 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 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: Inhibit protein synthesis (diphtheria toxin) Increases cytosolic cAMP levels (cholera toxin) Disrupt nerve transmission (tetanus and botulinum toxin) 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 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