Exam Pathogens PDF

lOMoARcPSD|38054369 Patients with specific defects in their immune system (e.g mutations in PRRs esp TLR3) are more likely to develop herpes encephalitis RESPIRATORY SYSTEM Fungal infections to upper respiratory system Candida albicans is responsible for most mycoses in upper RS Fungal...

lOMoARcPSD|38054369 Patients with specific defects in their immune system (e.g mutations in PRRs esp TLR3) are more likely to develop herpes encephalitis RESPIRATORY SYSTEM Fungal infections to upper respiratory system Candida albicans is responsible for most mycoses in upper RS Fungal infections to lower respiratory system Fungal pneumonia has a variety of causes Most URTIs are of viral aetiology (e.g rhinovirus, coronaviruses, influenza virus, parainfluenza virus) Also have bacterial causes (Mycobacterium tuberculosis, Haemophilus influenza type B (epiglottis, laryngotracheitis), Streptococcus pyogenes (bacterial pharyngitis) LRTIs typically have viral / bacterial causes Influenza virus, rubellavirus, measlesvirus, Bordetella pertussis, Haemophilus influenzae, Streptococcus pneumoniae contribute to bronchitis and bronchiolitis Pneumonia (inflammation primarily of the alveoli), has many viral / bacterial causes but major cause is community-acquired pneumonia Streptococcus pneumoniae ○ Also fungal causes such as Aspergillus fumigatus (aspergillosis) Microbiota of respiratory system Exposure to antibiotics can disrupt the composition of the RS microbiota (Dolosigranulum spp. and Corynebacterium spp) leading to increased susceptibility to infection & inflammation Commensals are important source of infection (endogenous): Staphylococcus and Streptococcus spp. Antimicrobial multiple lines of defense by mucus secreted by goblet cells (immobilise microbes, which are trapped and transported by cilia to the pharynx where they are swallowed) ○ Mucus also have lysozome activity (break down bacterial cell walls), expresses lactoferrin (bacteriocidal, fungicidal) and has variety of antimicrobial chemical properties Alveoli lack cilia and macrophages are key line of defense here ○ Secreted IgA (primarily in lower RS, found in mucus) ○ IgG (primarily in upper RS), also provides protection through adaptive immune response BACTERIA, VIRUS, PROTIST, FUNGI Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Type Transmission Virulence mechanism Symptoms Other facts (incl. Immune response (gram) treatments, etc) Aspergillus Resistant Common in Small (2 um) - can Necrosis and Azoles (e.g fumigatus across decaying escape mucociliary inflammation, loss of voriconazole) which - Aspergillus, range of pH matter & clearance and reach alveolar function has a number of pneumonia and can dominant alveoli Invasion and side effects grow at fungus in High in melanin - dissemination ○ Targets the 37oC garden soil protect against oxidative Damage to fungal cell damage by reactive endothelial cells, membrane Spores are oxygen species (ROS) hyphal fragments Selectivity of anti- cells and lysis by immune disseminate in the fungals is a produced cells bloodstream & challenge due to sexually / Highly hydrophobic - adhere to endothelial related to host (both asexually promotes binding to cell surface eukaryotes) respiratory epithelium & environmental dispersal Gliotoxin - mycotoxin capable of altering host defences through immunosuppression ○ Neutrophils are their principal target ○ Interrupts function of leukocytes by inhibiting migration and superoxide production and causes apoptosis in macrophages Elastases - proteases Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 that cleaves elastin in order to break down these macromolecular polymers for uptake Streptococ Gram- Spread from Gram-positive - single Mostly caused by Classified by their hemolytic cus positive individuals with membrane & thick Streptococcus pyogenes. activity pyogenes cocci acute infections peptidoglycan cell wall Most common disease is Alpha-hemolytic - - Pharyngitis through aerosol M protein - promotes pharyngitis (Strep throat) and converts (Strep droplets, fomites, attachment to host cells, is followed by: haemoglobin to a throat) direct contact allowing colonisation Scarlet fever grenist colour and inhibits (systemic infection, Beta-hemolytic - opsonisation by progression to rash complete lysis of alternative complement across face and body, RBCs; includes pathway fever and white serotypes ○ It is also coating of tongue Gamma-haemolytic targeted by Rheumatic fever / - non haemolytic antibodies for heart disease, engulfment by autoimmune diseases Young children are phagocytes characterised by most at risk, being ○ It is both a inflammation immunologically defence and Glomerulonephritis, naive to circulating weakness for inflammatory disease serotypes the pathogen of the kidney Usually self-limiting Hyaluronic acid Last two are not and generally capsule protects from direct causes of the resolve within a phagocytosis, seen as bacteria but the week self & aids in autoimmune attachment response Treatment Streptolysin O (beta- Antibiotics (β- hemolytic activity) and lactams such as streptolysis S and penicillin, haemolysins and cephalosporin: exotonics that can inhibit bacterial cell damage host immune wall synthesis) - Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 cells reduces severity ○ Strep O - inhibit and likelihood of phagocytic further clearance of complications bacteria by No vaccines neutrophils available (major SpeA and SpeC - complications are superantigens from the pathogen responsible for the rash triggering auto- observed in scarlet immunity) fever suffers and for streptococcal toxic Treatment failure usually shock syndrome. result from: Exotoxins (e.g SPEs) Intracellular are responsible for the persistence in rash in scarlet fever tissues poorly Streptokinase - inhibits accessed by blood clots by activating penicillin plasminogen, promotes Protection by spread of pathogen in associated β- host tissue lactamase- M protein and SPE are producing bacteria involved in Streptococcal toxic shock syndrome, a life threatening complication Streptococ Gram Spread from Bacterial capsules - Inflammation of the Vaccine Prevnar-13 Colonises mucus of cus positive, individuals with allow it to colonise the alveoli leading to - protects against nasal epithelium pneumonia non-spore respiratory aerosols mucus of nasal coughing, chest pain 13 serotypes of S. e- forming or fomites epithelium and difficulties pneumoniae (of 97 pneumonia, Doesn’t have to ○ It is also breathing known serotypes) pharyngitis, be from another antiphagocytic Also cause infections Penicillin is used to Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 tonsilitis infected & can reduce in upper RS and treat - but individual - it total amount of other organs, causing increasing could be that complement conjunctivitis and resistance you’re harboring that is meningitis ○ Ability of S. it asymptotically deposited on Death from pneumonia ⇒ there’s some bacterial respiratory failure due e to take up stress to allow it surface to avoid to alveoli filling with exogenous to be disease- immune fluid (immune cells, DNA causing detection plasma, blood) contributes PgdA - resist mucosal Can spread to lower to spread of lysozyme breakdown RS & lead to antibiotic Adhesion factors to pneumonia; enter the resistance promote adhesion to the bloodstream and lead and RS epithelium to bacteraemia, evasion of Pneumolysin (PLY) - meningitis, or spread vaccine- cholesterol-dependent locally and cause an induced cytolysins, bacterial infection of the inner immunity toxin that binds to host ear (otitis media) cell membranes to form macromolecular pores, leading to cell lysis and death Autolysin LytA - to digest its own bacterial cell wall, to release PLY Mycobacter Intracellular Exclusive human ESX system - comprises of 5 Myobacterium bovis ia bacteria bacteria (no molecular transport pathways, 3 (a bacterium which tuberculosi environmental which have been shown to have has antigenic s- Non-motile, reservoir) a role in virulence similarities to M. Tuberculosis highly ESX-1 - secretes Tuberculosis but in aerobic, Transmitted with proteins that lead to cattle) rod-shaped individuals when phagosomal membrane These bacili gave bacteria coughing, sneezing, rupture partial resistance to speaking or spitting ○ ESAT-6 and infection with M. Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Unreactive - respiratory CFP10 are tuberculosis - BCG to gram droplets powerful vaccine stain antigens that (coating of elicit a cell- Antibiotic resistance in TB the cells mediated Drug Susceptible- make it immune TB (DS-TB) - appear response Shown below are weakly ESX-3 - involved in iron the four drugs in the gram- & zinc uptake that aids standard regimen of positive) in replication & hinders first-line drugs ⇒ so phagosome maturation Rifampin, they’re ESX-5 - releases Izoniazid, stained proteins which play a Pyrazinamide & with Ziehl- role in Ethambutol Neelsen immunomodulation (known as RIPE). (ZN) stain Multi-Drug instead Hip1 - a gene that Resistant TB impair proinflammatory (MDR-TB) - MDR- Have cytokine production TB occurs when a unusual cell maturation and antigen M. tuberculosis wall presentation of dendritic strain is resistant Arabinogal cells, which could to isoniazid and actan / show/dampen T cell rifampin, two of the peptidoglyc response most powerful first- an (AGP) Mycolic acid - major line TB drugs. cell wall component of its wall ○ To cure core, which is hydrophobic, MDR-TB, a mycobacter providing protection combinatio ial outer against chemical n of membrane damage from anti- second-line (MOM), bacterial compounds drugs, (see outer layer produced by host & below) are (or capsule) allows survival in used. phagocytes Extensively Drug Resistant-TB Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 (XDR-TB) - XDR- TB occurs when a M. tuberculosis strain is resistant to isoniazid and rifampin, as well as key second-line drugs. Influenzavir Genome is Fomites, respiratory Antigenic drift - strains Most infection are Neuraminidase us segmented, droplets generated evolve and adapt mild and will reseolve inhibitors are AIV and IBV negative- through speaking, allowing them to infect without intervention in structural mimics of (exclusive to sense, coughing and people who have had less than 2 weeks SA that are humans) single sneezing prior infections Upper RS symptoms effective against cause stranded ○ Occurs when - nasal stuffiness, IAV / IBV if used significant RNA Significant viral runny nose, sore within 48 hours of disease in seasonality polymerase throat, sneezing, appearance of humans contribute to flu (low makes mistakes earache symptoms humidity, cold temp when Lower RS - coughing, ○ These bind enables replicating, breathing difficulties to NA and transmission) leading to small Fever above 37.8oC block its changes in viral ability to epitopes that Potential complications cleave SA - accumulate Pneumonia, inhibit their overtime bronchitis, asthma dispersal Antigenic shifts - gene and ear infections ○ Use of reassortment Cytokine production these NA (occasionally a virus can compromise inhibitors can arise that has gene integrity of respiratory leads to segments that are epithelium leading to resistance derived from multiple alveoli filling with fluid mutations different types of in NA influenza virus - Each year, an combining human, bird, inactivated vaccine swin strains together) composed of two Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Hemagglutinin (HA) - IAV and two IBV binds to epithelial cells trains and is of upper tract via 2-5 delivered by sialylated glycans intramuscular PB1-F2 - induces host injection cell apoptosis & impairs ○ Which Type 1 IFN production strains are selected for vaccine changes each year Live attenuated influenzavirus vaccine - delivered by nasal spray Influenza Virus PA, PB1, PB2 viral RNA polymerase involved in mRNA synthesis and replication of the genome. HA surface protein involved in virus entry. NA surface protein involved in virus exit. Surface glycoproteins are targets for neutralising antibodies as we generate a protective immune response M matrix protein involved in virus assembly. NP nucleocapsid protein, protects genome. Entry Trimers of HA on the surface of the virus binds sialic acid (carbohydrate group commonly attached to many cell surface proteins) Tropism of influenzavirus - combination of presence of sialic acid & availability of cellular-furin like proteases that are required for influenzavirus to be infectious Sialic acid (SA) can be attached to a carbohydrate chain through either a 2-3 or 2-6 linkage ○ HA from human influenzavirus are specific for 2-6 while HA from avian influenzavirus bind the 2-3 configuration Once attached, the virus is internalised through receptor-mediated endocytosis, forming an endosome A drop in the pH of endosome triggers a membrane fusion event that exposes the segmented viral genome to the cytoplasm Replication Genome segments are transported to the nucleus where viral RNA polymerase (present in virions) synthesises mRNA and copies the genome Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Host RNA polymerase makes RNA from DNA template ○ Virus is making RNA from a RNA template ⇒ only a viral enzyme can do this To make a viral protein ⇒ need to make complimentary copy of that mRNA (influenza is negative sense) ○ Positive sense RNA viruses have a genome containing viral mRNA that can be readily translated into proteins. However, negative sense RNA viruses consist of a genome containing viral RNA that is complementary to the mRNA. Exit Viral mRNAs are translated by cellular ribosomes, and viral transmembrane proteins are processed through rough endoplasmic reticulum and Golgi apparatus Virus particles assemble at plasma membrane and released via a budding mechanism with genome segments loaded into nascent virions (viral envelope derives from the plasma membrane) Neuraminidase (NA) promotes release from surface of cells by cleaving sialic acid residues (not allowing HA to remain interacted with sialic acid) ⇒ facilitating their dispersal Seasonal epidemics and pandemics Worldwide outbreaks of novel flu strains that derive from animal flu strains These novel derive from a reassortment of viral genome segments from strains of different origins in a process called antigenic shift ○ Antigenic drift involves the accumulation of a series of minor genetic mutations. Antigenic shift involves “mixing” of genes from influenza viruses from different species. Tuberculosis Risk factors HIV co-infection Undernutrition Diabetes mellitus Smoking Heavy alcohol consumption Crowded living condition Immunocompromised Pathogenesis After inhalation, the bacteria enter the alveoli. The cells are phagocytosed by macrophages but can survive and multiply within these phagocytes in part because of the protection afforded to the bacterial cell by the waxy mycolic acid in their cell walls. If not eliminated by macrophages, the infection can progress, causing an inflammatory response and an accumulation of neutrophils and macrophages in the area. Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Several weeks or months may pass before an immunological response is mounted by T cells and B cells. Eventually, the lesions in the alveoli become walled off, forming small round lesions called tubercles, also known as granulomas. ○ Bacteria continue to be released into the center of the tubercles and the chronic immune response results in tissue damage and induction of apoptosis (programmed host-cell death) in a process called liquefaction. ○ This creates a caseous center, or air pocket, where the aerobic M. tuberculosis can grow and multiply. ○ Eventually, most lesions heal to form calcified Ghon complexes. These structures are visible on chest radiographs and are a useful diagnostic feature. But even after the disease has apparently ended, viable bacteria remain sequestered in these locations. Tubercles may eventually rupture and bacterial cells can invade pulmonary capillaries; from there, bacteria can spread through the bloodstream to other organs, including the central nervous system. ○ This release of organisms at a later time is termed reactivation tuberculosis (or secondary TB). ○ This is mainly observed in people with alcoholism, the elderly, or in otherwise immunocompromised individuals. Innate immune response to TB Chronic bacterial infections are often caused by organisms that have an intracellular phase; ○ this requires that they are adept at the penetration, evasion, and exploitation of the host immune response. Airway epithelial cells, alveolar macrophages and dendritic cells (DCs) are the first cell types to encounter M. tuberculosis in the alveoli upon primary infection. ○ All of these cell types express pattern recognition receptors (PRRs) that can recognise various pathogen-associated molecular patterns (PAMPs) from M. tuberculosis. ○ In response they will begin to secrete chemokine and cytokines to initiate the immune response. Toll-like receptor 2 (TLR2) can recognise M. tuberculosis proteins and polysaccahrides and TLR9 can recognise the bacterial DNA. ○ Members of the NOD-like receptors can also recognise other components of the bacteria. ○ Together this drives the expression of pro-inflammatory cytokine and chemokines which facilitates the recruitment of immune cells to the site of infection. An infiltration of neutrophils, monocytes, macrophages and more dendritic cells begins. ○ In contrast to most infectious pathogens, the recruitment of these innate immune cells actually benefits the bacteria because they can be infected with M. tuberculosis, thus providing a niche for the bacteria to replicate. M. tuberculosis can modulate the phagocytic process by inhibiting the fusion of the phagosome with the lysosome to ensure its own survival. ○ The bacteria also posses virulence factors which can promote the necrotic death of infected neutrophils and the recruitment of macrophages, which can become long reservoirs for the bacteria. This innate stage is important for initialising the subsequent adaptive, cell mediated (T cell) response. DCs can phagocytose the bacteria, mature and migrate to lung draining lymph nodes. They will upregulate MHC-I and MHC-II and present antigens to T cells. Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Adaptive immune response to TB Following primary infection with M. tuberculosis, the onset of the adaptive immune response is typically delayed, with MTb specific T cells sometimes not detectable until up to 42 days post exposure (compared to an average 4-5 days for other pathogens). This lag time is potentially due to the ability of MTb to modulate the capacity of dendritic cells to mature and present antigens to T cells Once in the lymph nodes mature dendritic cells will present MTb antigens, derived from the phagosome via the MHC-II presentation pathway to naive CD4 T cells. ○ Additionally, antigens can escape the phagosome and be cross-presented on MHC-I to naive CD8 T cells. Upon finding an MHC-peptide complex which is specific for its T cell receptor (TCR), a naive T cell then undergoes clonal expansion and differentiation. This results in the generation of MTb specific activated CD4 T helper 1 cells which can secrete IFN-gamma and MTb specific CD8 cytotoxic T cells (CTLs). CD4 Th1 cells will engage with macrophages presenting their cognate MHC II:peptide and via the secretion of IFN-gamma and CD40:CD40L interactions, will enhance the capacity of the macrophage to kill phagocytosed bacteria. CD8 T cells will engage with cells expressing their cognate MHC I:peptide and directly lyse them using the cytotoxic molecules perforin and granzymes. Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Diagnosis The Mantoux skin test involves injecting the subject with a tuberculin protein derivative. The injection should initially produce a raised wheal. ○ The test should be read in 48–72 hours. ○ A positive result is indicated by redness, swelling, or hardness; the size of the responding region is measured to determine the final result. ○ However, prior vaccinations with the BCG vaccine can also cause a positive result. Immunopathology of the Mantoux (Tuberculin) Skin Test Delayed type hypersensitivity (DTH) is one form of cell-mediated immunity, which involves CD4+ T cell activation and subsequent activation of macrophages (mononuclear phagocytic cells). Purified protein derivative (PPD) of M. tuberculosis also known as tuberculin elicits a DTH response when injected into individuals who have memory CD4+ T cells specific for mycobacterial antigens. These memory T cells are induced in active tuberculosis disease, but they are also induced in TB contacts (people who have been infected with M. tuberculosis but who have not progressed to disease). People who have been vaccinated against tuberculosis with Bacillus Calmette Guerin (BCG), are also Mantoux positive. ○ Therefore a positive Mantoux test is not indicative of TB disease. Following intradermal injection of tuberculin in a sensitised individual, antigen specific T cells are activated to secrete cytokines that mediate the hypersensitivity reaction. ○ Local production of TNF acts upon endothelial cells in dermal blood vessels to induce expression of adhesion molecules E-selectin, ICAM-1 and Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 VCAM-1. ○ These molecules bind receptors on leukocytes and recruit them to the site of the reaction. ○ The initial influx at 4 hours is of neutrophils, but this is replaced at 12 hours by monocytes (macrophages) and T cells. ○ This infiltrate extends out and disrupts the collagen bundles of the dermis and increases to a peak at 48 hours. ○ Macrophages constitute 80-90% of the total cellular infiltrate. The tuberculin lesion normally resolves within 5-7 days. Additional tests that are performed in the diagnosis of TB include: a chest X-ray, sputum samples to look for the presence of acid-fast bacilli the QuantiFERON-TB Gold test to test for IFN-gamma production by MTb specific CD4 T cells, the new Xpert MTB/RIF test (a molecular test, based on nucleic acid amplification) GASTROINTESTINAL SYSTEM Structure of GIT Oral cavity Stomach ○ HCl + proteases aid digestion ○ Acidity fluctuations (food contents dependent) - after high protein mean pH ↓ 1-2 and on an empty stomach pH ↑ 4-5 ○ Mostly gram+ve cocci ○ A few microbes survive inside large food particles if passed through quickly Duodenum ○ High peristaltic flow from stomach ○ Breakdown of food: mixing stomach chyme with bile from gallbladder and digestive enzymes: lipase, trypsin and chymotrypsin etc + bicarbonate from pancreas shift pH ↑ to 5-6 ○ Mostly gram+ve cocci, rods and yeasts Jejunum ○ High flow ○ pH 7-8 ○ Goblet cells secrete mucous protects against pH stress and microbes (from them reaching deeper tissues) Ileum ○ Peyer’s patches: small bulges of lymphoid tissue: macrophages, dendritic cells, B & T lymphocytes: fight against foreign microbes Transfer antigens from the lumen of the intestine to the lymphocytes ○ Paneth cells: on crypt in lumen >>> kill bacteria, fungi and some enveloped viruses Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 ○ secrete antibacterial defensins: kill bacteria disrupting membrane function ○ secrete antimicrobial lysozyme and phospholipase A2 Large intestine ○ Long residence time: microbial digestion rather than host enzymic digestion which occurred in SI and stomach Relying on normal microbiota to start breaking down the residual food products ○ Like microbial anaerobic fermenter Large volume, low flow rate, mixes well Depletes oxygen, digests slurry ○ Microbiota aids in digestion and contribute to production of faeces Lactic acid bacteria (e.g. bifidobacteria) - can synthesize vitamins e.g. vitamin B12, folate, riboflavin GIT defence mechanism Acidity in stomach pH 4 - limits organisms reaching small intestine Pancreatic enzyme / juices Bile from liver via gall bladder ○ Pancreatic enzymes & bile - toxic to microorganisms Intestinal motility: peristalsis (makes it difficult for microorganisms to attach & colonise) Mucosal villous lining: protective, antimicrobial GIT immune response Normal microbiota in small and large intestines (competitive exclusion - utliise nutrients, secrete microbial compounds, take up attachment sites) ○ Stimulate lining GIT and immune system ○ Metabolise carcinogens in dietary foods - protective (they are not able to cause problems such as promoting cancer in the gut) ○ Provide synthesized vitamins: vitamin K, biotin, folate ○ Support muscular activity of the small intestine: no bacteria = reduced muscular activity Germ-free mice have reduced peristaltic flow in the muscles of the gut lining Anaerobic large intestine limits newcomers (most microorganisms are not anaerobes - they require oxygen for life & growth - limit the ability for pathogens to colonise the area) Ecology and microbiota of the large intestine Most numerous genus in normal adult = Bacteroides spp (anaerobic Gram negative non-sporing rods) >1011/ml E. coli is widely present BUT ~108/ml = minor proportion Anaerobes predominate: Bacteroides, Clostridium, Bifidobacteria Facultative aerobes: dependent on relatively small number of facultative (they can exist in the presence of O2 or low O2 conditions - high O2 would kill the anaerobes) organisms to remove O2 ○ The whole gut is dependent on a small number of them to remove oxygen to protect these below ○ Gram –ves: Enterobacteriaceae, eg E. coli Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 ○ Gram +ves: Enterococcus, Streptococcus, Lactobacillus Important: cultivable numbers vs microbes present ○ Whether something will be able to be grown in a media (cultivable) but if a microbe shows up as being potentially present through sequencing data through metagenomic analysis would mean it is present Transmission of microbial diseases of the GIT Faecal (anal) > oral route Food/water: ○ Contaminated with MICROORGANISM and/or PREFORMED TOXIN Food poisoning: ○ INFECTION: microbe is ingested, colonises the GIT, then replicates and can cause disruption to the lining of the GIT, eg. Salmonella gastroenteritis ○ INTOXICATION: bacteria produce toxins in the food before it is ingested eg. botulism, Staphylococcus aureus food poisoning Intoxication does not mean alcohol poisoning - it means you are ingesting bacteria that produce toxins (don’t get it confused) Primarily caused by bacteria and fungi ○ You can eat the actual organism itself (infection) OR the organism can produce toxins in a food product (intoxication) ALSO, spread from person-to-person via shed then ingested faecal microbes eg. Typhoid Mary, Polio BACTERIA, VIRUS, PROTIST, FUNGI Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Type Transmission Virulence mechanism Symptoms Other facts (incl. Immune response (gram) treatments, etc) Clostridium Gram- Acquired via Neurotoxin - most Pathogenesis: botulinum - positive, consumption of potent toxic material we Symptoms result from muscle Ingest toxin directly botulism anaerobe, food / water know paralysis caused by the toxin Resistant endospore contaminated with ○ Causes the produced endospores Non- former toxigenic strains of disease Difficulty swallowing Low pH of stomach diarrhoeal C. botulinum botulism Difficulty breathing triggers spore ○ Once it makes it Muscle weakness germination Or food into the Double vision Vegetative cells contaminated with a bloodstream, it Slurred speech produce toxin in preformed toxin targets Vomiting GIT, released on neuromuscular Nausea cell lysis junctions where Stomach pain toxin in diarrhoea Treatment endocytosed Antitoxin into neuronal Mechanical cells ventilation ○ Affects synaptic Induced vomiting proteins to enema prevent ACh release - results in flaccid paralysis Endospores - allow bacteria to survive harsh conditions (e.g. pasterurisation of food) ○ Tough outer coat allows them to survive low pH environment of stomach Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 ○ Low pH triggers germination and metabolise in GIT Salmonella Gram Acquired via SPI-1 & SPI-2 Fever Treatment enterica negative, consumption of (pathogenicity island) - Rash Antibiotics (some serovar facultative contaminated food / invasion of non Weakness multiresistance) typhi - enterobacte water phagocytic cells Stomach pains typhoid fever riaceae, ○ SPI-1 - Headache Control intracellular salmonella Death Sanitation Non- pathogenicity Gastroenteritis Hand washing diarrhoeal Humans island 1 Travel advice “boil are the only ○ These encode Chronic carriage can be it, cook it, peel it, or known type III linked to gall bladder cancer forget it” carriers secretion Vaccine: oral or systems (T3SS) injection for invasion of non-phagocytic cells and intracellular replication Specialised fimbriae - adheres to small intestine Flagellin (fliC) - invades SI Vi antigen - polysaccharide capsule, evades immune system by inhibiting phagocytosis ○ Shields O antigen (LPS) from antibodies Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Typhoid toxin (intracellular activity - bind and intoxicate a range of different cell types), AB toxin (damages host cell DNA, Typhoid fever symptom development) Intracellular pathogen - survives in macrophages, inhibits phagocytosis Salmonella Ingestion of Survive in stomach low pH Symptoms are dose- Treatment Reservoir: enterica NT contaminated food / The food you eat dependent Rehydration, self- intestines animals, (non- water exists as little Nausea limiting from birds to typhoid) particles in your Vomitting It leads to massive humans Gastroenteri Generally stomach ⇒ some of diarrhea dehydration of the patient - ○ Typhi is tis associated with raw these are large Abdominal pain causing serious organ only unique meat, poultry, enough for the damage / failure - rehydrate to humans seafood, eggs, fruit, microbial cells to with clean food and water vegetables stay protected inside so you are not inoculating it as they pass the pathogen again through the stomach - Infection is self- So it’s not like they can limiting (immune survive the acidic system is good at conditions, they are clearing this able to avoid by existing infection as long as inside these particles of you’re not food constantly SPI-1 & SPI-2, reinfecting fimbriae, flagella (read above) Control Flagellin genes (fliC Faecal and fliB) (S. Typhi only contamination of Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 expresses one flagellin food ⇒ hand variant) washing Attach to specific receptors on epithelium Invade epithelial lining of ileum and colon - multiply but cannot escape phagosome Cause acute inflammatory response Activation of mucosal adenylate cyclase ↑ cyclic AMP ↑ secretion >> diarrhoea Infection confined to intestines Entamoeba Two forms Contaminated Pathogenesis: ingest cyst > Gastroenteritis Control It is still unclear histolytica - Trophozoit food / water excysts in SI, divides into 8 Abdominal pain Safe drinking water what triggers E. amoebic e (free trophozoites > lives in lumen of Blood diarrhoea Hand washing histolytica to dysentery feeding), LI > forms ulcers in intestinal (breaking intestinal Improved sanitation become invasive cyst mucosa > bloody dysentery > barrier and blood Diarrhoeal (survival) forms cysts > defaecated, vessels) survives in environment ○ Once they have reached Gal/GalNAc lectin - major the blood surface protein vessels the In trophozoite form, this trophozoites protein allows the protist may to adhere to the host disseminate epithelial cells of causing intestine secondary Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Also has a role in killing ameobiasis, host cells & aiding the spreading to pathogen evade the the liver, host immune system by brain, spleen, mimicking human lungs via glycoprotein CD59, blood where which is an inhibitor of they can form the Membrane Attack an abscess Complex (MAC) 90% asymptomatic Complications: secondary amoebiasis: spreads to liver, brain, spleen, lungs via blood > trophozoites invade > forms abscesses, particularly in the liver Giardia Single- Person-to-person Ingest cyst > stomach Chronic infection Control Lives in SI of intestinalis celled, two Usually water-borne acid excysts > colonises leads to malnutrition, Faecal mammals (you can - Giardiasis nuclei, upper SI, competes for weight loss contamination of also be infected multiple nutrients > damages ○ Pathogen food with water Diarrhoeal flagella epithelial layer by damages the Water sanitation contaminated by attaching to it with a lining of Hand washing animal faeces) Two forms large sucking disc intestine - trophozoite Anchoring avoids limiting how Pathogenesis (free washing away (SI = nutrients is feeding), rapid flow) taken up cyst Decreases absorption Greasy / watery (survival) of nutrients: diarrhoea malabsorption of fats, Abdominal cramps fluids Nausea Secretes cysteine Bloating proteases which can Flatulence damage host tissues, Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 have a role in immune modulation by degrading chemokines. Sucking disc structure - protist attach to the intestinal lining and can directly, mechanically damage the epithelial layer Norovirus Non- Person-to-person Pathogenesis Gastroenteritis Outbreaks: close - enveloped Effective pathogen because: communities, aged-care Gastroenteri virus, able Exposure to Lacks durable immunity: facilities, hospitals, cruise tis to persist aerosols of strain specific immunity ships, sporting events, for a long norovirus from only for several weeks schools, elderly: severe, Diarrhoeal time in vomiting person after infection longer external Short incubation period environmen Direct or indirect 24-48hrs t faecal Persistent: faecal contamination shedding up to 60 days Low found on fomites infectious Ingest norovirus virions > P2 dose, Ingest faecally capsid protein binds to HBGA highly contaminated food on surface of mucosal epithelial infectious or water cells, enterocytes > infect macrophages, dendritic cells, B lymphocytes and lamina propria of SI > blunt villi and microvilli > commensal bacteria enhance infection > inflammation > oedema Some strains of norovirus can use M- Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 cells in GIT to traffic into underlying tissue, by passing epithelial barrier ○ Can then infect immune cells (lymphocytes, DCs) Viral NTPase - inhibit production of IFN-beta during infection Antigen variation - escape immune recognition & allow reinfection Rotavirus Non Viroporin NSP4 (viral Infects and - enveloped, enterotoxin) - action on replicates in Gastroenteri doubled- chloride channels leads enterocytes of SI tis stranded to water loss Non-inflammatory RNA ○ Regulates (unlike norovirus, (dsRNA) calcium we don’t see a segmented homeostasis to huge amount of genome favour viral immune response) replication Virus shed ○ Also acts on in large enteric neurons quantities, (neurons that low innervate the infectious intestine) to dose increase intestinal motility Poliovirus Non- Faecal-oral route 2B protein ‘viroporin’ - Most infections asymptomatic Control Live-attenuated Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 (enteroviru eveloped a small virus encoded Fever, headache, Hygiene & Sabin vaccine s) virus, Contamination of ion channel sore throat sanitation strain of poliovirus - icosahedral environmental ○ Alter membrane 0.5% neurological contains a mutation Poliomyelitis capsid, surfaces (e..g permeability of symptoms in the 5’ non-coding containing hospitals, nurseries, infected cells to section of RNA Non- single daycare centres, increase genome diarrhoeal stranded, nursing homes) release of new ○ This positive - Surfaces virions mutation sense RNA e.g. door ○ Activates reduces handles, release of ability of Humans clothes, proinflammatory this strain are the only telephones, cytokine IL-1B to infect natural host toilet seats, from infected neurons walls, etc cells 3A protein - inhibit Survival of viruses is trafficking of MHC-I multifactorial peptide complexes to Environmental allow evasion of CD8 T factors cell killing ○ Suspension medium ○ Presence of organic matter ○ Temperatur e& humidity Intrinsic factors ○ Nonevelop ed ○ Virus type and strain ○ Viral inoculum Fomite properties ○ Porous or Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 nonporous ○ Antiviral properties Intoxication: Enterotoxigenic E. coli (ETEC) Pathogenesis & virulence Fimbriae attach to SI epithelial wall ○ thread like structures extend from cell surface ○ adhesin protein at tip: affinity for specific molecule Help avoid being washed away by rapid flow of food Produce toxins (E. coli labile toxins) ○ Toxin can be produced in food and ingested or after host colonisation ○ similar in structure and effect to cholera toxin ○ attach to surface SI epithelial cell ○ disrupt ion/water flow across membrane ○ cause massive secretion water and salts into lumen of intestine ○ In acute cases salts and fluid loss ⇒ dehydration, death ○ Rehydration therapy very effective: isotonic salt solutions readily taken up in stomach Poliovirus Replication Poliovirus attaches and enters host cells by interacting with host cell receptor, CD155 ○ This is an epithelial adhesion molecule, also referred to as poliovirus receptor (PVR). Virus capsid and PVR interaction allows viral RNA genome to enter host cell cytoplasm Ribosomes in host cell are used to translate positive sense RNA genome into proteins, as if it were messenger RNA (Note: negative-sense RNA cannot be read directly by a ribosome and must be converted to +RNA first). ○ Genome is translated from a single open reading frame into a polyprotein which then cleaves itself into smaller viral proteins Synthesising new RNA (or DNA) requires a template, from which a complementary strand can be made ○ In order for poliovirus to replicate its own genome, it must make a complimentary strand of -RNA to act as a template when synthesising more +RNA ○ General flow of genetic information: DNA ⇒ RNA ⇒ protein (therefore cells only contain polymerases capable of producing RNA from a DNA template (DNA-dependent RNA polymerase) This means that RNA viruses must encode their own RNA-dependent RNA polymerase (RdRp) in order to replicate their genomes. In poliovirus, this is the 3Dpol protein The viral 3Dpol protein can use the +RNA genome to make a -RNA complimentary strand - to serve as a template to make more +RNA Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Pathogenesis Once an individual is infected with poliovirus, the virus replicates in the mucosal tissue of the gastrointestinal tract It can also drain to and replicate in lymphoid tissue, including the tonsils and Peyer’s patches Antibody responses and poliovirus Neutralising antibodies found in the bloodstream are crucial for preventing the virus from spreading to the CNS, but do not prevent infection or control transmission In contrast, mucosal IgA can prevent or restrict viral replication (and therefore infection) in GIT, limit sheeding and transmission of virus During primary infection with poliovirus, specific antibodies take time to be generated ○ For it to be useful in preventing infection and disease, they must be pre-existing ○ Antibodies can be transferred to an individual via passive immunity (mother to child) or due to vaccination There are 3 serotypes of poliovirus ○ Antibodies bind to antigens with a very high degree of specificity ⇒ surface antigens of each poliovirus serotype are different enough from each other that they cannot be recognized by antibodies generated by other two serotypes Recall that the generation of high affinity neutralising antibodies, mucosal IgA and immunological memory specific for protein antigens requires help from CD4 T helper cells The figure below shows the key steps in the generation of protective antibody responses, which can arise following natural infection or vaccination. ○ Central to this response is the generation long-lived terminally-differentiated B cells, termed plasma cells, and memory B cells. ○ Plasma cells reside in the bone marrow and mucosa and continually secrete high-affinity antibodies, even after the antigen has been cleared. ○ Memory B cells do not secrete antibodies, but can rapidly respond when the pathogen is re-encountered, and undergo further rounds of affinity maturation. Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Vaccination Salk vaccine - intramuscular injection ○ Contains inactivated virus, so there is no risk of transmission Sabin vaccine - oral polio vaccine containing attenuated virus - effective against all 3 serotypes ○ There were a few cases that traced back to this vaccine - mutations of the virus following vaccination allowed microbe to revert to a virulent form Today, there are six different vaccines to stop polio transmission: Inactivated polio vaccine (IPV) – protects against poliovirus types 1, 2, and 3 Trivalent oral polio vaccine (tOPV) – protects against poliovirus types 1, 2, and 3 - following the "OPV Switch" in April 2016, tOPV is no longer in use Bivalent oral polio vaccine (bOPV) – protects against poliovirus types 1, and 3 Monovalent oral polio vaccines (mOPV1, mOPV2 and mOPV3) – protect against each individual type of poliovirus, respectively Antibodies As can be seen from the graphs below, Immunoglobulin M (IgM) is the first antibody produced in response to both vaccines. ○ This is because IgM can be expressed without isotype switching. ○ IgM is also produced prior to somatic hypermutation which leads to affinity maturation, hence IgM typical has a lower affinity for antigens. Isotype Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 switching is required for the production of IgG and IgA antibodies. SKIN SYSTEM Normal skin microbiota Could cause infection by generally don’t due to: ○ Intact stratum corneum and epidermis ○ Shedding of stratum corneum (most microorganisms can’t exist there long enough to establish residence / infection) ○ Host immune system Pathogens further prevented by ○ Low skin pH (5.5) and high salt ○ Resident microbes BACTERIA, VIRUS, PROTIST, FUNGI Bacterial skin infections – from top to bottom Epidermis - Impetigo Caused by Strep. pyogenes alone or with Staph. aureus Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 ○ Can be a polymicrobial infection (multiple microbes causing an infection) Does not scar as infection is superficial No significant immune response Resolves spontaneously or with antibiotic treatment Epidermis - Staphylococcus scalded skin syndrome (Ritters disease) Disease caused by toxin carried by certain strains of Staphylococcus = exfolitin Occurs in young children - spontaneous recovery in 7-10 days; scarring absent Secondary bacterial infections can sometimes cause more serious disease ○ Since you’re really damaging the outer layer of the skin - you can get secondary infection by more serious pathogens Dermis - Erysipelas Usually caused by Streptococcus pyogenes Most common in very young children (as immune system develops) or elderly individuals (immune system declining) Bright red lesions due to immune reaction Treat with antibiotics that are effective against Streptococcus Dermis appendages - Acne vulgaris Common in adolescence when the endocrine system is very active Hormonal activity stimulates overproduction of sebum by oil glands àpromotes growth of Propionibacterium acnes Inflammatory response can produce a comedo - a plug of sebum and keratin in the oil gland duct - visible as pimples and blackheads Treat with antibacterials/antibiotics or with retinol to reduce oil gland function Dermis appendages - Folliculitis Infection and inflammation of the hair follicle Staphylococcus aureus is most common cause On base of eyelid = stye Dermis and appendages - Furuncles (boils) and Carbuncles Furuncles - extension of folliculitis Carbuncles - result from coalescence of furuncles ○ Chills and fever associated indicate systemic spread of Staphylococcus Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Deep Dermis and Subcutaneous Fat - Cellulitis Originates from superficial skin lesions or following trauma Lesion hot and red; patient suffers chills and fever Usual cause = Strep pyogenes; less common = Staph aureus Sometimes other organisms eg Vibrio vulnificans ○ A marine microorganism - if you have a wound injury in salt water ⇒ if you develop cellulitis, it is because of this organism Rapid diagnosis and treatment essential (as this is a very fast moving infection, treatment has to be rapid and initiated immediately) Superficial Fascia - Necrotizing fasciitis Involves superficial facia and subcutaneous fat Surrounding tissue substantially undermined resulting in patchy anaesthesia or gangrene Two causes: 1. Streptococcus pyogenes “Flesh eating bacterial disease” Systemic infection can lead to streptococcal toxic shock syndrome (TSLS) Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 2. Mixed infection of facultative and obligate anaerobes usually of bowel origin Frequently Clostridium perfringens Invades deep in tissues and produces bubbles of gas Much of damage due to alpha toxin - if this enters bloodstream can cause hemolysis ⇒ death ○ Can hydrolysed lipids in cell membranes & kill the cells Antibiotics can’t cure; surgery/amputation may be needed Sometimes treated with hyperbaric oxygen therapy (chamber where the patient is placed - high pressure and high oxygen levels are pushed into the dead tissue) ○ Oxygen is toxic to the anaerobes - will kill them Staphylococcus aureus Tough walls – is Gram positive Salt tolerance – can grow in 7.5% NaCl pH tolerance – grows from ph 4-10 Temperature tolerance – grows optimally at 37oC and can tolerate higher temperatures Staphylococcusis highly adapted to life on the skin Type Transmission Virulence mechanism Symptoms Other facts (incl. Immune response (gram) treatments, etc) Staphylocc Gram Person to person Cell capsule No vaccines us aureus positive (small/thin) – prevents * in epithelium of phagocytosis by Treatment is based on nostrils immune cells (biofilms) severity ○ Not avoid it Simple skin Risk of acquiring completely, but infections - topical increases with evade it or oral antibiotics activities / places sometimes Deeper / more that involve Toxins – various severe infections - crowing, skin-to- secreted toxins (TSST- may need skin contact, shared 1, exfolitin etc.) that prolonged equipment or can directly degrade treatment supplies skin tissues, promote excess inflammation Antimicrobal resistance Downloaded by Jieaa K Jain ([email protected])  lOMoARcPSD|38054369 Most prevalent and kill immune cells Resistant to causes of Invasins – secreted commonly used nosocomial enzymes that break antibiotics (originating in a down host tissues and MRSA = methicillin- hospital) aid invasion resistant bacteraemia, Immunoglobulin- Staphylococcus hospital-acquired binding proteins –bind aureus – but are pneumonia, surgical to and neutralise