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Infectious Disease: Unit 1 > Intracellular Bacterial Infections > Flashcards

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Advantages of intracellular lifestyle

  • Nutritional:
    • Pathogens avoid competition for space and nutrients with other microbes
  • Downregulate genes important for citric acid cycle - rely on hosts for those
  • Protection from immune system:
    • Avoid a number of innate and humoral defenses
    • Lack of sterilization allows some bacteria to lay dormant for decades, only to emerge under immunosuppressive conditions
  • Such protection allows easy dissemination around the body

Disadvantages of intracellular lifestyle within phagocytic cells

  • Can be eaten up and digested by cell
  • Phagolysosome: membrane-enclosed organelle that forms when phagosome fuses with lysosome
  • After fusion, food particles/pathogens contained within phagosome usually digested by enzymes contained within lysosome
    • Phagolysosome formation follows phagocytosis
  • Harsh environment encountered inside phagocytes + slow growth characteristic of some intracellular pathogens –> chronicity of many of these infections

Advantages of residing within non-phagocytic host cell

  • Limited phagocytic and bactericidal activity by host cell
  • Free ATP, free food, some good enzymes to play with and nothing is trying to actively kill it = good life.

Strategies used by different intracellular pathogens to avoid antimicrobial defenses

  • NADPH oxidase complex inhibition: prevents formation of complex
    • e.g. Legionella pneumophila
  • Detoxify reactive O2 species
    • e.g. Salmonella
  • Escape into cytoplasm from phagosome
    • e.g. Listeria
  • Increase natural resistance associated macrophage protein (NRAMP) homologues to help maintain nutrients within cell
  • Limit expulsion of Fe2+ by phagosome
    • Activated phagocytes usually reduce concentrations of iron available to intracellular pathogens to levels non-compatible with life

Antibiotic considerations of intracellular bacteria

  • Intracellular location of some microbes: critical aspect for failure of some abx for treatment of pathogens from infected hosts
  • Intracellular activity of abx depends on:
    • Penetration of eukaryotic membrane
    • Subcellular localization
    • Deleterious interactions with intracellular milieu, including pH
    • Abx susceptibility of intracellular pathogen
  • Weak base abx (aminoglycosides, macrolides) concentrated within lysosomes by pH-dependent mechanism
    • Preferential localization within lysosomes and partial inactivation by acidic pH: major disadvantages
  • Lack of peptidoglycan in cell wall of chlamydiae + intracellular lifestyle = poor activity of b-lactams

Intracellular pathogens that escape into cytosol

  • Listeria lyses phagocytic vacuole, escaping into cytosol
  • Advantages:
    • Access to large amounts of nutrients
    • Minimize exposure to antimicrobial defenses associated within vesicles/phagolysosomes
  • Disadvantages:
    • Cytosolic antimicrobial peptides + cytosolic inducible NO synthase can target them
    • Cytotoxic CD8+ T cells can lyse infected cells expressing microbial peptides on MHC I
  • Intracellular movement: once in cytosol, Listeria hijacks actin (polymerizes) and uses it to motor around cytosol as well as invade neighboring cells without being exposed to extracellular compartment

Intracellular pathogens that remain in vacuoles: fusogenic

  • Fusogenic = fusion of phagosome with lysosome
    • Bug is taken up and goes through entire maturation ultimately ending up in phagolysosome
  • Coxiella burnetii, obligate intracellular Gram (-) bacterium
    • Only intracellular pathogen to reside within phagolysosome
  • Nascent phagosome matures through endocytic pathway, eventually acquiring properties of lysosomes
  • Pathogen-containing vacuole acidifies
  • Coxiella not cytopathic –> reaches very high numbers within single vacuole

Intracellular pathogens that remain in vacuoles: non-fusogenic

  • Several intracellular pathogens contained in membrane-bound compartments that avoid fusion with lysosome
  • Mycobacterium, Legionella, Chlamydia
  • No processing of bacteria to put on MHC
  • Causes granuloma formation

Genetic basis for classification of obligate vs. facultative intracellular pathogens

  • Facultative microorganisms:
    • Capable of both intra- and extracellular growth
  • Obligate intracellular pathogens
    • Have established such an intimate relation with their host that they cannot reproduce outside intracellular environment
    • Loss of essential biosynthetic metabolic pathways = obligate dependency of host cells

Obligate intracellular pathogens

  • Chlamydia spp.
  • Coxiella burnetii
  • Ehrlichia spp.
  • Mycobacterium leprae
  • Rickettsia spp.

Facultative intracellular pathogens

  • Bartonella spp.
  • Brucella spp.
  • Francisella tularensis
  • Legionella pneumophilia
  • Listeria monocytogenes
  • Mycobacterium spp.
  • Nocardia spp.
  • Salmonella enterica
  • Shigella spp.
  • Yersinia

Mnemonic: Listen Sally Yer Friend Bruce/Bart Must Leave Now

Listeria, Salmonella/Shigella, Yersinia, Francisella, Brucella/Bartonella, Mycobacterium, Legionella, Nocardia


Zipper vs. trigger mechanisms contributing to invasion and dissemination of intracellular pathogens

  • Can be taken by professional and non-professional phagocytes by zipper or trigger mechanism
  • In both cases, reorganization of actin cytoskeleton results in changes at membrane surface, allowing uptake of bacteria
  • Zipper:
    • Tight interaction between bacterial cell surface ligands and host cell receptors –> closure of host cell surface around bacterium
  • Trigger:
    • Bacterial products induce cell surface to ruffle, projecting membrane extensions that surround bacteria
    • Products secreted by type III secretory systems of Salmonella and Shigella induce this kind of uptake