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Non-typhoidal Salmonella, • Describe what non-typhoidal Salmonella (NTS)…

- - - - Human-restricted
    - - Fecal - Oral
    - - Systemic enteric fever
    - - Gall bladder
      - Possible chronic carriers
  - - - Broad
      - Zoonotic
    - - Gastroenteritis
      - Invasive
    - - Rare chronic carriage
    - - Animal products
      - Zoonotics
- - - - Invasive
      - Recurrent
      - Systemic
    - - Fever
      - Sepsis ± Shock
    - - HIV
      - Infants / Young
      - Malnutrition
      - Malaria
      - Sickle cell disease
      - Elderly
    - - High mortality
      - Common relapse
- - - - Amino acid decarboxylases
        
        Glutamate / Arginine systems
        
        Consumes protons to maintain cytoplasmic pH
      - Proton pumps
        
        Actively expels H+
        
        Maintains interior pH
    - - Acid-shock proteins triggered
      - Protection against acidic pH
    - - LPS modification
      - Vi capsule
      - Reduced acid penetration
    - - Raised local pH of stomach acid
      - Improves survival through the gastric barrier
  - - - Distal ileum
      - Colon
    - - Factors
        
        Abundant receptors
        
        Lymphoid tissues
        
        Slower flow
      - Favours
        
        Adherence
        
        Invasion
  - - - Fimbriae & Adhesins
        
        Attaches and invades M cells
        
        Direct invasion of enterocytes
        
        Secondary
        
        After M-cell entry
      - M cells
        
        Thinner mucus layer
        
        Fewer digestive enzymes
        
        Active transcytosis of particles
        
        Particles to immune tissues
      - Peyer's patches
        
        Innate response
        
        iNTS entry
    - - Encodes
        
        Type 3 section system 1 (T3SS-1)
        
        Active at intestinal surface
      - Injection
        
        Bacterial effector proteins
        
        Into epithelial cells
      - Membrane ruffling
        
        Forced intake
        
        Injects actin-modifying effectors
      - NTS-filled vesicle
        
        "Wavelike" effect
        
        Engulfs bacteria
        
        Membrane-bound NTS filled vesicles
      - Result
        
        Enables bacterial uptake into non-phagocytic enterocytes
    - - SopB
        
        Activates chloride secretion
        
        Increased fluid into gut lumen
      - SopE / SopE2
        
        Triggers strong pro-inflammatory signalling
      - SipA / SipC
        
        Stimulates cytokine release
  - - - Neutrophils & Macrophages
      - ROS & Nitrogen released
      - Converts thiosulfate into tetrathionate
        
        Thiosulfate is abundant in host gut
    - - ttr operon
      - Tetrathionate respiration
        
        Terminal electron acceptor
      - Competitive advantage
        
        Normal gut commensals can't use tetrathionate
    - - Microbiome dysbiosis
  - - - SifA
        
        Maintains vacuole membrane integrity
        
        Promoters long membrane tubule formation
        
        Sifs
      - SseJ
        
        Remodels vacuole lipids
        
        Lyosomes
        
        Blocks fusion
      - Result
        
        Allows SCV to become a protected niche
        
        NNTS can survive & replicate
    - - SPI-1 switched off after engulfed
      - SPI-2 genes activated
    - - SPI-2 encoding genes
      - Salmonella-containing vacuole formed
    - - T3SS-2
        
        Specialised for living in host cells
      - Effector injection
        
        Across SCV into host cytosol
      - SPI-2 encodes a Type III secretion system (T3SS-2)
- - - - Gives salmonella an advantage
      - Anaerobic environment
    - - Recruitment
        
        IL-8, TNFα, IL-1β
      - Inflammation
      - Tissue damage
      - Fluid secretion
        
        Diarrhoea
    - - PAMPs
      - LPS & Flagellin
  - - - IFN-γ
      - Activates macrophages
        
        Death of intracellular bacteria
    - - Not long lasting
    - - IgA & IgG
      - Limits
        
        Mucosal colonisation
        
        Systemic spread
- - - - Kills the bacteria in the end
    - - Th1 cells
      - Activates macrophages
      - Intracellular NTS destroyed
    - - Gut barrier / Microbiota recovery
        
        Normal flora rebound
      - Inflammation subsides
    - - Inflammation resolves
      - Growth advantage removed
    - - IgA
      - Luminal bacteria cleared
      - Limited invasion
  - - - SPI-2 (Macrophages)
      - Prevents full exposure to antibodies & complement
      - Th1
        
        Does not fully clear the infection
    - - 2,500 serovars
        
        Treatment is serovar-specific
      - Different O & M antigens
        
        LPS & Flagellin
    - - Effectors dampen signalling & inflammation
        
        NF-κB/MAPK
      - Flagellin
        
        Evades TLR5
    - - Short-lived
      - Gut plasma cells
        
        Secretes IgA after infection
      - IgA quickly disappears
      - Memory B cells (Intestinal)
        
        Not strongly maintained
  - - - Requirement
        
        No need for antibiotics
      - Self-limiting
        
        Gastroenteritis
        
        Requires supportive care only
      - Reduced AMR
        
        Limits selection pressure
        
        Reduces resistant strains
    - - Requirement
        
        Drugs needed for treatment for severe
      - Severe infection
        
        Ceftriaxone
        
        Fluoroquinolones
        
        Azithromycin
      - Increased AMR
        
        Growth promoters
    - - Overuse
        
        Animal agriculture
        
        Unnecessary treatment
      - Spread
        
        Resistant clones travel by food trade & travel
- - - - Well-adapted to the host
      - Colonises distal gut
        
        Weak inflammation
      - Balanced immune response
        
        Tolerant of low-level colonisation
    - - Chronic carriers
        
        Down-regulators virulence factors
      - Prevent host damage & immune activation
    - - Small amounts do not affect the microbiome
    - - Persists silently in some locations
      - Examples
        
        Gall bladder
        
        Cecum
  - - - Limit NTS introduction
      - Isolate herds from rodents
      - Cleaner resources
    - - Regular testing
      - Test food products
        
        Early removal of contamination / carriers
    - - Poultry
      - Reduced egg contamination / colonisation
    - - Cooking meat / eggs
      - Avoid cross-contamination
      - Chilling food