03 - January 23, 2013.docx

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Cell and Systems Biology
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Gray- Owen

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MIJ 03 – January 23, 2013 Pathogenesis of Neisseria – first lecture two weeks ago Crohn’s disease – inflammation through lower GI tract; due to mutation that triggers inflammation Inflammatory bowel disease – overzealous immune response – curable in that can excise the colon Inbalance – anything that is going to effect the balance of the host immune response (normal immune response) in the gut and flora or pathogens in the lumen of the gut – can lead to inflammation – if these are out of balance – lead to inflammation – >100 genes linked to inflammatory bowel disease – only account for a small portion of the disease – if have one of the susceptibility alleles – will not get – if have symptoms of Crohn’s disease – do not necessarily have one of these susceptibility alleles – very complex Across the epithelial barrier in the gut, massive number of bacteria, viruses, etc Microbiome – balance – commensal bacteria necessary for health IBD patients tend to have different microbiome than healthy people – more restricted, less diversity of bacteria – fecal replacement therapy has beneficial effe cts Mutations = ones that affect normal epitheial barrier function; microbial sensing; immune homeostasis Mutations cluster in general function – Any time any of these are disrupted on the right on the side No one particular cause NOD2 – mutations most common susceptibility loci – other things can also affect this What triggers IBD? Susceptibility alleles present but may never show signs of disease; If susceptible in immune homeostasis and damage barrier – immune response does not shut itself down Trigger of the flare up may be pathogen that destroys the epitheial barrier – not as simple as this – epitheial barrier turning over constantly – Microbiome and IBD Rather than look at bacteria individually as good or pathogenic, consider as a whole ecosystem Microbiome determine how food is processed and how basal immunesystems has – reduced diversity of bacteria in people with inflammatory bowel disease If inflammation – kill of anaerobic bacteria – but could be that absence of certain bacteria that leads to – probiotic bacteria – need for normal development of gut – in autobiotic mice that are sterile – adding one species of bacteria – allow normal development of intestine – some of bacteria may have large ability to swing from health and disease Invasive E coli is a feature of Crohn’s disease Very common aerobic bacteria In gut – different pathovars, different strains that cause different types of disease Most e. coli in healthy gut does not adhere to epithelium Bacteria not on apical surface of epithelium – most in luminal contents, passing through or in the mucus Pathogenic e. coli have in common that they adhere to apical surface – tend to stay Pathogenic e. coli – type three secretion system – reorganize actin cytoskeleton that allows bacteria to attach avidly – what most pathogenic e. coli does Adhere but no through a type three secretion system and do not remain on pedestal on cells – bust through epitheial cell and destroy the epitheial barrier More highly invasive E. coli – no effector proteins Half of patients with CD have E. coli that invaded – many people have an invasive phenotype in gut but not associated with inflammation and People with CD have it – colocalizes with inflamed tissues – thought to drive the infection Adherent and invasive E. coli LF82 – grew epitheial cells on filter support Staining in red is tight junction; green is nuclei of epitheial cells; cells not permeable – tight junctions between cells When infect with pathogenic E. coli (both the entero pathogenic and the adhering) – junctions destroyed – cells die and detach from each other – spaces for bacteria to get through Cells filling up with adhering and invading E. coli Destroying the barrier function If pathogen breaks down barrier – may be triggering event for inflammation Other bacteria does this too. – cause or effect? AIEC localized to inflamed tissues – looking at biopsies of inflamed tissues vs non inflamed tissues – does bacteria cause the inflammation or just colonize the inflamed tissues? How effect immune sytem regulation? These bacteria – no virulence factors – if infect macrophage – adhering invading E. coli – drive potent inflammatory response – driving inflammatory response – can have two effects – cause inflammation Inflammatory cytokines start to break down epitheial barrier E. coli AIEC – single cell on epitheial layer – in patient, binds to apical surface of epitheial cell, but does not bind to normal healthy intestine – more bacteria binding to apical surface of CD patients – something unique about the apical surface CEACAM regulation of – block CEACAM six – bacteria no longer adherent In healthy individuals, no CEACAM six in the tissues – epitheial lining of small intestine – purple is nuclei Control – no ceacam – and in Crohn’s disease patients – large variation in the amount – most people had CAECAM expressed at apical surface of inflamed tissues – some express massive amounts of CAECAM 6 This was driven by pro-inflammatory cytokines – INF gamma and TNF alpha increase CEACAM expression on the cells – increase the number of bacteria that can accumulate on the tissues Bacteria engulfed by phagocytes – drive inflammatory response – as this response increases, CEACAM expression increases on apical surface of epitheial gut Increase CAECAM expression – allowing more bacteria to bind and colonize the tissues CEABAC – mice that overexpress human CEACAM – mice do not have CEACAM six, so no receptor for these bacteria WT mice pretty resistant to these pathogens – mice that express either two or ten copies of CEACAM in section A CAECAM 6 is expressed in the intestines where these bacteria colonize CAEBAC mice have all of these – mice line that has normal human levels of CEACAM six, and over express it (ten copies) – how respond to infection? Feed orogastric – CB2 has normal levels (completely resistant to infection), and when overexpress CAECAM in gut, mice become ill and succumb to infection Receptor needs to be there not in low level but need to over express the receptor in order to get good – cause and effect – expression of receptor – result in pathology CAECAM overexpression promotes disease progression following orogastric AIEC infection – GI problems when overexpress CAECAM – more weight loss; more symptoms of the disease Over expression of the receptor is bad – bacteria not pathogenic in normal healthy mouse Luciferase expressing strains of AIEC – see bacteria in intestine – right hand picture, bacteria in lungs – Bacteria caused massive amount of damage – if look at non-infected tissues, they’re healthy and when infected with AIEC, massive damage to tissues – only occurs in transgenic mice – wild-type mice – when CEACAM over expressed, massive inflammation and massive tissue damage Systemically – this type of damage is occurring over a week or ten days – some mice were dying within a day or two – see large number of transgenic animals had bacteria in blood spleen, liver, and lymph nodes Highly virulent bacteria – getting into GI tract, attaching to tissues – replicating in tissues rapidly – Crohn’s disease model end up being bacterial systemic infection model because so virulent and effective at getting at the tissues Bacteria put in in luciferase – other bacteria, commensal bacteria, also get into the tissues – not just the few pathogenic bacteria that cause pathogenesis – breaking the barrier down and getting into the tissues and spilling out AIEC attach to CEACAM – trigger may be low-level inflammation with people with Crohn’s susceptibility alleles – damage or viral infection – lead to upregulation of CEACAM 6 in the tissues – once this happens and once density of CAECAM at surface gets high enough – bacteria are going to be able to get into the tissues down below and interact with phagocytes, the sentinel cells – survive through unknown virulence factor – Feeding back to epithelia – causing breakdown in tight junctions in epithelial – allowing more to spill – drive the immune response – triggered by this bacteria (and possibly others) Outstanding questions Different AIEC strains affect the mice – AIEC strains differ Vaccinate animals CEACAM 1 and 6 controlled by early transcription factor NF kappa B – coexpressed with cytokines driving inflammatory response – some indication that – epitheial cells may turn up CEACAM 6 – purpose of epithelial – no idea other than that – Crohn’s disease = syndrome Neisseria – changes is appearance, suppress immune response, avoid antibody and complement, but other strategies that bacteria use – most times, bacteria and viruses obey these nechanisms – Classify immune evasion mechanisms into different groups in this Cell paper Many levels of immune system Highlight different types of things bacteira do Listeria monocytogenes – it does a lot of different things t
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