13 Lecture _Immune Responses to Bacterial Infection_BABS3041_2024.pdf

Immune Response to Bacterial Infection Associate Professor Li Zhang School of Biotechnology and Biomolecular Sciences Room 4106, E26 [email protected] Learning outcomes The general principles of the immune system responding to bacterial infections The key effector immune components to different ty...

Immune Response to Bacterial Infection Associate Professor Li Zhang School of Biotechnology and Biomolecular Sciences Room 4106, E26 [email protected] Learning outcomes The general principles of the immune system responding to bacterial infections The key effector immune components to different types of bacterial pathogens The outcomes of immune response to bacterial pathogens The interactions between innate and adaptive immune systems in responding to infections Bacteria http://www.bacteriainphotos.com/ Cell wall structure of Gram positive and negative bacteria Bacterial virulence 1. Adhesion and invasion: the ability to invade tissues or cells. 2. Toxins: exotoxins and endotoxins. Endotoxin refers to the lipopolysaccharide (LPS) component of Gram negative bacteria. Site of infection Epithelial surfaces Interstitial spaces, blood, lymph Intracellular Overview of bacterial infections and immune responses 1. Bacterial pathogens contact with an epithelial surface of a new host (skin and mucosal surfaces). 2. Bacterial pathogens either colonize the epithelial surface or penetrate it to replicate in the tissues or cells. 1. Innate immune system takes actions to eliminate pathogens 2. Adaptive immune responses are developed if innate immune responses fail to clear out the infection. 3. Immune responses are regulated. Innate receptors detecting bacterial pathogens Surface pathogen recognition receptor (PRR): Lectin receptors: lectins are proteins that bind carbohydrates (mannan, betaglucan) Toll-like receptors (TLRs 1, 2, 4, 5, 6). fMet-Leu-Phe receptor Intracellular PRR: Nucleotide-binding oligomerization domains (NOD) proteins: recognizing muramyl dipeptide (MDP). Secreted PRR: Mannan-binding lectin Pathogen Associated Molecular Pattern (PAMP) Cell wall constituents – Peptidoglycan – Lipopolysaccharide (LPS) – Mannan (polymer of mannose) Formylmethionine – First amino acid in prokaryotic protein synthesis, not seen in eukaryotes. The recognition of bacterial pathogens by innate immune system leads to: 1. Destruction of bacterial pathogens by phagocytes 2. Induction of inflammation, recruitment of more immune cells and effector molecules 3. Activation of complement system Recognition of PAMPs leads to the development of inflammation The responses of the immune system to infections Innate immune responses eliminate the bacteria (small number of bacteria number and virulence are low). Adaptive immune responses (larger number of bacteria or with greater virulence) Innate immune responses (4-96 hours) Adaptive immune responses ( 96 hours- one week) Adaptive immune responses Both B cells and T cells are involved in the defences against bacteria. Adaptive immune responses occur in secondary lymphoid tissues. Multiple clones of B cells and T cells are involved (many different epitopes exist on a pathogen). Protection from antibodies Neutralisation of toxins and other bacterial virulence factors Opsonisation Complement activation Ab-Ag complexes in blood are carried by red cells via C3b receptors and cleared by macrophages in liver and spleen TD-antigen Most protein antigens TI-1 antigen (B cell mitogen) Polyclonal activation: TI-1 antigen is called B cell mitogen Poor induces of isotype switching, affinity maturation, memory. IgM > IgG TI-1 antigen: LPS (binds to TLR4 and CD14) and bacterial DNA. TI-2 antigen Have highly repetitive structures (polysaccharides of bacterial capsule, polymeric proteins), activate B cells by extensively cross-linking the BCR Marginal zone B cells recognize TI-2 antigen, have low level of somatic mutations and low frequency of Ig class switch, IgM > IgG. Marginal zone B cells are rare at birth, accumulate with age. < 5 years old not respond well to polysaccharides BAFF: B cell activating factor T cell response in bacterial infection 1.Dendritic cells residing in tissues uptake bacterial antigens. 2. Activated dendritic cells increase synthesis of MHC class II and other co-stimulate molecules (B7.1, B7.2) on their surfaces. 3.These dendritic cells move away from the infection sites through the lymphatic system to enter secondary lymphoid tissues. 4. Dendritic cells present antigens to naive T cells and deliver other signals to activate T cells Activation Proliferation Survival Differentiation Function of effector CD4+ T cells Th1: help macrophages Th2: express a range of cytokines that influence B-cells differentiation and antibody production, recruitment of eosinophils and mucus production. Th17: production of antimicrobial peptides, recruitment of neutrophils Tfh: help B cells in geminal centers, class switch and affinity maturation. Treg: regulation of immune responses Effector mechanisms used in infections caused by different infectious agents 1. For most of infections, both the cell-medicated and the humoral aspects are involved in helping in clearing or containing the pathogens. 2. The relative importance of the different effector mechanisms may differ depend on the infectious agent. Main immunological effectors for different types of infectious agents Summary of immune responses to skin infections The outcomes of Immune responses to bacterial infection 1. Infection resolved a) bacteria eliminated by innate responses. b) bacteria eliminated by both the innate and adaptive immune responses with immunity (memory) for future protection 2. Failure of protection 3. Persistent infection Mycobacterium tuberculosis infection M. tuberculosis survival & multiplication in alveolar macrophages Macrophages produce IL-12 IL-12 promotes Th1 cells Th1 cells produce IFNγ IFNγ enhance macrophage activities Persistent infection, most in latent. Tubercle Innate and adaptive interaction Activation of endothelium Bacteria Chemokines Cytokines Epithelial cells Neutrophils Macrophages Dendritic cells Adhesion of phagocytes Chemotaxis IL-12 IL-18 NK Complement Increased vascular permeability IFNγ MBL, CRP phagocytes Antibodies, CD4+, CD8+ T cells, Th17 cells Examples of innate system and adaptive system interaction 1. Innate immune responses are a necessary for an adaptive immune response to be initiated. a.Cells of innate system present antigens to T cells. b. IL-12 secreted by NK cells and macrophages contribute to Th1 development. 2. Effector molecules or cells generated from the adaptive immune responses reinforce the innate immunity. a. Ag-Ab activates complement system. b. Cytokines secreted by T cells activate macrophages.