Innate Immunity Class Notes PDF

11/5/24 “innate” = “present from birth” (Compare with “adaptive” or learned immunity) Innate immune responses have evolved to defend the body against common threats. Barriers – first line defenses to prevent entry of infectious agents. Sensors – cells or bioche...

11/5/24 “innate” = “present from birth” (Compare with “adaptive” or learned immunity) Innate immune responses have evolved to defend the body against common threats. Barriers – first line defenses to prevent entry of infectious agents. Sensors – cells or biochemical agents that look for known signs of external agents. Effectors – cell or biochemical systems that can quickly respond to general threats 3 Barriers: Skin Multiple layers of epithelial cells Outermost are dead and keratinized! Hard for anything to penetrate -- Repels water Hostile environment -- arid, high salt. External layer flakes off (and is replaced), shedding any MOs that might have attached. Effective barrier in most cases Issues Degradation by constant moisture Mechanical abrasion or penetration (insect vectors) Penetration by specialized biochemistry (e.g., hookworm larvae, schistosome cercaria) Limited use for obtaining nutrients or air or excreting waste! 4 2  11/5/24 Barriers: Mucosal Membranes Areas of the body that require some transport (both directions) and/or constant moisture! Has to be a Barrier and a Door! Also tend to be contained or constrained spaces – more difficult to shed ”outer” layer. 5 Mucosal Membrane – Shed and Wash Still uses shedding philosophy Secretes mucous – sticky Moves mucous along path to specialized disposal area Intestinal and genitourinary tract – move to outside body Sinuses, eyes, and Respiratory tract – move to stomach (and acid) Also sheds outermost cells 6 3  11/5/24 Mucosal Membrane – Antimicrobial Substances Wide range of killing enzymes and peptides. Lysozyme degrades peptidoglycan Peroxidases form reactive oxygen antimicrobials; break down hydrogen peroxide Lactoferrin and transferrin bind iron (required for most MO growth) Specialized defense peptides (book calls HDPs) Defensins form pores in microbial membranes 7 Recruiting Microbial Allies – normal Flora Competitive exclusion of pathogens Cover-binding sites, Consume available nutrients Production of toxic compounds Cutibacterium species degrade lipids, produce fatty acids E. coli synthesizes colicins in intestinal tract Lactobacillus in vagina produce low pH à We have seen where disruption of normal flora leads to disease symptoms 8 4  11/5/24 But what if get past skin and mucosal barriers? Defenses in Blood and Lymph! Set of specialized cells derived from bone marrow “hematopoietic stem cells” Three general classes: Red blood cells (erythrocytes) -- oxygen transport Platelets (from megakaryocytes or thrombocytes) – clotting White blood cells (leukocytes) – body defenses! 9 White Blood Cells Originally named for their microscopic appearance Granulocytes Granules in cytoplasm seen with different special stains Mononuclear phagocytes Smooth nucleus with clear cytoplasm Lymphocytes (will cover next week) Smaller, with nucleus filling most of cell As we could identify specific surface proteins, found that there are many sub-categories of each! 10 5  11/5/24 Granulocytes Neutrophils Born to die – life span measured in hours (suicide squad) Greatest number of white cells in blood Can phagocytose bacteria kill by fusing with granule contents Can also Degranulate, attacking anything in the area! Increase infection. Major component of pus. AKA Polymorphonucleocyte (PMN) or ‘Poly’ 11 Granulocytes Eosinophils (or “Eos”) Dramatic staining of granules by eosin. Granules include histaminase Role in parasitic infections and allergies Basophils Granules contain histamine Roles in allergic reactions, inflammation (Similar to tissue Mast Cell) 12 6  11/5/24 Mononuclear Phagocytes Monocytes Circulate in Blood Migrate into tissue and become tissue macrophages. Macrophages Professional phagocytes Specialized by tissue Host defense. Also housekeeping. Dendritic Cells Sentinel cells Continually gathering material from wide area – present to other immune cells! 13 Lymphocytes Major part of “Adaptive Immunity” (next week’s topic) Two primary subtypes (look same!) B-cells – for humoral immunity T-Cells – for cellular immunity Related: Natural Killer Cells Innate ability to kill certain types of cells. 14 7  11/5/24 With individual cells rushing around in bloodstream – how do you communicate? Cytokines – produced by cells, diffuse to other Chemokines: chemotaxis of immune cells Colony-stimulating factors (CSFs): multiplication and differentiation of leukocytes Interferons (IFNs): control of viral infections, regulation of immune responses Interleukins (ILs): produced by leukocytes; important in innate and adaptive immunity Tumor necrosis factor (TNF): inflammation, apoptosis Can work together or in sequence to create specific responses Can be damaging to host: Cytokine Storm caused by overproduction of cytokines in response to certain pathogens (Tulermia, COVID) 15 Interferon Response -- mechanism PRRs detect viral RNA in cell (e.g., dsRNA) Makes and secretes interferon – too late to save self! Neighboring cells sense and respond by synthesizing INACTIVE viral proteins (iAVPs) to prime defenses If (and only if) virus detected in a primed cell, iAVPs are ACTIVATED àDegrade all mRNA àStop protein synthesis àCommit suicide (Apoptosis) à(book adds specialized terms of Pyroptosis and Necroptosis. I’m good with Apoptosis) 16 8  11/5/24 What Triggers a Response? Need to recognize that the body is under attack! àPattern Recognition Receptors PRRs Specialized PRRs in book, looking for: Any Microbe (Microbe-associated molecular patterns à MAMPs) Pathogens (Pathogen-assoc... à PAMPs) Evidence of Damage (Damage-assoc... à DAMPs) 17 If you were building a list of things to look for to warn of microbes – what would you add? 18 9  11/5/24 Some answers... Survey – group work? Peptidoglycan Lipopolysaccharide (endotoxin) fMet dsRNA Certain sugars (mannins) D-Amino Acids DNA in the wrong place (e.g., not in nucleus!) Flagellin (lipoplrotein) ssRNA in endosome (or ER). (where should it be?) 19 And where would you look? 20 10  11/5/24 Where PRRs 21 Toll-like Receptors (TLRs) Anchored in membranes of sentinel cells Surface TLRs monitor extracellular environment TLRs in phagosomal or endosomal membranes of organelles characterize ingested material Specific for distinct MAMPs Dendritic cells have both TLRs and CLRs (C-type lectin receptors) 22 11  11/5/24 Also have PRRs in the cytoplasm! Book classifies by “RIG-like” (RLR) and “NOD-like” (NLR). More interested in what cytoplasmic markers the PRRs can identify 23 Not just Cells à Soluble Enzymes in a “Cascade” Required proteins already synthesized and circulating, but as inactive precursors. Multiple activation steps, each step activates precursor enzymes of the next step, rapidly amplifying the response Also, multiple control/inactivation steps When you need it, need if FAST.(sprinkler system) But also do not want it to run out of control! Examples Blood Clotting (everyone knows) Complement system 24 12  11/5/24 Complement in a nutshell Nine proteins (C1 to C9), plus signaling peptides Always present as precursors Multiple initiation triggers Invading MOs Strange Sugars (Lectins) Bound Antibodies (coming in another class) All come together at protein “C3” to activate Cleave off “C3a” (signaling peptide) and “C3b” (active enzyme to continue cascade system) Including cleaving more C3! Possible effects include: Opsonization (make tasty for macrophages and others!) Inflammatory response (fire alarms) Punching holes in membranes (trying to lyse cells) 25 Phagocytosis Talked about first as a way to grab nutrients – to eat. Also a defense. Same steps Grab anything suspicious Surround with pseudopods and fuse Direct lysosomes (or granules) to fuse, digesting contents. Spit out the bones. 26 13  11/5/24 Macrophages Professional Phagocytes, front line defense Pick up everything that needs cleaning: dead cells, trash, invaders. Live weeks months (longer?). Regenerate lysosomes as needed. Also able to alert and recruit other immune cells If in a tough fight – can form giant cells. Combine with special lymphocytes (T cells) to form granulomas Granulomas can wall off organisms or material – but organism may still be alive inside. Example of Tuberculosis interference with lung function. 27 Inflammatory Response PRRs (or complement) detect invader Cytokines mark the area, attract help. Neutrophils first on scene (remember pus formation) Inflammatory mediators such as TNF (see cytokines, earlier), histamine, etc. Blood vessels increase in size, bringing more blood (redness!) and heat (warm to touch) to site. Also become leaky, allowing release of anti-microbial peptides into the tissue. Stimulates “adhesion molecules” on epithelial cells, attracting white cells (leukocytes ) and letting them pass through vessel walls into surrounding tissue. Local inflammation creates local tissue damage during response Normally controlled, with tissue restored after inflammation subsides Some areas (e.g., brain) extremely sensitive! 28 14  11/5/24 29 Side note: “-itis” means inflammation Gastritis – inflammation of the stomach Meningitis – inflammation of meninges (in brain) Otitis media – inflammation of middle ear Gingivitis – inflammation of gums (and so on) Many causes, including infections But most symptoms are body’s defenses Swelling Redness pus 30 15  11/5/24 Excessive Inflammation Blood infections (sepsis) can lead to systemic inflammation and “shock” E.coli example Toxin induced stimulation S. aureus example Cytokine Storm F. tularensis example 31 Side note: Not all inflammation comes from infection! Chronic inflammation is part of: Rheumatoid Arthritis Chronic stress response Obesity Excessive Red meat (and many other causes) Anyone with free time – “Why Zebras Don’t Get ulcers” by Sapolsky Understandable presentation of effects of chronic stress 32 16  11/5/24 Last bit -- Fever Proinflammatory cytokines can tell the brain to reset they bodies thermostat!! Raising body temperature can (maybe!) Inhibit growth of temperature sensitive microbes Increase metabolism of host immune cells Increase the reaction rates of some antimicrobial enzymes If time, Special case of “Ague” 33 Homework – What is the link between Macrophages and Tattoos? 1. What is the link between macrophages and tattoos? 2. What is the net effect on the structure and duration of the tattoo? 3. Provide a citation, including full, free access link. If not taking Micro-Test 2.2, In-class assessment (index Card) What is one way that Microorganisms can penetrate the skin barrier? 34 17