Lecture 31 - Innate Immunity 2024 PDF

31 – Innate Immunity BioMi 2900 Macrophage engulfing a bacterium by David Goodsell  Innate immunity 1. Innate vs. adaptive immunity 2. Physical and chemical barriers to infection 3. Innate Antimicrobials 4. Cellular defenses - phagocytosis 5. Toll-like recept...

31 – Innate Immunity BioMi 2900 Macrophage engulfing a bacterium by David Goodsell  Innate immunity 1. Innate vs. adaptive immunity 2. Physical and chemical barriers to infection 3. Innate Antimicrobials 4. Cellular defenses - phagocytosis 5. Toll-like receptors / PAMPs, MAMPs 6. Inflammation 7. Complement  Goals for today: Understand the first responses to a microbe entering your body: How does the innate immune system recognize invading microbes? What are the major ways to prevent microbial infection? How are invading microbes killed and removed by the innate immune system?  1. Innate vs. Adaptive Immunity Innate Immunity Adaptive Immunity Not strongly induced, always on Very specific, must be induced guard Reaction to recognition of an antigen Not specific to one pathogen – usually a peptide or organic molecule Phagocytic cells - recognize and Phagocytic cells activating engulf invaders Lymphocytes Main effectors: Antibodies , cellular responses Main effectors: Physical barriers, antimicrobials Slower response – days (when Fast response – immediate to hours confronting a new threat) Memory – some immune cells are retained to recognize that specific threat if encountered in the future We are born with these defenses, lots We develop these highly specific of eukaryotes (and even microbes) responses have these systems  Innate immunity and Covid-19 in children - Children typically develop fewer serious complications from Covid- 19 - One reason for this is the upregulation of innate immune functions in their nasal cavity, reducing viral load before it can affect the lungs 2. Innate Barriers and Defenses - The best defense is to prevent the entry of microbes! - The human body is outfitted with mechanical, chemical and microbial barriers  2. Innate Barriers and Defenses Barrier Skin Gut Lungs Eyes, type: nose, mouth Mechanical Sloughing dead cells, tight junctions between epithelial cells, (dry – skin; other places - movement of mucus or other fluids) Chemical Fatty acids, Low pH, Surfactant, Lysozyme, Defensins Protease, Defensins Defensins other enzymes Microbial Normal microbiota (Clostridium difficile can’t colonize a healthy intestine due to competing microbes)  Skin – a highly effective barrier The human skin is a highly effective barrier to bacterial colonization: - Dry (microbes need water!) - low pH (most disease- causing microbes are neutrophiles) - Lower temperature (~35 ˚C) - Complex layering (see cross-section on the right) - SALT (skin-associated lymphoid tissue) kills invading microbes  Gut epithelium – a weak spot in the barrier The main problems: - Intestinal epithelium is close to lots of microbes (gut microbiota!) - Also has a large surface area! - At the same time, the epithelium has to allow for diffusion of nutrients (can’t be fortified like the skin!)  Tight junctions and mucus - Tight junctions are proteinaceous Mucus layer threads that tightly hold neighboring epithelial cells together - Without TJs, there would be a gap between cells, which microbes could exploit for entry - Mucus is an additional layer separating microbiota from epithelium  lumen - In addition to barrier functions, the intestine also produces antimicrobial chemicals (antimicrobial peptides, AMPs) epithelium - AMPs kill bacteria Paneth cells produce AMPs  3. Innate Antimicrobials Many tissues in your body produce antimicrobial + agents: - (cationic) Antimicrobial peptides – such as defensins ( redness, heat, swelling also attracts immune cells to the site of infection  Local containment As inflammation progresses, cytokines induce clotting in small vessels which helps restrict/contain the invader and the inflammatory reaction. Some cytokines have systemic effects, such as inducing the hypothalamus to increase body temp – fever. As invader is cleared by macrophages, fluids and cells drain from the area via lymph system. Allows phagocytes to present antigens derived from degradation of the invader to adaptive immune cells in lymph nodes… BUT if infection in not contained… entry of bacteria into the bloodstream can lead to septic shock. Massive systemic release of cytokines => systemic inflammation, and clotting in small vessels => organ failure, death!  7. Complement Complement system – 30 proteins produced by the liver, circulate in serum recognize pathogens to trigger activation Once activated, other components… – Induce inflammation – Signal to attract immune cells – Bind the pathogen to enhance destruction by phagocytic cells via opsonization – Lyse the pathogen Nature Immunology 11, 785–797 (2010)  Opsonization Complement protein C3b or antibodies bound to the surface of an invading bacterium act as opsons Promote adherence and ultimately phagocytosis  Complement activation: “Alternative pathway” shown here C3 b a b MORE PHAGOCYTES! MORE PHAGOCYTES! 5b b Bacterium C5 Membrane attack complex Complement activation requires several accessory factors that are not shown here!  Innate immunity – Summary I AMPs/lysozyme/lipases EAT! TLR4 cytokines e.g. LPS Bacterium MAMPs phagocytic cell (or flagellin, HELP LTA, CpG…) KILL! Complement proteins Transmigrate, ATTACK!!! MAMPs = microbe-associated molecular patterns  Innate immune components summary II Barriers Cellular components Thick epithelium Phagocytic cells Tight junctions (neutrophils, macrophages, Chemical attack dendritic cells) Lysozyme AMPs Complement proteins C3, C5 and helpers  Summary III The innate immune system is the unsung hero of our defenses against potential pathogens Mechanical, chemical and microbiota barriers are the first line of defense against microbial invasion Acellular responses include the production of antimicrobial peptides by certain cell types, also complement in the serum that can help identify and neutralize invaders Cellular responses include recognition of microbial molecular signals (PAMPs or MAMPs) by receptor proteins on immune cells. Recognition then activates and mobilizes appropriate responses. One response to invaders includes the release of cytokines and chemokines to initiate the inflammatory response.