01 - January 9, 2013.docx

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University of Toronto St. George
Cell and Systems Biology
Gray- Owen

MIJ485H – January 8, 2013 BACTERIAL IMMUNE EVASION Constant exposure to microorganisms Organisms have learned to overcome immune system MULTIPLE levels of the immune system – it defends itself against bacteria on MULTIPLE levels What immune mechanisms combat infection of mucosal surfaces – what types of things protect against that? Antimicrobial peptides; mucus; barrier function of the epithelial cells; IgA, IgG; other bacteria, as in competition with commensal bacteria; neutrophils and macrophages; complement system – MANY DIFFERENT LEVELS OF PROTECTION - Also nutritional immunity – if inject bacteria into blood, cannot grow because cannot acquire nutrients – the most important one is IRON – not enough in blood for support of growth of bacteria Neisseria – pathogenic Neisseria – cause gonorrhea, invasive meningococcal disease – also have commensal Neisseria in human tissues that have adapted to live in humans and NO WHERE ELSE (no other reservoirs) Adaptation resulted in them losing features of other bacteira to live in other environments They have learned to suppress our immune system s Two pathogens – meningitis have capsule Variants of each of these pathogens – reinfected is due to multiple different strains Commensal bacteria – live in the same niche as the pathogenic Neisseria - In the UK, a study where people snorted lactamica – less likely to be colonized by meningitis All have in common – 1 small genome; 2 similar mechanisms to colonize tissues Unclear why commensals do not cause disease, while pathogenic ones do Infectious process seems same regardless of which strain – pathogenic or commensal Mucus FLOW – will not reach epithelium Type 4 pillus – like lasso that attaches to epithelium then retracts using a molecular motor and overcome the mucus barrier and hold itself in place in mucus flow – once down at cell surface, other adhesions bind to CEACAM receptors, allowing them to stick to the tissues – Neisseria has curious propensity to stay on apical side, instead pass through epitheial barrier and pass into subepitheial space Neisseria bathing in human nutrients SO FAR, no competitors, bathed in nutrients BUT neisseria immune cells – need to deal with this?? Meningococal disease – not a lot compared to gonorrhea Blood leaking from blood vessels – death follows quickly M disease – 1/5 chance of dying Disease progresses very quickly – need for prophylactic vaccines In the nasopharynx and into lungs, blue is resident flora where colonized – after that, should be sterile – meningogal in nasopharynx Gonorrhea – many more cases than m disease If asymptomatic – evolutionary advantage that women will then spread the disease Direct impact on HIV – people with gonorrhea shed more virus, more infectious – if have gonorrhea and exposed to HIV, more likely to be infected by HIV In men, uretha colonized by commensals – maybe gonorrhea In women, uretha and vagina colonized – gonorreha live in the cervix pH in vagina kills most gonorrhea But Menigocoal in blood or brain – then considered pathogen, but not if in throat Neutrophils – easy to diagnose – in pus produced at tip of penis In women, bacteria are higher up from surface of external genitalia – may not realize they are infected – problem is the bacteria can drive up, cause scarring in uterus, inflammation, infertility, ectopic pregnancies Pathogenic Neisseria – a plastic genome Huge motivation to develop meningococcal vaccine Gonorrehea vaccine less popular due to association with sex Strains have arisen that are now untreatable A common gene pool? Commensal strains in throat – bacteria can take up Neisseria has a signature tag 5 GCCGTCTGAA – when bacteria secretes DNA in environment, the bacteria next to it, when recognize the sequence, will integrate the DNA into the chromosome – recombination within and BETWEEN strains 1% transformation efficiency – Transformation-mediated exchange of virulence determants by co-cultivation of pathogenic neisseriae - Resistant to both antibiotic in an hour – - Put bacteria and grow in culture – shuffle DNA – NOT by conjugation – pumping out DNA - This occurs for anything in the bacteria – antibiotic resistance markers, surface proteins Phase and antigenic vafriation of surface epitopes - Almost every antigen on Neisseria surface is variable - LPS, proteins, and polysaccharide capsules can be turned up, turned down Adhesins – must maintain this function – protein-protein interaction BUT incredibly variable Opa proteins – conserved in transmembrane domain and periplasmic space but cell surface differences – they are different but still bind the receptors Menstruation is Opa- A selection for what’s there – a constant variation of Opa – select for function wanted at that particular time, in those tissues Phenotype trumps genotype – sequence is not predictive of function Change each time you subculture – all expressing different Opa variants – affects bacterial binding to host cell but also aggregation of bacteria in colony, so opacity changed Genetic mechanisms of antigenic variation Environmental stimulus – ex. Presence of sucrose – rare for Neisseria – one env cue is iron Phase variation – constantly have a mix of phenotypes of potential functions – do not respond as a population – depending on which antibody is around, - what ever allows establishes and persists infection Recombination – coinfection – emphasis on fitness Leader peptide Opa genes composed of signature – in between CTCTT repeated Then Neisseria – add or subtract a five nucleotide repeat If out of frame, Opa variant not expressed, add five nucleotides again not expressed, since out of frame THIS IS TRANSLATIONAL All eleven genes are transcribed at all times at high rate; all genes are making this __________________ Randomly making combinations – happening in eleven loci – Recombination Surface looks in the yellow cassettes – always recombination in different genes of bacteria; new variants generated all the time Absolutely must maintain function – needs to recognize CEACAM protein or LOS sugars Neisseira has no spare parts – small genome CEACAMs – family of cell adhesion molecules that function in cell cell binding Opa proteins bind host side of receptors Neiseria selectively binds four different ones – CEACAM1, 5, 6, and?? These receptors do different things – different features Lipid anchor Some have transmembrane and cytoplasmic domains Can have different outcomes of binding – 1 is inhibiting receptor; 3 activating receptor Good handle for pathogens to bind to in bacteria hosts Viruses and bacteria bind CEACAMs Only targeted by pathogens that have one host – Ecoli are unique in that they live only in humans Evolutionary pressure of microbes on this family of CEACAMs Divergent evolution – Targeting a Niche CAECAM – black is bacterial binding to CEACAM1/3/4; gray is bacterial invasion into cells There are certain Opa variants such as 58 that bind all four CEACAMs; other Opa variants that are unique to one Depending on the CECAM expressed by host cell and the Opa expressed by the bacteria – DIFFERNET OUTCOMES, different binding, different signalling in cell Mice has only the CAECAM1 receptor – So supplement mice with human receptor – - ASK Tissues filled with gnococcal in transgenic mice – can get infection with gonorrhea Can get infection in nasal pharayn with Neisseria mening
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