HostPathogen Interactions Close encounters of the pathogen kind

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Host-Pathogen Interactions-Close encounters of
the pathogen kind
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Cellular Microbiology

• Bacteriology
• The study of bacteria
• Early discipline did not address the aspects of
  the environment on bacterial factors
• Absent (unobserved) features of pathogens
• The discipline of cellular microbiology addresses
  host-pathogen interactions to elucidate
  pathogenesis (the creation of a pathologic
  condition).
• Pathogen A microorganism that causes disease
• Disease Absence of ease uneasiness, discomfort
  inconvenience, annoyance disquiet, disturbance
  trouble
• Bacterial pathogens often infect animals and
  plants
• Interact, invade, colonize and infect hosts
• Culminating in disease (but not always)
• Aggressive, Opportunistic, Quiescent
• Infection The agency, substance, germ, or
  principle by which (an infectious) disease is
  communicated or transmitted morbific influence

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Human Pathogens of Significance

• Many although certain pathogens are still global
  threats or major etiologic agents of life
  threatening disease
• Pandemic strains (cholera, typhoid)
• Antibiotic resistance (endless battle that health
  professionals are currently losing)
• Chronic pathogens associated with genetic
  disorders
• Opportunistic pathogens (taking hold with
  entrance wounds, immune deficiency, age)

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Diversity and niches

• Enterics
• Extracelluar, intracellular, invasive, shedding
• Respiratory
• Lung, tracheal, bronchial infections
• Sepsis
• Blood infections (serum resistant!)
• Skin infections (wounds, cuts)

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Pathogenic Escherichia coli

• Related but distinct from commensal E. coli
  within the intestinal flora
• Pathogenic strains of E. coli
• Six categories
• EPEC, EHEC, ETEC, EIEC, EAEC, DAEC
• UPEC (Uropathogenic E. coli bladder infections,
  UTIs)
• Novel virulence genes
• Plasmids
• Adherence, colonization factors
• Antibiotic resistance
• Toxins
• Shiga toxin

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Shiga toxin

• Secreted multimeric AB type toxin from certain
  E. coli strains
• STEC (Shiga toxin) /VTEC (Vero toxin) positive
  strains (not all!)
• Holotoxin binds a host cell receptor via B
  units
• A unit is internalized (into the host cell
  cytoplasm)
• Highly potent toxin that depurinates and cleaves
  rRNA inhibits protein synthesis, induces
  apoptosis (programmed cell death)

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Attaching and Effacing

• Intestinal E. coli attach to gut intestinal cells
  and efface (smooth out) microvilli
• Remodel actin cytoskeleton using injected toxins
• Type III secretion system injects a bacterial
  synthesized receptor molecule in addition to
  other toxins to subvert host cell function
• The pathogen can colonize the gut, escape immune
  reponses, proliferate and eventually be shed into
  the environment (diarrhea)
• Mechanism of diarrhea is not understood, but ion
  imbalance and intestinal cell disruption are
  involved

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Attaching and Effacing (A/E)
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Hemolytic Uremic Syndrome(HUS)

• Kidney failure due to intravascular damage
• Often seen in infants, young children with EHEC
  O157H7 infections (Shiga toxin ve)
• Walkerton, Ontario
• Believed that increased burden on kidneys due to
  cell death causes glomerulitis (damage to kidney)
• Low urine output, increased toxicity
• Antibiotic therapy worsens condition!
• Patients often have permanent kidney damage
• Dialysis or kidney transplant

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Uropathogenic E. coli (UPEC)

• Shiga toxin negative
• P pili and type I fimbrae are involved in binding
  to host cells within the urinary tract
• Massive influx of PMNs to bladder, cytokine
  production, pathogen ascends to kidneys
• Toxins and proteases assist colonization, cause
  tissue damage
• Pathogen can enter bloodstream causing sepsis
• Severe fever and malaise

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Shigella (EIEC)

• Shiga toxin producing E. coli
• Highly invasive pathogen
• Causative agent of dysentery (severe diarrhea,
  intestinal damage)
• Not travelers diarrhea, but often seen in
  tropical countries, poor water quality
• Possesses large virulence plasmid
• Encoding a T3SS and other virulence determinants

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Model of Shigella infection
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Membrane ruffling/invasion

• Shigella has an active and directed mechanism to
  invade M cells (intestine)
• Not phagocytosis
• Injection of Type III effector IpgB1
• activates Cdc42 and Rac1 (Rho GTPases) to promote
  membrane ruffling (via actin remodeling)
• IpgB1 activity is involved in Shigella invasion
  to M cells (movie)

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Shigella mediates Actin based motility within
cells

• Upon invasion, Shigella is taken up by
  macrophages (phagocytosis)
• Induces cell death (apoptosis)
• Escapes these dying cells to re-enter the
  epithelial intestinal layer
• Shigella protein IcsA (surface associated)
  mediates actin based motility within host cells
• IcsA coated latex beads also polymerize actin
  within cells (movie)

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Model of Shigella infection
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Points to consider

• Diversity in pathologies caused by highly related
  pathogens
• Clues to virulence factors
• Genome sequencing of isolated pandemic strains
• Environment and host
• Free living vs colonization of host
• Gene expression patterns, nutrient acquisition
• Getting to the infective niche
• Enteric must pass through stomach (acid pH)-must
  have acid tolerance
• Invasion or extracellular (avoidance of the
  immune response
• Or resistance to host response

CELLULAR MICROBIOLOGY
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Upcoming Lectures

• Salmonella, Vibrio, Listeria
• Legionella, C. difficile, Chlamydia
• Tuberculosis, MRSA, Streptococci
• Review / Practice Quiz (not for marks) during
  class time
• Reach for the Top/Real time keypad based
  interactive system