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Lecture 3: Innate Immunity and Infections (w/ brief intro to adaptive immunity) Chapter 5 Infections Viruses, bacteria and

and fungi Spread of infection Pathogens can get in body through numerous routes Breath, wound, eat, skin, etc Can spread through blood or lymph, etc Bacteria differentiation Gram stain: used for classifying bacteria, most can be classified but a few cant Gram + Gram Other (ex. Acid-fast, nothing) Shape Cocci: spherical Bacillus: rods other Oxygen requirements Aerobic Need oxygen for oxidative phosphorylation

If dont have O2 they die Find on skin and lungs Microaerobic Need some oxygen but not much. a lot of oxygen will kill them Find in GI tract (not much air in here but theres some) Facultative anaerobic Can use oxygen if they have it, but can survive without it Obligate anaerobic Cannot tolerate oxygen Find in deep tissue wounds Toxin formation Endotoxin (from Gram (-) bacteria, release by bacterial cell death) Released when bacteria dies Ex. LPS lipopolysaccharide Quarum sensing release endotoxins and kill bacteria of other species A lot of our antibiotics are derived from bacteria => look for something that kills other bacteria and doesnt hurt humans Eg. Penicillin created by bacteria from fungi Exotoxin (from Gram + bacteria, secreted from live bacteria) Released from live bacteria Ex. Botulinum toxin, tetanus Spore formation

Spores allow bacteria to survive difficult environment and are almost indestructible Can survive hot, cold, dry, etc If bacteria makes itself into spore they are difficult to eliminate Yes/No (ability) most bacteria cannot make spores Intracellular Yes/No Most bacteria live outside of our cells Some required to be inside cell to survive Over 90% of cells in body are bacterial cells But bacteria are much much smaller than human cells Staphylococcus aureus: most common nosocomial disease MRSA - is most common, MRSA- is 2nd most common MRSA = Methicillin Resistant Staph Aureus ~90% of nurses carry Staph. aureus, many also carry MRSA Know whether Gram +/- and cocci/bacillus (from chart on slide of bacteria) 90% of cells in the body are bacteria & bacteroides is number one and ecoli is number 2, however, our cells out number it by weight General structure of bacteria Gram has an outer cell wall Outer membrane prevents purple dye from entering during gram stain, ends up being pink or red Has thick peptidoglycan layer + outer membrane layer Gram + has peptidoglycan layer without outer membrane or wall

Purple stain stays there Staph aureas +/- are the number 1 and 2 spots of no diseases DNA and plasmids Bacteria can share ___ Bacteria can transfer DNA horizontally allows antibiotic resistance to spread very quickly Plasmids are extra genetic material. Plasmids: small piece of DNA, give bacteria super power (e.g. ability to break down antibiotic) Once one gets super power it can transfer to friends One has plasmid can go to another (even if not same species) mate and give copy of plasmid and now both have superpower Drug manufacture: use this method to manufacture proteins Take DNA to make protein, inject it into a plasmid, it replicates and then we kill bacteria and harvest protein Ex. Insulin and most peptide drugs Stages of viral infection of a host cell Viruses are completely different from bacteria and consequently, antibiotics that work on bacteria are ineffective on viruses We have very few antiviral medications ALL viruses are intracellular Viral membrane will fuse with our DNA and our body/machinery will reproduce the viral DNA About 5% of our DNA is of viral origin. Gene therapy: take a virus, disable it so it cant replicate, put it in our . Virus does not have a life without the host cell Viron (a single virus particle) has genetic material, envelope much smaller than bacteria

Looks for specific receptor (not only species specific but cell type specific) Binds to receptor and Gains entry Uncoats (gets rid of envelope) Exposes genetic material, material inserts into our DNA Uses our machinery to make and its proteins and to make copies of its own DNA Takes our plasma membrane and more viruses released ~5% of our DNA is actually derived from viruses that we acquired over many years Viruses: positive aspect of viruses = gene therapy (whatever gene was defective/missing is inserted into patients DNA) types of fungi molds and yeasts are both fungus most medically relevant fungi candida albicans causes opportunistic infections yeast infections normal gut flora aspergillus spp. Highly aerobic Respiratory infections Immunocompromised patients Tinea (general fungus for skin fungus dermatophyte) Tinea capitis: head Tinea pedis: fungus on feet (athletes foot)

Tinea curis: groin (jock itch) Tend to happen in places that get moist and stay moist The immune system is complicated Has to protect us from every possible pathogen from every possible entry Lots of specialized players Our immune system can kill bacteria and viruses easier than fungi, protozoans, and helmiths (worms) because these are eurkaryote cells and are more similar to our cells Hematopoietic cells RBCs Megakaryocytes platelets Mononuclear phagocytic system Monocyte Dont really do anything, when they leave the blood they become macrophages Macrophage Kuppfer cell: liver Get first crack, because blood goes here first from GI tract Microglia: brain You dont want these activated Traumatic brain injury or stroke Dust cell: lung Osteoclast: bone (not immune cells) Multinuclear giant cell

Dendritic cell (NOT macrophages) Langerhans cell: skin Polymorphonuclear leukocyte/granulocytes => will see granules and inside them will be stuff to kill things Neutrophil (most common) Basophil Eosinophil Mast cell (outside of cell in tissue) Lymphocytes All look the same under normal (Giemsa) stain used with blood if we stain for the different CDs, we can distinguish lymphocytes B cells Plasma cells Make antibodies Memory cells Keep copy in case pathogen ever comes back T cells Tc cytotoxic T cells (CD8+) Th helper T cells (CD4+) 2 types of helper cells (Th1 & Th2) Know that they are different but dont need to know what how different Memory cells

NK - natural killer cells My mnemonic for remembering the order of immune cells (from most to least common) Never (neutrophils) let (lymphocytes) monkeys (monocytes) eat (eosinophils) bananas (basophils) Macrophages, dendritic cells and mast cells are not typically found in blood only tissue Overview of the immune system Humoral (extracellular) all fluid outside cells Innate: myeloid cells (neutrophils, macrophages, mast cells, eosinophils) Does NOT change Non-host (not on one of your self cells) epitopes (some part of protein that immune cell can grab onto) Bacteria try to limit amount of epitopes Adaptive Change over time based on specific threats body is encountering at time B-cells (antibodies, also Th cells, APCs; Antigen Presenting Cells) Produce antibodies that are very specific (can make antibody that will not bind to your protein but will bind to classmates version of that protein) Takes time to develop these pathogen specific antibodies Cell-mediated (intracellular) => virus are intracellular pathogens Innate Does not change Always our cells? NK cells (Natural Killer T cells) MHC existence

Adaptive Change over time based on what weve been exposed to Cytotoxic T cells If cell is abnormal it kills it They kill our cells that are infected Cells of innate immunity Macrophages are all the same, they will move into the blood and Dandritic cells will take up residence in Macrophages all over body waiting for something to happen Macrophages at site of trauma see damage and possibility of bacteria Responsible for innate response Engulfs bacteria and releases cytokines For us, cytokines are magic fairy dust they do whatever they are supposed to do Will release some cytokines that initiate inflammation Trigger chemokines (will ) that allow neutrophils to come up to bacteria Neutrophils have been circulating in blood and now come rushing in and kill off bacteria => looking for a fight Neutrophils eventually go away after destroying everything and macrophages will come back and clean everything up Sequence of events in the process of inflammation (all these have inflammatory response) Sprained ankle Caused by trauma to tissue Swells within minutes

Increased blood flow (redness and warmth) Endothelial cells retract from each other allowing neutrophils and plasma proteins to leave Movement of plasma proteins from inside vascular space to outside Localized edema Caused by proteins leaking out Want this to happen because it sets your ankle and keeps it stable Clean wound, no bacteria But lots of broken tendons/ligaments that need to be cleaned by neutrophils & repaired with the help of macrophages Mosquito bite Dont bleed => foreign proteins to prevent Platelet aggregation, prevents tissue from bleeding Note: mosquitoes (and other biting insects) must produce anti-coagulant to prevent blood from clotting while they are eating The raised bump is the local edema that results from inflammation, similar to the sprained ankle Acute inflammatory response Vasodilation (red and heat) => gets more blood into the area, more blood flow Increased vascular permeability (leads to edema) => Cellular infiltration (pus is neutrophils, pus is dead neutrophils, pus seen in infection) Thrombosis (clots) Keep from bleeding out Platelet aggrigation Stimulation of nerve endings (pain)

Degranulation and synthesis of biologic mediators by mast cells during inflammation Degranulation of pre-formed vesicles Histamine increases vascular permeability (e.g. causes runny nose & water eyes w/allergies) Antihistamine will block the effect of histamine by binding and blocking Neutrophil chemotactic factors and eosinophil chemotactic factors attract neutrophils & eosinophils Synthesis of eicosanoids 20 carbon molecules derived from fatty acids We cant store them so we make them until immune attack is finished 4 families of eicosanoids Prostaglandins, prostacyclins, leukotrienes, thromboxanes Have various inflammatory and immune function (as well as other functions) Phospholipase A2 Removes arachidonic acid (AA, 20 carbon fatty acid that gets head ripped off) & eicosapentaenoic acid (EPA) from plasma membrane Blocked by steroids Cyclo-oxygenase (COX) Converts AA to prostaglandins, prostacyclins, and thromboxanes Cause pain Blocked by COX inhibitors NSAIDs (non-steroidal anti-inflammatory drugs), e.g. aspirin, ibuprofen block both COX-1 (multi function) & COX-2 (inflamation specific) Selective COX-2 inhibitors, e.g. Vioxx, Celebrex dont have side effects of NSAIDs, have other problems (e.g. cardiac death)

Nature of leukocyte infiltrates in inflammatory reactions Ischemic necrosis (infarction) Dead cardiomyocytes trigger inflammatory response Edema, increased vascular permeability almost immediately Neutrophils are early response peak at ~1day Stop the problem, start cleaning up mess (debriding) => digesting dead cardio myocytes Monocytes come in later and convert to macrophages, start repair process Repair process: replace damaged tissue with scar tissue Scar tissue is not contractile (heart doesnt work as well after MI) Often results in significant loss of heart function, e.g. MI CHF Other macrophages leave and one macrophage remains to stand guard Process of phagocytosis Wound, e.g. splinter, damages tissue and introduces bacteria Phagocytes, e.g. macrophages & neutrophils, endocytose (phagocytose) bacteria Non-host epitopes, or If we can have antibodies bound to it, this greatly increases phagocytosis (opsonisation) Endocytic vesicles within phagocyte combine with lysosomes break down bacteria Diapedesis of phagocyte, e.g. neutrophil neutrophis is short lived typically 4 day life cycle if we have inflammation, signal endothelial cells to stop neutrophils, create space for neutrophil to exit vasculature chemotaxis (another version of cytokines)

neutrophil looks for highest concentration of chemotactic factors and is able to find site of infection/injury phases of phagocytosis recognition either non-host epitopes, bound antibody (opsonization), or complement (C3b) engulfment (endocytosis) and bacterium is in phagosome phagosome fuses with lysome, bacterium is killed and digested selected cytokines that mediate inflammation and the acquired immune response cytokines are very complecated, there are many of them and they often have multiple function fortunately, you dont have to know the specific function of any cytokines cytokines associated with stages of inflammation initial response first few seconds to minutes swelling starts, increase vessel leakage, endothelial adhesion (what stops rolling neutrophils = first line of defense) recruitment of cells neutrophils (increase if we have a big infection) are stopped in capillaries close to damage site, diapedesis, chemotaxis send signals to system to send new neutrophils remove debris => neutrophils repair & regeneration => macrophages complete resolution scar healing of fibrosis loss of function

cant fix problem chronic inflammation => usually due to angiogenesis: make new blood vessels going into area mononuclear cell infiltrate scar tuberculosis granuloma results from mycobacterium tuburculosis causes calcium deposits caseous necrosis leaves gunky scaring keep from breaking out but cant get rid of TB, if become immunocompromised, TB can be activated again Wound repair primary intention basement membrane continuous easy healing with no scar secondary intention basement membrane discontinuous deeper or wider wound when it heals, it doesnt come back together nicely leaves scar Keloids Little wound big scar More prone in African Americans (also Africans), ~25% of them

excessive collagen production doesnt always happen If get keloids on skin more likely to get adhesions in surgical procedures Preview of Adaptive Immunity Antibodies Adaptive immune system adapts to whatever pathogens your body has seen Very specific but much slower (takes about a week to kick in) Y shaped Red: variable region; vary from antibody to antibody antigen binding domain Where they bind to bad things: viruses (before it has infected a cell), bacteria etc. Blue: constant region 5 different classes: IgG, IgM, IgD, IgA1, IgE all IgMs have same constant regions, all IgEs have same constant region, etc. how antibodies bind to antigens variable region binds to specific antigen usually a protein binding regions have receptors for very specific portions of a protein that is not on your cells prevent toxins/viruses/bacteria/worm/etc from ever causing harm macrophage has receptor for constant region (opsinization) [candy coating]

macrophages look for bacteria/viruses etc covered in antibody constant regions opsinization greatly increases efficiency of phagocytosis eosinophil and worms worm is too big to ingest so eosinophil degranulates (spills out enzymes) to degrade it degranulates in order to kill the parasite B Cell Fundamentals take DNA and area that codes for variable region of antibody, take it and chop out parts randomly produced cell that will produce some sort of antibody maybe its good, maybe its not want to make sure its not self-reactive (would cause autoimmune disease) throw proteins at them (nurse cells do this) if B cell responds to any of them it will be killed because it is self-reactive negative selection: keep the ones that dont bind dont know whether useful or not put them in circulation Nave B cell; have antibodies on the surface but have not found antigen yet once it binds to antigen; we know it is useful have antibody that attacks foreign antigen clonal expansion: make many copies of this B cell somatic hypermutation: whenever these cells replicate: there is sloppy replication of variable region; daughter cells will have slightly different/mutated variable regions some will bind better, some will bind worse keep better ones, remove worse ones

with every generation we get antibodies that bind more and more specifically a given B cell makes only 1 specific antibody MHC TCR binding (Major Histocompatibility Complex T cell Receptor) Variable binding domain (one binding domain) T cell receptor made in random way similar to Bcell Antigen always presented by another cell on an MHC Needs right MHC and right Tcell receptor and right antigen to work MHC MHC-I: present self-antigen to cytotoxic T cells (Tc) useful for virally infected cell In a cell, a piece of one of your proteins in presented on MHC-I If T cell binds to this, then cell is virally infected (it is producing foreign protein) could also be mutated DNA T cell kills this cell Exception: herpes I, II, etc. which infects neurons (we dont get new neurons so we dont want to kill them) MHC-II: present foreign antigen to helper T cells (Th) Presentation at the cell surface of exogenous derived antigens via MHC-II Macrophage ingested something that is foreign to us Macrophage could have eaten one of our cells after necrosis but hopefully when presented, T cell wont react Dont want T cell to kill macrophage T cell will sound alarm and set things into motion dont need details at this point Professional Antigen Presenting Cells (APCs)

Cells that will phagocytize bacteria and present them to Th cells Macrophages, B cells and dendritic cells will do this CD8+ T cells (Tc): peptide + MHC-I End result is apoptosis CD4+ T cells (Th): peptide + MHC II Macrophage chewed up foreign bacteria, T helper cell reacts and tells macrophage to keep chewing these up Antibody is all on surface of B cell, then when find and bind to antigen: Receptor mediated endocytosis, chewed up and presented to helper T cell If antigen is foreign, T cell tells B cell to go bind to as many as possible and kill them all If we had self-reacted B cell and found antigen: no T cell would recognize it and B cell wouldnt go any further Second checkpoint to avoid autoimmune problems Innate cell mediated immunity Escape detection: turn off MHC-I so that proteins are never presented We are one step ahead: Natural killer cell (illiterate Gestapo policeman) Checks MHC-I and accompanying surface proteins and makes sure they look fine If MHCs are not there, are too few, mutated or accompanying proteins arent there Something is wrong: killer cell kills that cell Prevents virus from avoiding cytotoxic T cells MHC are on all nucleated cells including leukocytes Everyone except RBCs have to show these (but we are reluctant to kill neurons)