YR1 Lecture 1H - Host Pathogen Interactions - Western Sydney University PDF

Host-Pathogen Interactions A/Prof Slade Jensen Microbiology and Infectious Diseases School of Medicine Western Sydney University [email protected] Learning objectives Understand the complexities of host-pathogen interactions Non-specific host defences Specific host defences Pathogenic me...

Host-Pathogen Interactions A/Prof Slade Jensen Microbiology and Infectious Diseases School of Medicine Western Sydney University [email protected] Learning objectives Understand the complexities of host-pathogen interactions Non-specific host defences Specific host defences Pathogenic mechanisms 2 Overview Non-specific host defences Exterior defences Innate immunity Specific host defences Cell mediated immunity Antibody mediated immunity Types of acquired immunity Pathogenic mechanisms (bacteria) Virulence factors 3 Non-Specific Host Defence Non-Specific Host Defence Exterior Defences – Physical, chemical, biochemical Innate Immunity – Phagocytes – Complement – Interferons – Natural killer cells Exterior Defences Figure 9.2 Exterior defenses. Most of the infectious agents encountered by an individual are prevented from entering the body by a variety of biochemical and physical barriers. The body tolerates a variety of commensal organisms, which compete effectively with many potential pathogens. Non-Specific Host Defence Exterior Defences – Physical, chemical, biochemical Innate Immunity – Phagocytes – Complement – Interferons – Natural killer cells Phagocytes Phagocytes – Granulocytes Neutrophils Eosinophils Basophils https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiologytextbook/immune-system-21/innate-immunity-196/phagocytes-969-3103/ – Macrophages Granulocytes especially neutrophils predominate in initial phase of infection macrophages dominate later Mechanism of Phagocytosis Chemotaxis – chemical attraction of phagocytes to microbes Phagolysosome contains lysozyme & other enzymes that destroy the microorganism Figure 9.10 Phagocytosis. (A) Phagocytes attach to microorganisms (blue icon) via their cell surface receptors which recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide. (B) If the membrane now becomes activated by the attached infectious agent, the pathogen is taken into a phagosome by pseudopodia, which extend around it. (C) Once inside the cell, the various granules fuse with the phagosome to form a phagolysosome. (D) The infectious agent is then killed by a battery of microbicidal degradation mechanisms, and the microbial products are released. Inflammation Damaged tissues Inflammation is a local response to microbial invasion Histamines, kinins, prostaglandins, leukotrienes Signs/Symptoms – redness, pain, heat & swelling Vasodilation & increased permeability of blood vessels Phagocytic migration (granulocytes & macrophages) Phagocytosis Tissue repair Chemotaxis induced by microbes, other neutrophils & kinins Complement components Marrow >> additional granulocytes Fever http://classes.midlandstech.edu/carterp/Courses/bio225/chap15/lecture3.htm Complement System Cleavage of C3 into C3a & C3b results in: - Inflammation - Phagocytosis - Cell lysis - Membrane Attack Complex (MAC) Interferon AVPs enzymes that disrupt various stages of viral replication short half life no effect on cells already infected Figure 9.21 The action of interferon (IFN). Virus infecting a cell induces the production of IFN. This is released and binds to IFN receptors on other cells. The IFN induces the production of antiviral proteins, which are activated if virus enters the second cell, and increased synthesis of surface MHC molecules which enhance susceptibility to cytotoxic T cells (cf. Ch. 10). NK, natural killer; MHC, major histocompatibility complex. Natural Killer (NK) Cells Destroy tumour cells and those infected by viruses – recognise cells as non-self Activated by interferons or macrophage-derived cytokines Not phagocytic – cytotoxic effect – release enzymes that enter infected cells and induce apoptosis (cell death) Specific Host Defence Adaptive Immunity Figure 9.1 Innate and adaptive immunity. An infectious agent first encounters elements of the innate immune system. These may be sufficient (1) to prevent disease but if not, disease may result (2). The adaptive immune system is then activated (3) to produce recovery (4) and a specific immunologic memory (5). Following re-infection with the same agent, no disease results (6) and the individual has acquired immunity to the infectious agent. Adaptive Immunity Cell mediated immunity – components T lymphocytes (various types) – defence against: bacteria and viruses within phagocytic or infected host cells fungi, protozoa and helminths Antibody mediated (humoral) immunity – components B lymphocytes & antibodies – defence against bacteria, bacterial toxins, and viruses in bodily fluids Cell Mediated Immunity T lymphocytes are activated by antigen presenting cells (APCs) – professional - dendritic cells, macrophages, B cells display antigen via MHC class II – non-professional – many cells in the body display antigen via MHC class I MHC (major histocompatibility complex) molecules present self and non-self antigens on the surface of a cell Helper T Cells Differentiate into effector and memory helper T cells via MHC II antigen presentation Activated helper T (effector) cells stimulate the activity of: – macrophages, cytotoxic T cells & B cells Figure 10.10 T-helper (Th1) cells trigger the killing of intracellular parasites within macrophages (M). Recognition of the infected macrophage by the Th1 cell TCR results in lymphocyte activation with release of IFNγ. This then activates the macrophage, which turns on its microbicidal mechanisms to kill the intracellular parasite. Clonal Proliferation Figure 11.7 Generation of a large population of effector and memory cells by clonal proliferation after primary contact of B or T cell with antigen. A fraction of the progeny of the original antigen-reactive lymphocytes become non-dividing memory cells, whereas the others become the effector cells of humoral or cell-mediated immunity. Memory cells require fewer cycles before they develop into effectors, thus shortening the reaction time for the secondary response. Cytotoxic T Cells Stimulated cytotoxic T cells, via MHC I antigen presentation, destroy tumour cells and those infected by viruses - similar killing mechanism to NK cells - enhances killing via interferon release Figure 10.11 The cytotoxic T lymphocytes are activated when their specific cell surface receptors recognize an infected cell by binding to a surface MHC class I molecule that is associated with a peptide fragment derived from a degraded intracellular viral protein. Figure 10.12 Cellular defences against viral infection. Cytotoxic T (Tc) cells specifically recognize surface MHC class I plus peptide derived from degraded viral protein and kill the infected cells before the virus replicates. Natural killer (NK) cells can do the same, though far less effectively; however, their activity is enhanced by interferons (IFNs) produced by Tc and Th1 cells. Local production of IFNs also prevents adjacent cells from becoming infected by intercellular viral transport. Antibody Mediated Immunity B lymphocytes are activated by: – T-dependent antigens – require activated helper T cell intervention e.g., bacteria, proteins, hapten-carrier combinations – T-independent antigens – do not require T cells – usually polysaccharides or protein subunits e.g., lipopolysaccharides, capsules – immune response weaker (less sustained) T-dependent B cell activation Figure 11.11 The mechanism by which T-helper (Th) cells are primed and then activate B cells. Activated B Cells Undergo class switching – IgM, IgG, IgA or IgE production (determined by cytokine signal from T helper cell) Differentiate into antigen-specific plasma (effector) cells and memory B cells – plasma cells secrete antibodies Clonal Proliferation Figure 11.7 Primary and secondary responses Figure 11.7 Generation of a large population of effector and memory cells by clonal proliferation after primary contact of B or T cell with antigen. A fraction of the progeny of the original antigen-reactive lymphocytes become non-dividing memory cells, whereas the others become the effector cells of humoral or cellmediated immunity. Memory cells require fewer cycles before they develop into effectors, thus shortening the reaction time for the secondary response. Antibody-Antigen Binding Degree of binding = affinity Effects of antibody-antigen binding: – neutralise toxins – inactivate viruses – prevent attachment of pathogens Figure 10.7 Because of its size, an antibody can block various microbial interactions Antibodies and Innate Immune Mechanisms – activate complement (classical pathway) – activate phagocytic, mast and NK cells Figure 10.16 Integration of antibody with the innate immune mechanisms Immunisation Introduction of antigen to provoke immune response – examples inactivated toxins killed microorganisms living but attenuated microorganisms Acquired Immunity (Active) Individual exposed to microorganism Immune system response – production of antibodies – production of immune cells – production of memory Examples – natural exposure to pathogen – immunisation Acquired Immunity (Passive) Individual does not synthesize antibodies – provided by an outside source Transient Examples – transfer of antibodies across placenta – medical administration of immunoglobulin Pathogenic Mechanisms Pathogenic Mechanisms Entry – Skin, mucous membranes, parenteral route Attachment Immunoevasion/immunosuppression Host damage Virulence factors Virulence Factors Immunoevasion/immunosuppression and host damage – capsules – biofilms – cell wall constituents – enzymes – toxins Capsule Produced by some bacteria bacteria capsule – e.g., Streptococcus pneumoniae http://www2.bc.cc.ca.us/bio16/PAL/Lecture%202.htm Increases virulence – prevents phagocytic cells adhering to bacterium – resists phagocytosis – prevent complement activation Host can make antibody to capsule – destroyed by phagocytosis Biofilms A special bacterial adaptation that facilitates colonisation is a biofilm Biofilms can consist of various microorganisms http://www2.binghamton.edu/biology/faculty/davies/images/bi ofilm.jpg Cells are embedded within an extracellular matrix In the case of artificial valves or indwelling catheters the biofilm forms on these structures Cell Wall Constituents M Protein of Streptococcus pyogenes – mediates attachment – evades phagocytosis http://www2.bc.cc.ca.us/bio16/PAL/Lecture%202.htm Protein A of Staphylococcus aureus – prevents interaction between antibody and phagocyte Enzymes Leukocidins: attack certain types of white blood cells – kills cells preventing phagocytosis – releases and ruptures lysosomes Coagulases: cause blood to coagulate – Blood clots protect bacteria from phagocytosis – Staphylococcus aureus are coagulase positive Enzymes Kinases: dissolve blood clots – Helps to spread bacteria - bacteraemia Streptokinase (Streptococci), Staphylokinase (Staphylococci) Hyaluronidase: breaks down hyaluronic acid (found in connective tissues) – Spread through connective tissue Collagenase: breaks down connective tissue – Clostridium perfringens uses this to spread through muscle tissue Toxins exotoxins secreted by some bacteria rapidly dispersed (soluble in body fluids) endotoxins component of outer-membrane of Gram-negative bacteria Exotoxins Produced by some bacteria (mainly Gram-positive) – Secreted or released into the surrounding medium (soluble in body fluids) Genes for exotoxins are often carried on bacterial plasmids or bacteriophages Heat labile Destroy host cells or disrupt certain cellular functions Can be extremely potent - 1 mg of botulinum toxin will kill 106 guinea pigs Response to Exotoxins Highly antigenic Exotoxins can be inactivated (heat, formalin or phenol) - no longer cause disease but stimulate the production of antitoxin Toxoids Toxoids - injected to stimulate the production of antitoxins and provide immunity Three Types of Exotoxins AB toxins - the B portion of the toxin binds to the host cell receptor and is separate from the A portion which mediates the enzymatic activity responsible for the toxicity Membrane disrupting toxins - insert into host cell plasma membranes, e.g. haemolysins or phospholipases Superantigens - stimulate massive T cell release of cytokines (toxic effects) Exotoxin Diseases http://classes.midlandstech.edu/carterp/Courses/bio225/chap15/lecture3.htm AB Toxins The AB toxins can also be grouped into functional categories: – Neurotoxins damage to nervous system major symptom is paralysis – Enterotoxins damage to intestines and tissues of digestive tract major symptom is vomiting and diarrhea – Cytotoxins damage to variety of cells http://www2.bc.cc.ca.us/bio16/PAL/Lecture%20 2.htm damage caused by cell lysis or interference with cell function Endotoxins — Part of outer leaflet of cell membrane of most Gram-negative bacteria — lipid A component of lipopolysaccharides — Death of bacterial cell liberates endotoxin — antibiotics lyse bacterial cells temporarily releasing endotoxin — Endotoxin exposure does not promote formation of effective anti-toxin Effects of Endotoxin All endotoxins produce the same signs and symptoms – fever – chills and rigors – septic shock – hypotension – decreased tissue perfusion – disseminated intravascular coagulation – organ failure – death Exotoxins vs Endotoxins http://classes.midlandstech.edu/carterp/Courses/bio225/chap15/lecture3.htm Summary Host-pathogen interactions Non-specific host defences Exterior defences (physical, chemical, biochemical) Innate immunity (phagocytes, complement, interferons, NKC) Specific host defences Cell mediated immunity (T lymphocytes) Antibody mediated immunity (B lymphocytes, antibodies) Types of acquired immunity (immunisation, active, passive) Pathogenic mechanisms Virulence factors (immunoevasion/immunosuppression, host damage, etc.) Summary Immune responses to viruses Cytotoxic cells Virus fragments displayed on surface of infected cells via MHC I - recognised by cytotoxic T cells, which release enzymes that induce apoptosis of infected cells Infected cells with reduced numbers of MHC I molecules on their surface can be recognised and killed by NK cells via a similar mechanism Cytotoxic cells signal neighbouring cells via cytokines to enhance killing Interferons Virally infected cells release interferons, which signal neighbouring cells to produce antiviral proteins (interfere with viral replication) Interferons also signal neighbouring cells to increase surface MHC I molecules to enhance T cell recognition Summary Immune responses to viruses (continued) Antibodies Antibodies can directly bind to and neutralise a virus Antibodies can cause virus particles to stick together in a process called agglutination – easier target for immune cells Antigen-antibody complexes can trigger phagocytosis Antibodies can activate the complement system Summary Immune responses to bacteria Complement-mediated lysis Bacteria can be attacked by activated complement proteins via three pathways: Classical pathway – antibodies bind to bacterial cells Alternate pathway – complement proteins bind directly to bacteria Lectin pathway – mannan-binding lectin binds to bacterial mannose residues Activated complement proteins can form the membrane attack complex (MAC) – inserts into membrane (of Gram-negative bacteria) and facilitates osmotic lysis. Activated proteins can also enhance inflammation and phagocytosis Phagocytosis Phagocytes engulf and breakdown bacterial cells and can display bacterial fragments on their surface via MHC II – recognised by helper T cells Summary Immune responses to bacteria (continued) Phagocytosis is enhanced by complement proteins and antibodies bound to the surface of bacteria (opsonised bacteria) Cell-mediated immunity Bacterial fragments are displayed on the surface of phagocytes via MHC II (antigen presentation) Helper T cells recognise these fragments and release cytokines, which stimulate killing by phagocytes and promotes humoral immunity by activating B cells