Immuno Week 1: Barriers to Infection PDF

IMMUNO WEEK 1 SESSION 1: BARRIERS TO INFECTION LO 1: IDENTIFY THE PHYSICAL BARRIERS THAT PROTECT FROM MICROBIAL INFECTION. 1. Tight junctions a. between epithelial cells block microbial passage 2. Stratum corneum a. (outer layer of sk...

IMMUNO WEEK 1 SESSION 1: BARRIERS TO INFECTION LO 1: IDENTIFY THE PHYSICAL BARRIERS THAT PROTECT FROM MICROBIAL INFECTION. 1. Tight junctions a. between epithelial cells block microbial passage 2. Stratum corneum a. (outer layer of skin) flakes o removing adherent microbes 3. Mucus a. captures pathogens and foreign agents & prevents microbial attachment to host cells b. removed by sneezing, coughing, peristalsis, vomiting, diarrhea, ciliary action c. Goblet cells OR mucosal tissues produce mucus 4. Epithelial layers i. produce protective substances b. Acidic pH (HCl) - of stomach degrades microbial structures c. Enzymes and binding proteins – breakdown microbes d. Antimicrobial peptides (AMP) - directly lyse microbes LO 2: IDENTIFY THE CHEMICAL BARRIERS THAT PROTECT FROM MICROBIAL INFECTION. 1. Defensins a. Penetrate microbial membranes and disrupt their integrity – forming pores that lead to osmotic lysis b. Constitutively secretes at mucosal surfaces to maintain levels of normal microbiota (reduces overgrowth that might be pathogenic) c. Function poorly in physiological conditions – operate best in sweat, tears, gut lumen and phagosome d. Produced by: paneth cells, epithelial cells, neutrophils 2. Pentraxins a. Upon binding, phagocytes engulf and digest the attached pathogen (phagocytosis) b. IL-6 primary cytokine driving pentraxin c. Liver output of pentraxins can be significantly increased when hepatocytes are stimulated by IL-1, IL-6, TNF-alpha and locally in tissues by infiltrating immune cells upon innate receptor activation 3. Lysozyme a. Enzyme found in saliva, tears, mucus, plasma and tissue fluids b. Hydrolyzes the 1,4 beta linkages between NAG and NAM  increasing permeability & causing the bacterial cell wall to collapse and the bacteria to burst 4. Phospholipase A2 a. Found in body secretions b. Penetrates bacterial cell wall + hydrolyzes membrane phospholipids  produce free fatty acids and lysophospholipids 5. Cathelicidins a. Released by skin and mucosal epithelial cells  b. damaging to bacteria, fungi virus and parasites  create disruption in the cell membrane c. active human cath. Is LL-37 (37 residues in length) d. LL-37 is released in the skin and mucosa to disrupt microbe membranes through micelle formation 6. Fatty acids a. Found in perspiration and sebaceous secretions b. Shown to impact the generation of peptidoglycan of Gram+ and Gram- bacteria (limits growth) c. May also disrupt cell membrane (similar to LL-37) d. Can block horizontal transfer of genetic information between bacteria (conjugation) 7. Lactoferrin a. Found in body secretions and tissue fluid b. Sequesters and transports iron in body fluids (teras, saliva, milk) c. Binds to Gram+ (interrupt peptidoglycan synthesis) and Gram- (disrupt the outer membrane) cell walls 8. Transferrin a. Found in plasma b. Main protein that sequesters and transports iron in the blood LO3: RECALL THE MECHANISMS OF ACTION OF THE PHYSICAL AND CHEMICAL BARRIERS TO INFECTION Chemical Barriers - Complement system & cytokines 3 functions: 1. Microbial lysis 2. Inflammation 3. Enhanced phagocytosis Complement proteins coat the bacterial surface and extracellular viral particles to make them more easily phagocytosed (especially encapsulated bacteria) Cytokines- proteins produced in response to antigen Interleukins – cytokines that operate between WBCs (ex: IFNs) 1. Macrophage activated by microbe encounter leads to production of IL-12 2. NK cells activated by IL-12 3. Activated NK cells release IFN-gamma 4. IFN increases toxin production by macrophage to aid destruction of phagocytosed microbes Chemical Barrier- Acute phase proteins Positive APPs- increase certain plasma proteins (associated w immune reactivity) Negative APPs- decrease certain plasms proteins (involved in transport) 1. Ferritin a. sequesters free iron in cells b. levels in the plasma reflect amount of stored iron (detection of iron deficiency) 2. fibrinogen a. blood coagulation factor 3. Hepcidin a. Prevents ferritin from releasing iron  4. Serum amyloid A a. Chemotaxis of immune cells 5. Albumin a. Maintains osmotic pressure of blood 6. Transferrin a. Transporter of iron in blood b. Sequesters free iron from microbe ** Acute phase proteins in immunity operate to limit resources to microbial species and promote immune capture and destruction of invaders ** LO4: DEFINE THE ROLE OF THE NORMAL FLORA IN INFECTION PREVENTION Commensal bacteria - Outcompete pathogens and stimulate microbial surveillance by immunity Aspiring pathogens must compete with commensal bacteria for nutrients and space Overuse/chronic use of antibiotics can destroy normal flora and allow opportunistic pathogens a change to attach and colonize  infection that may lead to disease Before birth, mammalian babies have no commensal microbes Highest density of bacteria is present in the large intestine Westernized diet (high sat. fats and sugars, low fiber), aging, and reduction in physical activity reduces microbiome diversity  increased fiber intake = more microbial diversity, less inflammation SESSION 2 - RECEPTORS FOR MICROBIAL DETECTION LO1: IDENTIFY INNATE RECEPTORS AND THEIR CELLULAR DISTRIBUTION AND THE RESULT OF CELL SIGNALING THROUGH THESE RECEPTORS Pathogen-associated molecular patterns (PAMPS)  Highly conserved structures of microbial species – little/no molecular changes over time  Damage-associated molecular patterns (DAMPS) Pattern Recognition Receptors (PRRs)  Activation of PRRs leads to cytokine production + secretion, inflammation & immune cell recruitment  Binding to PAMP promotes uptake of the microbe by phagocytes / cytokine production Types of PRRs: 1. Endocytic – promote receptor-mediated phagocytosis (macrophages & neutrophils) a. C-type lectin receptors : mannose receptors that recognize terminal sugars on microbe surface (including glucans on fungi)  b. Scavenger receptors : can bind to mediate uptake of bacteria expression lipoproteins c. Formyl Peptide Receptors (FPR): bind to fMET residues (AA coded by the AUG start codon)  fMET attached peptides released upon degradation of bacteria or host cells d. Opsonin receptors- complement system activation produces opsonins that can be recognized by complement protein receptors (CPRs) on phagocytes  opsonization “enhanced phagocytosis” 2. Signaling – trigger cytokine production (cell surface, endosomes, cytoplasm) a. Toll-like receptors (TLRs): found on cell surface for extracellular bacteria and endosomal membranes for intracellular microbes i. MyD88 recruitment to TIR ii. Mast cell activation by TLR ligation  endothelial cell contraction (increased vascular permeability) iii. TLR-4: recognizes bacterial LPS iv. TLR-7: detects single-stranded RNA from viruses v. TLR-9: detects unmenthylated CpG DNA from DNA viruses b. NOD-like Receptors (NLRs): cytoplasmic- detect bacterial cell wall components i. NOD1- degraded peptidoglycan of Gram- bacteria ii. NOD2- degraded peptidoglycan of other bacteria · Phosphorylated IKK attaches to NFkB with IkB  NFkB translocates to nucleus and induces cytokine production, phagocytosis and defensin synthesis ; IkB degraded - > induces transcriptions of cytokines - IkB phosphorylation occurs upstream L degragationas c. RIG-I-like receports (RLRs): detect viral RNA in the cytoplasm i. Viral RNA binds to RIG-I and MDA-5 and through CARDS interacts with MAVS ii. Results in phosphorylation of IRF3  dimers transcription factor for type 1 IFNs iii. Autocrine (infected) and paracrine (uninfected) type I IFN signaling induces the antiviral state iv. Phosphorylation and inactivation of eIF2 (inhibits viral protein synthesis) ↳ stops viral proteinSynthesis ↳ halting replication until body can get LO2: RECALL THE MAJOR CYTOKINES RELEASED UPON PATHOGEN RECOGNITION RECEPTOR LIGATION something there to kill virus Pro-inflammatory cytokines: TNF-alpha, IL-1, IL-6 1. Initial sources are tissue cells, tissue resident mast cells and macrophages 2. Leukocyte attachment and migration into tissues (capillary endothelium) 3. IL-6: Fever, muscle aches, joint aches (brain) 4. IL-6: Acute phase protein release, complement activation (liver) 5. IL-6: Increased output of neutrophils (bone marrow) 6. IL-6: increased glucose metabolism, local heat (adipocytes & monocytes) 7. Vasodilation, increased vascular permeability, upregulation of adhesion molecules on endothelia 8. Trigger fever and drive inflammation Inflammasome- PRR ligation induces IL-1 production (epithelial & T cells, macroph, neutro, monocytes) IL-1B stimulates an increase in prostaglandin E2 production  increases cAMP  fever IL-1B binding to its receptor elevates prostaglandin levels in the hypothalamus IL-12: produced early in response a. First cells activated by IL-12 is natural killer (NK) cells  destroy infected host cells Antiviral cytokines: type 1 interferons (IFN-alpha, IFN-beta) (do not directly induce fever) Chemokines: IL-8 a. Neutrophil attachment and migration into tissue b. Activate intracellular signaling enhancing a inity of integrins for ICAMs, strengthening adhesion c. Increases integrin binding ***Neutrophils are the first immune cells to infiltrate tissues*** LO3: IDENTIFY THE FUNCTION OF INNATE CYTOKINES AND CHEMOKINES IN PROMOTING EARLY IMMUNE RESPONSES TNF-alpha & IL-1 – drive inflammation, vascular permeability, induce adhesion molecule expression IL-6: trigger acute-phase response IL-8: attract neutrophils to infection sites Type 1 IFNs: induce antiviral state, inhibiting replication ****best host defense against viral infections**** IL-12: activate NK cells to kill infected cells LO4: DEFINE THE STEPS INVOLVED IN THE MIGRATION OF IMMUNE CELLS TO SITES OF MICROBIAL COLONIZATION 1. Rolling a. IL-1 and TNF-a induce selectin expression on endothelial cells b. Selectin ligands on leukocytes bind weakly to selectins, causing rolling 2. Adhesion a. TNF-a induces ICAM-1 and ICAM-2 expression on endothelia b. Neutrophils express integrins that can bind to ICAMs for firm adhesion 3. Chemotaxis a. IL-8 binds to neutrophil receptors, increasing integrin a inity b. Neutrophils follow chemokine gradient 4. Extravasation a. TNF-a weakens tight junctions b. Neutrophils squeeze through endothelial layers into tissues