Lecture 35 - Enteric Pathogens 2024 PDF

Enteric pathogens Lecture 35 1.Epidemiology 2.Gastrointestinal illness 3.A case study in enteric pathogens: Pathogenic E.coli  Toxins overview – memorize this Endotoxin (LPS) Exotoxins Proteases, Lipases Botox, Tetanus...

Enteric pathogens Lecture 35 1.Epidemiology 2.Gastrointestinal illness 3.A case study in enteric pathogens: Pathogenic E.coli  Toxins overview – memorize this Endotoxin (LPS) Exotoxins Proteases, Lipases Botox, Tetanus toxin, Clostridial alpha toxin (Clostridium spp.) Cytotoxins A-B toxins (pore-forming toxins, (modify the activity of host destroy host cells for cell proteins, after being taken tissue penetration and to up by the host cell) liberate nutrients) Examples: Examples: - Cholera toxin (Vibrio - Leucocidins cholerae) (Staphylococcus - Shiga toxin aureus) (Enterohemorrhagic E. - Haemolysins (many  Secretion systems in proteobacteria Tat – twin arginine transport system: export of proteins that have folded in the cytoplasm Sec system– unfolded proteins Type I - VI secretion systems: important for interactions with other cells (i.e. Pathogenicity) Also note OMV – outer membrane vesicle formation FEMS Microbiol Rev (2010) 34:107-133  8. Type III Secretion (T3SS) Used to deliver effector proteins from pathogen cytoplasm into the cytoplasm of a host cell, e.g., plant pathogen Pseudomonas no need for special receptor syringae; or human pathogenic E. coli mechanism to get proteins  Secretion systems and host cell reprogramming Hausner J et al, IAI, 2016 Effector proteins fulfil diverse functions, e.g. reorganization of target cell cytoskeleton, dampening the immune response, inhibiting phagocytosis etc. The number of effector proteins varies between species: - Pathogenic E. coli (Type III) ~ 25 – 50 - Legionella pneumophila (Type IV) ~ 330 - Vibrio parahaemolyticus (Type III) ~10 - Bordetella spp. (Type III/IV)~ 2 Summary When exposed to potential pathogens, the invader must first interact with our physical, chemical and microbiota barriers. One class of pathogenicity factors (PFs) enhances the ability of a pathogen to attach to human cells and a second class helps degrade physical barriers to invade cells and tissues. A third class of PFs includes toxins. Some cause host cell lysis, others alter normal cell function either locally or at a distance.  1. Epidemiology Evaluates the occurrence, determinants, and distribution of disease in a population to identify means of containment and control Endemic: disease is always present in a population at a predictable level Epidemic: sudden increase in the number of cases in a population (more cases than expected) Pandemic: an epidemic that has spread over several countries or continents, usually globally distributed, affecting many people John Snow and early epidemiology – The 1854 cholera outbreak in London (Vibrio cholerae causes the water-borne disease cholera  massive diarrhea and subsequent dehydration) Broad Street Pump Tower of London – moat drained in 1843 due to disease outbreaks (including cholera) 2. Gastrointestinal Illnesses In the US, most outbreaks of GI illnesses arise because of a breakdown in sanitation – food is contaminated or water treatment practices break down Common source epidemics – a single place, event or product is responsible  How to acquire enteric pathogens Tuladhar and Singh, J Nat Hist Mus, 2012 oliform bacteria (Escherichia, Enterobacter, Klebsiella etc.) e used as indicators of fecal contamination. oliform = Gram-negative, beta-galactosidase positive) The infectious dose – how many bacteria do you need to ingest to get sick?  Turn to thy neighbor: Why do bacteria differ in their infectious dose? Bottlenecks in infectious disease e.g. stomach pH (pH ~2!)  How to survive stomach acidity -log[H+], so low pH = high H+ concentration = protein denaturation Residence in the stomach is transient for most bacteria – enteric pathogens do not have to grow in low pH; they only need to survive! Outside/periplasm H+ H+ H+ H+ H+ H+ H+ H+ INSIDE The glutamate-dependent acid resistance system (GDAR) is an important transient low pH adaptation.  3. A case study of pathogenic Escherichia coli Pathogenic E. coli have complex names like (most important strain) “O157:H7” The “O antigen” of the LPS of E. coli comes in ~200 varieties, each one detectable by a specific serum. The “H antigen” refers to the E. coli ep Binding of many pathogenic E. coli to host intestinal e Initial binding of some E. coli strains occurs via a Type 4 pilus called a “bundle-forming pilus.” “intimate attachment” is via a bacterial protein called “intimin” binding to a protein called “TIR.” Tir is secreted into host cell using Type III Remodels the cytoskeleton under the cell surface. Destroys microvili, and creates a “pedestal.” “Effacing” of the intestinal epithelium: destruction of the microvilli by pathogenic E. coli  Dangerous E. coli – an overview Enteropathogenic E. coli (EPEC): No exotoxin, but activates aquaporins to cause diarrhea Enterotoxigenic E. coli (ETEC): Produces two toxins (heat labile and heat stable), similar to cholera, but milder Enterohemorrhagic E. coli (EHEC): Produce Shiga toxin, which kills EHEC produces Shiga Toxin Contains 1 A subunit, 5 B subunits A is processed to two fragments, A1 and A2 The A1 subunit of Shiga toxin attacks host cell translation machinery by cleaving 28s rRNA. Binds to Globotriaosylceramide receptor (Gb3). This is a type of ganglioside common in host membranes Shiga toxin is secreted by cell lysis (antibiotics can exacerbate Galactose disease!) Ceramide Galactose Glucose  A complication of EHEC infection: Hemolytic uremic syndrome (HUS) caused by systemic dissemination of Shiga toxin A complication (~7 %) of EHEC infection is Hemolytic Uremic syndrome. HUS develops when Shiga toxin ends up in the bloodstream at high concentrations and damages the kidneys.  Outbreak of E. coli O157:H7 associated with romaine lettuce 121 cases, 1 death “Shiga toxin- producing” E. coli, or STEC Source traced to Yuma, Arizona region Enterotoxigenic E. coli (ETEC) Causes traveler’s diarrhea (“Montezuma’s revenge”) 840 million cases/year, mostly in developing countries Contains 2 toxins LT (heat labile toxin) ST (heat stable toxin) LT 80% identical to cholera toxin ST, a small cysteine-rich peptide that mimics a host cell signaling peptide. Both toxins stimulate the opening of the  Variations of a pathogen Vibrio cholerae E. coli Non-pathogenic Non-pathogenic EPEC O1 O1 EHEC stx+ EHEC stx+ ETEC ETEC O139 UPEC EAEC EAEC stx+ AIEC Armed via EIEC “lysogenic DAEC conversion” (lysogenic phage carries toxin) Remember lysogeny?  Mix and match: Real-time pathogen evolution in pathogenic E. coli EAEC (O104:H4) strain that had acquired Shiga toxin as well as other virulence factors, but not the LEE pathogenicity island. High incidence of Hemolytic uremic syndrome (22%). Summary Enteric pathogens are often acquired through food contaminated with coliform bacteria Vibrio cholerae causes cholera disease Many varieties of pathogenic E. coli exist, including EHEC and ETEC EHEC uses a Type III secretion system to remodel and reprogram host cells EHEC also produces Shiga toxin, which inhibits translation in gut epithelial cells and cause the life- threatening complication HUS ETEC produces a cholera-like toxin which causes watery