BMF Intracellular Infection Responses (Responses to Intracellular Infection) PDF

November 2024 Responses to Intracellular Infections Dr. Patrick Walsh Class Year 1 ModuleBMF Title Responses to Intracellular Infection  IMMUNOLOGY LECTURES OUTLINE...

November 2024 Responses to Intracellular Infections Dr. Patrick Walsh Class Year 1 ModuleBMF Title Responses to Intracellular Infection  IMMUNOLOGY LECTURES OUTLINE TIME Barrier Immunity Physical barrier (Intro to Instant Imm lecture)Infection Mechanical barrier (Intro to Imm lecture) T H E W O R L D T O B E T T E R H E A LT H Chemical barrier (Intro to Imm lecture) Minutes- Hours Innate Immunity Cytokines (Intro to Imm lecture) Inflammation (Inn Imm lecture) Days-weeks Complement (Inn Imm lecture) Antigen Presentation (Inn Imm RCSI LEADING lecture) Response to Extracellular Inf Adaptive Immunity T cells – Cytotoxic and Help lecture (T cell lecture) Response to Intracellular Inf  LECTURE LEARNING OUTCOMES By the end of this lecture you should be able to: Using influenza as an example, describe a typical immune response to viral infection T H E W O R L D T O B E T T E R H E A LT H Describe the role of interferons in the anti-viral response Define the role of Natural Killer cells and cytotoxic T cells in anti-viral immunity Define the adaptive immune response to viral infection Describe how viruses escape immune detection and may lead to disease pathology Using mycobacterium as an example, describe the innate immune RCSI LEADING response to intracellular bacteria Describe the adaptive immune response to intracellular bacteria Describe how granulomas are developed and maintained  EXTRACELLULAR VS INTRACELLULAR T H E W O R L D T O B E T T E R H E A LT H Bacteria, Fungi, Viruses Bacteria Protozoa, Helminths Fungi RCSI LEADING Protozoa Need different types of response to fight different infections  How does the immune system recognise viruses? Viral pattern recognition receptors: T H E W O R L D T O B E T T E R H E A LT H Viral capsid proteins: TLR2/6 & TLR4 Viral RNA (RNA virus) – TLR3 Cytoplasmic RNA receptors – RIG-I RCSI LEADING OVERVIEW OF IMMUNE RESPONSE TO INTRACELLULAR INFECTIONS  Innate immune response to viruses After recognition, type I interferons (IFNs) are produced by infected cells T H E W O R L D T O B E T T E R H E A LT H  Induction of an anti-viral immune state = ‘shut down’ infected cells and cells nearby (limit spread of infectious agents)  Increase of antigen presentation in all cells  Activation of innate immune RCSI LEADING cells (NK cells, macrophages, dendritic cells)  Induction of adaptive immunity  Effects of Type I IFNs on immune cells MHC class I upregulation T H E W O R L D T O B E T T E R H E A LT H Activate DC and B cell macrophages Activate cytotoxic T cells (adaptive immunity) – Antibodies directly kill infected cells Activate NK cells (innate RCSI LEADING immunity) – directly kill infected cells OVERVIEW OF IMMUNE RESPONSE TO INTRACELLULAR INFECTIONS  NK cells in anti-viral innate immune response What are NK (Natural Killer) cells? Innate immune cells No specific antigen receptor T H E W O R L D T O B E T T E R H E A LT H Detect “altered self” cells Kill virally- Kill infected tumour cells cells RCSI LEADING They do not kill the pathogen, they kill the cells infected by pathogens!!!!  Mechanism of NK cells killing NKvirally-infected cells cells have two types of receptors – inhibitory and activatory Inhibitory receptor binds MHC class I Activatory receptor binds (e.g.) virally-infected cell T H E W O R L D T O B E T T E R H E A LT H UNINFECTED CELLS: INFECTED CELLS: Viruses can down-regulate Normal cells express MHC class I to avoid attack by MHC Class I CTLs Positive signal from No positive signal from inhibitory receptor inhibitory receptor to balance  NK cells not activated a positive signal from the activatory receptor RCSI LEADING  NK cells activated RCSI LEADING T H E W O R L D T O B E T T E R H E A LT H infected cells Mechanism of NK cells killing virally-  NK cells mechanism of action NK cells kill the infected cells in the same way as cytotoxic T cells (CTL) T H E W O R L D T O B E T T E R H E A LT H 1. Perforin 2. Granzyme 3. Cell death/apoptosis Also release the cytokine IFN-γ, drives Th1 responses and CTL RCSI LEADING activity OVERVIEW OF IMMUNE RESPONSE TO INTRACELLULAR INFECTIONS  Antibody effector mechanisms against viruses T H E W O R L D T O B E T T E R H E A LT H Insignificant for anti-viral immunity RCSI LEADING OVERVIEW OF IMMUNE RESPONSE TO INTRACELLULAR INFECTIONS  Cytotoxic T Lymphocytes (CTL) activation Virally-infected cell will display viral antigens on MHC class I molecule Infected cell is now decorated with MHC class I bound to viral antigens T H E W O R L D T O B E T T E R H E A LT H Cytotoxic T cells are pre-programmed to kill if they recognise an antigen on MHC class I RCSI LEADING  Cytotoxic T Lymphocyte (CTL) Killing Virally infected cell will display viral antigens on MHC class I molecule Activated cytotoxic T cells bind T H E W O R L D T O B E T T E R H E A LT H antigen on MHC class I Packed full of vesicles with toxic enzymes for killing Released once CTL is activated – Perforin forms pores in membrane – Granzymes activate apoptosis RCSI LEADING They don’t kill pathogens, they kill cells infected by pathogens!!! Slide 31 – T cell  FOLLOW THE INFLUENZA VIRUS! 1. Signalling – What is the main cytokine produced by virally- infected cells? A. IFN-α/β Menti meter B. IL-1 code: C. IL-10 2. Which immune cells are T H E W O R L D T O B E T T E R H E A LT H responsible for killing virally- infected cells? Menti meter A. Th17 & Th1 code: B. CTLs and NK cells C. Th2 & macrophages 3. Adaptive immune response – What is the role of antibodies against viruses? RCSI LEADING Menti meter A. Opsonisation code: B. Neutralisation C. Complement activation D. All of the above T H E W O R L D T O B E T T E R H E A LT H How can viruses learn to evade the host immune response? RCSI LEADING  Innate immune response to viruses Viral PRRs activated x T H E W O R L D T O B E T T E R H E A LT H Type I IFNs and pro-inflammatory citokines x synthesized RCSI LEADING Multi-faceted innate immune response  Viruses strike back Viral Goal – Survival!!!! Remember: hostile environment T H E W O R L D T O B E T T E R H E A LT H versus a versatile opponent – THE IMMUNE SYSTEM. Viruses have evolved a number of important strategies to evade the immune system. Inhibit viral detection and IFN production – RCSI LEADING resist immune response to infection  Mechanisms of how viruses can evade the immune response Viral genetic variation – mutate genes so aren’t recognised by MHC class I Down-regulate MHC class I or prevent it from T H E W O R L D T O B E T T E R H E A LT H getting to the surface Interfere with antigen processing: – Epstein Barr Virus has a protein that inhibits antigen processing – HSV prevents peptide generation and transport Same outcome = prevent detection RCSI LEADING BUT… Cells that downregulate MHC are now targets for NK cells  Mechanisms of how influenza can evade the immune response Antigenic drift = subtle changes in surface antigens on virus, generated by events like point mutations T H E W O R L D T O B E T T E R H E A LT H  anti-viral antibodies that neutralised the original virus will no longer work Y Y  Happens very frequently Y Y Y Y Y Y Y RCSI LEADING Y Y Y Y Y  Other immune evasion by influenza Antigenic shift = major changes in viral antigens, eg. caused by genetic recombination between T H E W O R L D T O B E T T E R H E A LT H different viruses  Completely new virus created, nobody has historical immunity  Doesn’t happen frequently RCSI LEADING From: Cellular and Molecular Immunology (Abbas et al)  Th1 are important against Mycobacterial infections IL-12 Th1 IFN-γ T H E W O R L D T O B E T T E R H E A LT H Key Functions: Intracellular bacterial Potent activation of infection macrophages Increases MHC class I and II and antigen presentation activation of Nitric oxide RCSI LEADING synthase and production of ROS  Th1 cells produce IFN-γ which activates macrophages to kill MTb IFNγ is a potent activator of macrophages: T H E W O R L D T O B E T T E R H E A LT H Upregulates costimulatory molecules CD80/86 (B7) on macrophage Upregulates co-stimulatory ligand CD40 Increases MHC class I and II and antigen presentation Get activation of Nitric oxide synthase and production of ROS RCSI LEADING Collectively, get enhanced microbiocidal activity  GRANULOMA FORMATION Th1 induced macrophage maturation results in granulomas formation Infection is sealed off by a wall of T H E W O R L D T O B E T T E R H E A LT H immune cells The centre may become hypoxic and undergo necrosis MtB can persist for years or decades in granuloma’s while host remains in good health MtB can be reactivated by steroid treatment, malnutrition, RCSI LEADING immunosupression (eg HIV) Ongoing Th1 response is critical for lifelong control  IMMUNE RESPONSES – SUMMARY OF TODAY’S LECTURES! Extracellular pathogens  goal of the immune system is to kill the pathogen Extracellular bacteria – neutrophils, macrophages, T H E W O R L D T O B E T T E R H E A LT H Th17, antibodies Helminth – Th2, IgE antibodies, eosinophils and mast cells Intracellular pathogens  goal of the immune system is to kill the infected cells RCSI LEADING Viruses – IFN response, NK cells and cytotoxic T cells, antibody neutralisation Intracellular bacteria – Th1, IFN-γ (here the immune  SGT – A healthy immune response XX November Immunology tutorial, divided in small groups T H E W O R L D T O B E T T E R H E A LT H You must pre-read the reference ahead of the tutorial!!! One thing that you liked of the Immunology lectures (content or delivery)? Go to www.menti.com and type One thing that can be improved (content or RCSI LEADING delivery)? Go to www.menti.com and type