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Lecture 2

IMM250 - Lecture 2 - Innate Barriers.docx

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Department
Immunology
Course Code
IMM250H1
Professor
Dana Philpott

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IMM250 – Lecture 1 – Innate Barriers 1. Overview a. Mucosa – Body surface potentially exposed to the environment and different microbes b. Different types of barriers protecting us from these organisms c. Epithelial cells – which binds the different mucosal surfaces. First line of cells which encounters pathogens d. Commensal Microbiota – e. Pathogen f. Two examples of pathogens i. Salmonella typhimurium ii. Shigella flexneri g. Innate barriers – if invaded and infected innate immunity is activated. h. Skin and mucosa membranes i. Humoral and cellular defenses – different proteins and cells involved in protecting us from the body from pathogens j. Inflammation k. Adaptive immunity – consequence of activating the innate immunity, adaptive immunity is primed 2. Innate host defenses against infection a. Anatomical barriers – physical barriers i. Mechnaical ii. Chemical iii. Biological factors b. Humoral components – blood borne factors i. Complement ii. Coagulation iii. Cytokines / Chemokines – proteins which drives inflammation and protect the body c. Cellular components – innate cells defenders i. Neutrophils ii. Epithelial Cells iii. Monocytes and Macrophages iv. NK cells v. Eosinphils 3. Mucosal surfaces – sites of microbial encounters a. Is the sites in which we come to contact with the microbes in the environment and potentially where pathogens are trying to come and infect us b. Any surface potentially exposed to the environment i. Skin ii. Upper respiratory tract / Trachea iii. mouth iv. Gastrointestinal tract v. Urogenital tract vi. Large intestine / small intestine 4. First line defense strategies a. Eye – lysozyme an enzyme – produced in tears. Dissolve the cell wall of the bacteria entering the eye b. Normal Flora – compete with pathogens c. Respiratory tract – epithelium cells are lined with cilia – finger like projections that stick off the surface of the surface of the tract constantly moves in a upwards fashion bringing particles upwards and keep them going into the lower airways. Drives the stuff upwards. d. Stomach – low pH of 2. Unfriendly condition for life. Inhibits the growth of microbes. Except for pylori a bacteria who can live in the low pH e. Normal microbiota – bacteria which lives in our gut and surface who fight and compete woth pathogens for nutrients and food, which helps from pathogens. f. Skin – a physical barrier produces antimicrobial fatty acids. And its normal flora inhibit pathogen colonization. 5. Anatomical Barriers a. Mechanical b. Chemical c. biological 6. Mechanical barriers- a. Skin – surface exposed to the environment with tons of bacteria i. Tight physical barrier – bacteria, fungus virus has a tough time getting in ii. Quick turn over of cells, constant desquamation of surface epithelial cells which binds the cells. loosing skin cells and with it you lose bacteria and pathogens trying to get in b. Mucous membranes – 1. Gastrointestinal tract – chemical forces of peristalsis: squeezing out the stuff in intestine all the time, with that you are squeezing out and pooping out bacteria and others. There’s an extremely rapid turnover of the epithelium cells lining the intestinal tract. If a pathogen is trying to get in through the epithelial cells, With a day or so a cells going to be lost, and peristalsis Is going to be pooped out in a days 2. Mucociliary escalator-ciliated epithelial cells of the upper respiratory tract, constantly moving and pushing particles and bacteria back up through the mouth. 3. Other Epithelium surfaces: Flushing action of the eyes a. Tears, saliva, urine, mucus 7. Chemical Barriers a. Skin – producing sweat which has antimicrobial factors which can kill microbes on the surface of the skin. b. Mucous Membranes: ii. Low ph. in the stomach i. Enzymes such as lysozyme, phospholipase A (eye) c. Gastro intestinal tract and respiratory tract we have anti-microbial factors that can directly kill bacteria. d. Surfactants in the lung (proteins) – opsonize bacteria; enhances our ability to see bacteria and these are taken up by cells called phagocytosis; Cells which eats up stuff and gets rid of them from our bodies. 8. Biological Factors a. Normal microbiota and systems are very good system against infection. Normal microbiota we have in our skin, upper airway gastrointestinal tract, respiratory tract, urogenital tract. Protects us form microbes. Produces antimicrobial substances. Within the normal microbiota by colonizing surfaces. It’s a very important factor in human surfaces. All the bacteria, fungus are included in this. 9. The normal Microbiota a. Our bodies are like mobile warm-blooded coral reefs, rich in microbial biodiversity and home to vast numbers of bacterial cells i. –more bacterial cells (1014) associated with the human body than there are human ones (only 1013)! b. •What are they? i. –Bacteria, Protozoa, Fungi, Archaea ii. –Metazoa? Viruses? c. •Where are they? i. –Skin and mucosal surfaces d. •composition of normal microbiota varies from individual to individual i. –some bacterial species carried only transiently ii. –most fairly permanent iii. –gut microbiota is defined early in life (around 2 years old)! e. Kind of as a coral reef within our bodies which is existing and protecting us against attacks from microbes f. We have more microbes in our body than human cells. g. Microbiota: i. Bacteria ii. Can also include protozoa, amoeba, fungus, archea and also viruses h. They live in our skin and mucosal surfaces i. The normal microbiota varies from individual to individual. Some bacteria species are only transient, mostly are permanent. Gut microbiota are defined relatively early in life as in age 2. It starts to eve out when humans are 2 years old 10. The core gut microbiota a. Variable between individuals b. Monozygotic and dizygotic twin paris have a similar degree of variance: early environmental exposure is the key determinant - If you look at twins or family members the microbiota are kind of similar rather than with friends or others , maybe because they all are sharing the same environment c. Marked interpersonal variation YET an identifiable core microbiome with similar “functional” outputs – metabolic outputs seem to remain constant Even though there is a huge variable. There seems to be similar identifiable core functional microbial. They don’t seem to have an identifiable component in the same. Different microbes but that they seems to be producing seems to be similar 11. Microbial Loads on Skin and Mucosa surfaces: a. Large intestines has the largest bacteria load b. Huge diversity of organisms in all of these sites, in which most of these are anaerobic. They don’t like oxygen. These are unculturable, but many people are trying to find different systems to make them grow i.e anaerobic chamners etc. 12. Beneficial effects of the gastrointestinal microbiota a. Protective function i. Forms a new surface of colonization of different surfaces and prevent pathogens from coming into the body ii. Takes nutrients out of the system so pathogens can’t take nutrition to function and unable to colonize b. Structural function i. Microbiota Fortifies a barrier between the epithelium cells ii. Induces the immunoglobulin called IgA – secreted by the gut and is very protective) c. Metabolic function i. Produces lots of components we use as fuel. Such as vitamin K, Biotin, Foliate metabolizes by the bacteria and makes it able for us to absorb ii. Make this Short chain fatty acids, break down carbohydrates that are unable to be broken by our guts into fatty acids which is a fuel to the epithelial cells for proliferation and rapid turnover iii. Produces lots of functions which are relative 13. Factors that impact on the establishment of the core gut microbiome – all these factors can influence how the gut microbiota takes shape as we grow into adulthood a. Host genetics – can influence healthy microbiota compositions developed b. Lifestyle – different diets, stress can affect the gut microbiota c. Early Colonization – infants that born by C section and vaginal section have completely different microbiota. And infants who are bottle fed Vs breast fed. d. Medical practices – antibiotics, increase of hygiene can change microbes e. They all lead to Dysbiosis – alterations in the gut microbiome – change within the normal microbiota which can create disease or affect health 14. Harmful effects of alterations in normal microbiota a. Antibiotic use perturbs normal microbiota – clears infections but these also affect the bacteria that live on you or with you. If you take a 10day antibiotic,it has a profound impact on the microbiota, there is a huge flux going on when you take antibiotics. Continued use of antibiotics can give some diseases: i. Clostridium difficile (diarrhea – pseudomembraneous colitis) – associated with mosomular hospital acquired infections. These guys can be in your gut without causing anything, when you take antibiotics you are killing the normal microbiota who is squishing this guys and keeping him in control. When we take antibiotics they can grow out and colonize places of the gut they don’t normally colonize. It’s very severe diarrhoea and pseudomembraneous colitis – ulcer type inflammation on the colon. Very hard infection to treat at the moment. ii. Candida albicans (vaginitis, thrush - oral cavity) – fungal infection. Presents in the gut or genital tract. When we are taking antibiotics we are pushing down normal microbiota and giving restriction factors place which keeps them in check. When these factors are gone the fungus can grow and start a disease. Makes ugly white stuff to grow in your mouth. b. Re-establishing normal proportions of microbiota –also in the gut 1. Probiotics – bacteria which has special beneficial health effects present in yogurt, which can normalize the gut microbiota 2. Prebiotics – nutrients you can put in different yogurt and milk products enhances the growth of bacteria in your microbiota who is already present a. Inulin – enhance the growth of certain microbiota, is a carbohydrate in your yogurt, can increase the microbiota in your body c. Possible implication in other diseases –imbalance of microbiota and other diseases i. Obesity ii. inflammorty bowel disease iii. allergy and asthma 15. Harmful effects of alterations in gut bacteria a. Escape of normal flora to abnormal sites – if the gut bacteria goes to an abnormal site it can cause disease i. Perforates appendix leads to peritonitis – appendix hangs of the colon; has lots of components is microbiota, if it gets infected it has a risk of being professed, and has a chance of bursting and releasing them out from the gut. It’s a serious disease. Infection is called as peritonitis. ii. Urinary tract infections: most frequent organism isolated in this infection is E. coli, a species found in abundance in the intestinal tract. Normally in our intestinal tract it doesn’t cause disease, but if it found in urinary tract it can cause disease 16. Your gut microbiota can make you fat? a. Genetically obese mice are colonized by “super-efficient” microbes that provide more energy for their hosts than the microbes in lean mice – Jeff scientist did a study on obese mice who were rally fat they cannot even walk. He found that the components of the microbiota in the obese mice are super-efficient and any nutrient which the mice eats is being broken down by the bacteria and provided to the host, and host stores it as fat. And obese humans have super-efficient microbiota that breaks down stuff and store it as fat. i. He took the poop of the fat mouse and gave it to the lean mouse, and this made the thin mouse fat b. Transferring these microbiota to lean mouse makes them fat 17. Human studies identify a core “microbiome” associates with obesity a. Obesity in humans have associated with i. Less microbial diversity in their guts – in normal microbiota we have around 31000 species present. These individuals have less diversity in the microbiota. ii. Reduced representation of “bacteroidetes” within the obese individual and over representation of others phyla that were present in the microbiota. iii. There were other Microbes that are more efficient at lipid and carbohydrates metabolism iv. Obesity with humans is associated with less microbial diversity on their guts (as shown in studies) v. He also noticed altered representation of different phyla in the obese individuals 18. Reshaping the gut microbiota a. Probiotic/ prebiotics – through yogurts: have to eat this probiotics always for them to grow and to remain in the gut, because they are transient colonization’s. If you eat it only one day, then it will be there only for like one day. The bacteria in the gut promote the growth of other bacteria in the gut. b. Fecal transplants? (Radical): take the microbiota from a healthy person and feed it to disease person. Might promote health and get rid of the disease of interest. This approach now is being used more and more now for the treatment of the C.difficile infection. Inflammatory bowel disease. c. These approaches may one day be used to prevent against excessive weight or treat certain diseases (C. difficile infection, inflammatory bowel disease) 19. Is there only one type of bacteria on the microbiota? a. There are many probiotics in the yogurts. There are no ‘special’ bacteria.  The Epithelium b. “First Line” of defense against infectious microorganisms: lines all the surfaces we talked about i. Bacteria are coming through the gut trying to get to the system and the epithelium system is the first system they encounter and they
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