240925 Immune Responses to Pathogens_1553, Part 2.pdf

Session 15 Immune Response to Pathogens, Part 2 MICRG 1553 - Lisa Kronstad, Ph.D. [email protected] September 25, 2024 Cholla D 1 Learning Objectives Given exposure, to be able to describe to a colleague the general steps in immediate innate, indu...

Session 15 Immune Response to Pathogens, Part 2 MICRG 1553 - Lisa Kronstad, Ph.D. [email protected] September 25, 2024 Cholla D 1 Learning Objectives Given exposure, to be able to describe to a colleague the general steps in immediate innate, induced innate, and adaptive immunity. Differentiate the immune response to an extracellular (bacteria) vs. an intracellular pathogen (certain bacteria and all viruses) Differentiate the immune response to bacterial vs. viral pathogens including the cytokines involved and their speci c roles Compare and contrast MHC class I and class II antigen presentation Be able to differentiate the cell types that express MHC class I versus those that express class II Describe how Zinkernagel and Doherty Experiment elucidated the mechanism of T cell recognition 2 fi Layers of Immunity Pathogens may “win out” - necessitating the induced innate immunity stage 3 Inflammatory cells kill invading bacteria 4 hr -4 days How does this process differ for viruses? 4 Kuby Figure 4.22 Induced innate response to viruses 4 hr -4 days EM of SARS-CoV-2 - the etiologic agent of COVID-19, isolated from US patient (NIAID-RML) 5 The Virus and the Virion Virion/viral particle Virus-infected cell (alive) Principles of Virology, ASM Press Viral infectious cycle 4 hr -4 days Innate immune response needs to be very different to virus vs. bacteria - cell needs to be eliminate Anti-bacterial in ammatory cytokines were IL-1β, TNF and IL-6 There is a different set of cytokines important for the viral response. 7 fl d Surface and Endosomal PRRs Surface and endosomal PRRs - two classes act differently in terms of downstream signaling Surface detect bacteria ->Il-1β/IL-6/TNF anti-bacterial response Endosomal detect viruses -> Interferon - anti-viral 8  4 hr Two Main results of PRR signaling -4 days Location paired with type of ligand leads to the most appropriate anti-pathogen state, bacterial vs. viral. 9 Viral infection leads to production of Type I IFN 4 hr -4 days Type I IFN (IFN-alpha/beta): synthesized within hours by virus- infected cells and is made by all nucleated cells 10 Viral infection leads to production of Type I IFN 4 hr -4 days Action on neighboring cells via interferon receptors leads to a signal transduction cascade leading to a block in viral replication = "anti- viral state” by 1) degrading RNA and 2) inhibiting protein synthesis 11 https://www.mdpi.com/1422-0067/21/4/1348/htm Viral infection leads to production of Type I IFN 4 hr -4 days Type I IFN induces expression of gene products that can cause problems for cells Most of our cells have IFN receptors Large quantities of IFN have dramatic physiological consequences: Fever Chills Nausea Malaise Generally, every viral infection leads to IFN production: “ u-like symptoms" 12 fl Viral infection leads to production of Type I IFN 4 hr -4 days Type I Interferon can repress IL-1⍺ and IL-1β, important for the control of Mycobacterium tuberculosis infections One mechanism that explains why many viral infections predispose patients to secondary bacterial infections 13 Layers of Immunity 14 Adaptive Immunity > 4 days 15 Professional Antigen Presenting Cells Dendritic cells are the major innate immune cell that "talks" to the T cells of the adaptive immune system Antigen presentation on MHC class I to CD8 T cells to kill virally infected cells Antigen presentation on MHC class II to CD4 T cells to activate B cells to produce antibodies to neutralize extracellular pathogens 16 Dendritic cells trigger Adaptive Immunity in lymph nodes > 4 days Pathogen-speci c B and T cells are activated by Dendritic cells in lymph nodes B cells and T cells then return to the site of the original infection 17 fi Professional Antigen Presenting Cells Three cell types that express both class I and class II are also phagocytes Macrophages Dendritic cells B cells Bridge the induced innate immune response with the adaptive immune response by presenting antigen 18 MHC class II presents peptides from endocytic pathway Class II gets peptides from the endocytic pathway Example 1: Phagocyte (e.g. macrophage, dendritic cell, neutrophil) performing phagocytosis Example 2: B cell internalizing antigen (e.g. from an extracellular bacteria) by endocytosis 19 MHC class II presents peptides from endocytic pathway A partner protein (CD4) is needed to stabilize the interaction between the TCR and the MHC class II with a peptide. CD4 T cells produce cytokines 20 MHC class I presents cytoplasmic peptides Viruses co-opt host cell protein synthesis machinery to synthesize their viral protein Certain of these proteins are degraded and the fragments are bound by MHC class I in the endoplasmic reticulum Class I presents peptides from the cytosolic pathway 21 MHC class I interacts with TCR and CD8 Stabilization of the MHC class I/peptide and TCR interaction requires another stabilizing protein called CD8 CD8 binds MHC class I 22 Viral peptide-specific CD8 effector cells have a predominant TH1 cytokine pattern High capacity to make IFN-γ but not TH2 cytokines 1) IFN-γ increases antigen presentation including class I MHC pathway 2) IFN-γ helps counteract the ability of some viruses to disrupt antigen presentation 3) IFN-γ can directly interfere with viral replication within cells 23 Comparison of MHC class I and II antigen processing pathways 24 MHC Class I and II summary 25 Internal Pathogens require T cells T cells are the key responders to internal antigens. What do T cells see? 26 Zinkernagel and Doherty Experiment CD8+ cytotoxic T cells recognize both the viral peptide AND the self-MHC molecule Following only this successful recognition, the CD8+ cytotoxic T cells then kill the infected cells using perforin and granzyme 27 Result of Class I and II presentation 28 Adaptive Immunity > 4 days Intracellular Virus or bacteria Phagocytosed Bacteria Extracellular bacteria and virions before entry 29 Adaptive Immune Response: Specificity Measles and In uenza viruses both have RNA genomes and would stimulate similar PRRs, yet antibodies generated are highly speci c 30 fi fl Adaptive Immunity > 4 days Antibodies protect during viral infection by: 1) Binding to virion to prevent entry into the host cell, termed neutralization 2) Binding to viral glycoprotein on host cell - effector cell i.e. NK cell, can then mediate ADCC 31 Adaptive Immunity > 4 days - Antibodies For bacteria antibodies can: 1) Neutralize a toxin so it can't bind to and enter a host cell 2) Opsonize: Coat the bacteria to tag it for phagocytosis 3) Activate complement leading to pore formation 32 Take Home Messages Pathogen immunity is divided into immediate (intrinsic), induced and adaptive Induced Innate immunity (4 hr - 4 day) relies on using host PRRs located in diverse cell locations to sense microbial PAMP The type of PAMP sensed leads to the appropriate immune response: anti-bacterial (IL-1β, IL-6, TNF) anti-viral (Type I IFN) Professional antigen-presenting cells, such as Dendritic cells, macrophages, and B cells, present antigens to T cells to stimulate the adaptive immune system Adaptive Immunity (> 4 days) include: MHC class I-restricted CD8+ T cells kill infected cells using perforin and granzyme B - cellular immunit MHC class II-restricted CD4+ T helper cells and B cell antibody production - humoral immunit The Zinkernagel and Doherty experiment demonstrated that the TCR recognizes both the peptide and the MHC molecule B cell antibody production during viral infection can prevent viral entry or help target an infected cell for killing B cell antibody production during bacterial infection can prevent toxin binding, lead to opsonization, or activate complement 33 y s Please complete TopHat discussion assignment One “Muddiest point” - area of confusion? One thing I liked __ (something that helped you learn) One thing I wish __ (Item for ∆/ change) Will return all e-mails within 24 hr period! [email protected] 34 ,