Day 9: Gastro-intestinal infections Flashcards
HC22
HC22: Gastro-intestinal tract
- Passageway digestive system
- Digest and absorb ingested nutrients and eliminate waste products
Peristalsis
Wave like muscle contractions in GI tract (by smooth muscles)
Microbiota must have done what to survive in GI tract
Undergo adaptations
Healthy gut barrier: layers of defense
- Biochemical mucus barrier: mucus with secretory IgA antibodies and antimicrobiral peptides: prevent bacteria from adhering to epithelium
- Physical barrier: enterocytes interconnected with tight junctions
- Immunological barrier: immune cells
> detect infection after barrier breach (by DCs)
» Can also reach through epithelium and actively sample the lumen
> Producer of sIgA (B-cell)
Normal microbiota of GI tract have unique composition, why
Not everything can survive on the same places of intestine > different densities
> different concentration oxygen and antimicrobial substances
> Different pH
Benficial effects of gut commensals
- Nutrient contribution
> Breakdown carbohydrates to short chain fatty acids: better to absorb - Strengthening gut integrity
> signalling for finetuning mucus production
> induce tight junction proteins, otherwise leaky - Regulating host immunity
> inducing tolerance against commensals and dietary antigens - Protect against pathogens
> niche competition: take their spot and use nutrients which are otherwise used by pathogens
Common symptoms enteropathogenic bacteria
- Nausea
- Vomiting
- Abdominal pain
- Diarrhea: watery or bloody (dysentery)
- Fever: suggests invasive organism as causative agent
Endogenous intestinal infection
Commensals become pathogenic, are already present
> change localisation
Microbiota composition dependent on:
- Diet
- Medication; antibiotics, immunosuppressive chemo
- Stress
Endogenous intestinal infection: bacteria go from … to …
symbiotic to dysbiotic > growth not in balance > invasion and epithelial damage and even autoimmunity
> can contain auto-antigens
» excessive inflammation damage intestinal epithelium: inflammatory diseases
Exogenous intestinal infections
- Bacteria products from outside the host enter (food related or environment like contaminated water) like salmonella
> transmission routes
» Environment, zoonotic and human-to-human
Deduce exogenous infectious agent on epidemiological data
- Source
- Incubation time
- Symptoms
Sources exogenous infectious agent
- Environmental
> Bacillus cereus
> Clostridium botulinum
> Vibrio cholerae - Zoonotic
> Campylobacter
> E. coli (EHEC, STEC)
> Salmonella - Human
> E.coli (EIEC/EPEC)
> Salmonella (Typhi . paratyphi)
> S. aureus
Incubation time bacteria
Slow > bacterial growth
> Salmonella and E. coli
Fast > toxin production
> B. cereus, C. botulinum, S. aureus
Spore formation (can become silent)
> B. cereus and C. difficile
Symptoms bacteria
Invasive infection > bloody diarrhea, fever
Non-invasive > watery diarrhea
3 main aspects of intestinal infection
- Colonization: adapt to, exploit, destroy intestinal integrity
- Invade: into deeper tissues
- Evade: Mechanical and immune clearance
Differen bacteria have … infection routes
different
> based on virulence factors: adhesion, invasion, toxin production
Adhesion factors
- Pili are most important
> multi-subunit hair-like extension from the surface of bacteria with an adhesin (lectin) on tip
> lectin can bind sugars of the host (attach to glycolipids and glycoproteins on host cell)
> first step of adhesion > prevent flow from host cell by peristalsis
» peristalsis is faster than bacterial movement
» initial attachment
> gram -positives mostly
What happens after initial attachment via the pili?
Non-pilus adhesins empower the adhesion
Invasion factors goal
- Actively induce uptake in nonphagocytic cells
- cytoskeleton remodeling involved
Two mechanisms invasins
- Zipper
- Trigger
Zipper invasion
Molecules on cell have increased interactions with actin protrusions until engulfed by enterocyte
> bind to cell matrix or cell-cell adherence host receptors: integrins and cadherins
> Listeria monocytogenes for example from meat or raw vegetables
Listeria zipper
Internalin A binds E-cadherin (epithelium)
> Internalin B binds Met (growth factor receptor, ubiquitously expressed)
> entry by endocytosis
> Listeriolysin O secreted, escape phagosome
> ActA triggers actin remodeling into tail, enabling mobility spread to neighbouring cells
> actin rocket
> form vesicle in next cell and repeat
Trigger invasion
Bacterium injects factors in the cell which directly induce actin remodeling to take up the bacterium
> Type 3 secretion system (T3SS)
Type 3 Secretion System (T3SS)
In gram negative bacteria: Samonella and E. coli and Shigella
> Needle-like structure > export proteins from bacteria into host cell through needle
> structural proteins: base, needle and needle tip
> effector proteins get secreted into host through this needle: promote infection
> Chaperones: bind effectors in bacterial cytoplasm, prevent aggregation and degradation, direct the effectors towards the needle, ATPases unfold the effectors in the host cell
> Effector functions: activation of cytoskeleton (invasion), disrupt phagosome maturation by inhibiting motor proteins, direct cytotoxicity, and disrupt tight junctions by inhibiting localization of new tight junction proteins
T3SS in Salmonella enterica typhimurium
In raw meat and eggs
Two independent T3SS
> SPI-1 (Salmonella pathogenicity island)
» Invasion of enterocytes
» Effectors SopA/B/E
> SPI-2
» Disrupt phagosome maturation
» prevent ROS formation
» effectors SseF/G, SifA
Types of toxins
- Endotoxins: components of bacterial cell wall like LPS > strong agonists of TLR4: acute immune response and cytokine storm
- Exotoxins: secreted toxins in environment or host cell
> enterotoxin: toxins that specifically interact with intestinal cells
Cholera toxin
Produced by vibrio cholerae: environmental (water), during outbreak fecal-oral transmission leading to diarrhea and dehydration
> A and B subunit> ganglioside receptor
> upregulation adenylate cyclase activity: cAMP upregulated
> calcium channels are massively opened, loss electrolytes and water followd due to osmosis: diarrhea (watery)
Enterotoxigenic E. coli (ETEC) toxins
2 distinct toxins
> Heat-labile toxin (LT), like cholera toxin
> Heat-stable toxin (ST)
» ST binds sulfatides on enterocytes to enter (lipids for lipid rafts)
» Intracellularly, ST dephosphorylates Claudin-1 (part of tight junction)
» Claudin-1 translocates to cytoplas,: loss of TJs
» ETEC can pass epithelial barrier
Shiga toxin
Originally produced by Shigella but easily transduced to
> Shiga toxin producing E. coli (STEC)
> Enterohaemorragic E. coli (EHEC)
- Shiga toxin binds Gb3 lipid
- Taken up in endosome and to Golgi and ER
- In ER: inhibition of protein synthesis and induction of apoptosis > inhibited enterocyte renewal.
- Metabolism stopped, quick renewal cells in intestine > holes in epithelium
- Also secretion through basolateral side > damage
- Shiga toxin spread in cell-to-cell vesicles
C. diffucile
C. difficile: spore-former and environmental bacterium
> increased risk when antibiotic use: space in niche is free
> diarrheal, colitis, colonic perforation
> repeated infection > fecal transplants used
> insensitive to antibiotics
C. difficile transferase (CDT) toxin
CDT is binary toxin (A and B subunits)
> Endocytosed by enterocyte through host receptors: release A subunit
> Depolymerization of actin is signalled
> loss cytoskeleton structure
- Destabilization of microtubules > protrusions
> Microtubule protrusions augment adhesion of bacterium
> helps bacteria to infect
Staphylococcal enterotoxins
- S. aureus enterotoxins: multiple types
- Intoxication rather than infection
- Toxin contaminated foods
- Nausea and vomiting
- Toxins through goblet cells and with Mast cells stimulation to make neuropeptides histamine and serotonins > vagal nerve stimulation > nausea (feeling sick)
- Direct stimulation of immune system: T-cell superantigen (can activate all T-cells unspecific) > cytokine storm > toxic shock syndrome
Categorize: Environmental toxigenic bacteria
Colonizing enterotoxigenic bacteria
Nonadherent toxigenic bacteria
Enteroinvasive bacteria
Environmental toxigenic: S. aureus, B. cereus
Colonizing enterotoxigenic: E. coli, V. cholerae
Enteroinvasive: Shigella, Listeria
Nonadherent toxigenic: Clostridioides difficile
Enterotoxins main effects:
Shigella, EHEC, ETEC, S. aureus and V. cholerae
- Shigella and EHEC: Alteration of cell viability
- ETEC: Alteration of actin cytoskeleton and intercellular junctions
- S. aureus: Targeting nerve endings
- V. cholerae and ETEC: Cell homeostasis alteration
Causatives diarrhea
V. cholerae
> Induction cAMP
> Calcium channel, efflux with water
ETEC
> tight junctions compromised
> lack control over water and ion flows
Shigella and EHEC
> Damage mucus layer and enterocytes
> Inflammation
> Further destruction of mucus layer and tissues
> Lack control water and ion flows
