Host-Parasite Interactions Flashcards
Principal Pathogen
- Regularly causes disease in a proportion of susceptible hosts who have normal specific and non-specific defense mechanisms
- Ex: Streptococcus Pneumoniae, Neisseria meningitidis
Commensal Organism
- Lives within or on the surface of the host, almost never perturbing homeostasis
- Ex: Diphtheroids, Lactobacilli
Opportunistic Pathogen
- Rarely causes disease except in hosts who have defects in specific or non-specific defense mechanisms
- Ex: Pseudomonas Aeruginosa, Staphylcoccus Epidermidis
Virulence
- A measure of the tendency of an organism to cause disease
- LD50 - dose of microorganism that will kill 50% of a susceptible population
Koch’s Postulates
1) the organism must be found in all cases of disease but generally not in healthy animals.
2) the organism must be isolated from diseased animals and grown in pure culture
3) the disease must be reproduced when the isolated organism is inoculated into susceptible animals
4) the organism must be isolated in pure culture from the experimentally infected animals
Kock’s Postulate (Molecular)
1) the gene(s) encoding the phenotype should be associated with pathogenic strains
2) inactivation of the gene(s) results in a reduction in virulence
3) restoration of the gene(s) into the avirulent mutant re-establishes virulence
Goal of all organisms
- Proliferation
- in the case of infectious agents, this requires both multiplication within a host and transmission to another host
Outcomes of Infection
- asymptomatic (most common)
- disease (reflects details of survival strategy by microbe)
- Death (unfavorable for both host and microbe)
Microbial Factors in Emergence of New Infections
- Short generation time
- Mutations
- Acquisition of new genetic elements
- Changes in vector distribution
Host Factors in Emergence of New Infections
- Changes in behavior
- Expanding populations
- Increased travel
- Contamination of environment
- Food and Water distribution
- Immunosuppression
Infectious Cycle
- Entry
- Establishment
- Persistence
- Damage
- Exit
Entry
- Entry sites
- Overcoming barriers both anatomical/functional and ecological
Anatomical Barriers to Microbe Entry
- Skin (thick, dry, acidic, constant shedding)
- Mucosa (mucin, motility, sIgA)
- Respiratory tract (hair, mucocilia, lysozyme, cough/sneezing)
- Alimentary Tract (saliva, acidic pH, digestive enzymes, sIgA, shedding)
- GU Tract (urine flow, pH)
Ecological Barriers to Entry
- Vast Microbiome
- Density of surface area
Salmonella infection through inflammation
- inflammation induced by Salmonella converts S2O3 into S4O6 via NO/ROS from PMNs
- confers a selective advantage to increase colonization within the gut out competing the microbiome
Establishment
- requires adherence
- a result of the specific molecular interaction between microbial adhesins and receptors on the epithelium
- non-adherent mutants are generally avirulent
Adherence - Role of the host
- host polymorphisms play major role in disease susceptibility
- surface carbohydrates including blood group antigens can alter risk of recurrent UTIs and norovirus infection
Biofilm
- composed of bacteria and ECM on a foreign body
- constitutes a site protected from phagocytes and the actions of antibiotics
- Staphylococcus Epidermidis can become established in biofilm
Persistance - Avoidance of host defenses
- Complement evasion
- Invasion
- Avoidance of phagocytosis
- Survival in the phagocyte
- Antigenic Variation
- Inactivation of antibodies
- Iron acquisition
Neisseria Meningitidis
- binds factor H
- Results in un-regulated complement activation by avoiding opsonization and contributes to vascular damage
Cellular Invasion - Trigger
- microbe engages host signaling proteins that regulate actin and causes the cell to form ruffles that engulf the organisms
- Ex: Salmonella and Shigella
Cellular Invasion - Zipper
- tight binding of bacterial ligand to a receptor that is coupled to the cytoskeleton results in recruitment of more receptors which in turn bind to ligand
- eventually the organism is completely surrounded by the host membrane
- Ex: Yersinia pseudotuberculosis, Y. enterocolitica, and Listeria monocytogenes
Type III Secretion Systems
- prevalent on gram negative pathogens
- allows delivery of virulence factors directly into the cytoplasm of host cells (triggered by contact with host cells)
- mediates invasion, avoidance of phagocytosis, and cytotoxicity
- Ex: Salmonella, Shigella, Yersinia, Pseudomonas, and some E. Coli
Inhibition of phagosome/lsysosome fusion
- Legionella pneumophila
- Toxoplasma gondii
- histoplasma capsulatum
Survival in phagocytic environment
- Leishmania
- Coxiella Burnetii
Antigenic Variation
- avoiding immune system by changing surface components recognized by thehost
- Neisseria Gonorrheaa posses several different alleles of opa genes; changes in opa expression occur with high frequency in the bacterial population
Antibody inactivation
- Protein A (staph Aureus)
- -binds immunoglobulins
- -inhibits phagocytosis
- -causes B cell apoptosis
- -inhibits immune response
Many mucosal pathogens make Ig proteases
Iron Scavenging
- Iron required for microbe survival
- transferrin receptors or Siderphores used to get iron
Siderophores
- small molecules secreted by bacteria that compete with host iron-binding proteins for iron, and bind to receptors on the bacterial membrane which in turn transport iron across the membrane
Host Damage
- Direct
- -Exotoxins (proteins (typically enzymes) liberated by growing bacteria) - B subunit binds specifically to cellular receptor; A subunit enters cell and causes characteristic effect
- Indirect
- -superantigens
- -endotoxins
Diphtheria Toxin
- single polypeptide chain that is cleaved to form A and B subunits
- B subunit binds to epithelial growth factor like precursor and is taken up by membrane via clatherin coated pits
- Acidification of endosome changes conformation to activate A subunit
- A subunit catalyses the transfer of ADP ribosyl group to NAD to elongation factor 2 causes protein synthesis to halt and cell death
Shiga Toxin
- produced by Shigella Dysenteriae
- 5 identical B subunits and a single A
- B subunit binds to globotrioacyl ceramide
- toxin enters endosome and is transported retrograde to ER
- A subunit catalyzes the depurination of adenine4324 of the 28S ribosomal subunits halting protein synthesis and resulting in cell death
Membrane Damaging Toxins
- Direct pore forming toxins (hemolysins)
- phospholipases - contain enzymes that hydrolyze phospholipids
Cholera Toxin
- produced by Vibrio Cholerae and heat labile protein of enterotoxigenic E. Coli
- B subunit binds to glycolipid GM1 ganglioside
- A subunit catalyzes the ADP ribosylation of Gs protein, locks it in GTP bound active state, which in turns activates adenylate cyclase
- increase in cAMP ultimately leads to increase in CFTR in the membrane leading to chloride secretion
Toxins that affect small GTPases
- large cytotoxins of Clostridium Difficile
- single peptide with binding, translocation, and enzymatic domains
- catalyze the transfer of glucose from UDP-glucose to Rho, Rac, and CDC42 causes them to become inactive
- results in depolymerization of actin, cell rounding, and loss of tight junctions causing diarrhea
Damage due to Host
- superantigens
- Endotoxin
Endotoxin
- lipid A component of LPS associated with gram negative bacteria
- binding of LPS-binding protein to CD14 receptor activates pro-inflammatory cytokines
- leads to activation of complement cascade, and release of inflammatory mediators
- can lead to DIC and shock
