Host Response to Infection

The Adult Human Comprises: 1014 Cells 1013 are Mammalian 9 × 1013 Microbes (at least)

Range of micro-organisms capable of causing infection & disease Viruses Bacteria Fungi Protozoa Helminths Arthropods Prions

Host Response to Infection Comprises 2 main arms: (1) Innate immunity (2) Adaptive (acquired) immunity Many components, for example phagocytes & cytokines, play a role in both responses

Innate Immune System Initial response to microbial challenge (first line of defence) Primitive in evolutionary terms but highly effective and can eliminate the micro-organism from the host Non-specific (defends against any pathogen); does not depend upon prior exposure to the microbial agent; no change with repeat exposure; no memory (A) Mechanical barriers; bactericidal substances; normal flora (B) Humoral component (acute phase proteins, interferons, complement) (C) Cell-mediated component (phagocytes, natural killer cells, eosinophils)

Innate Immune System Ability to recognize structures that are unique to microbes (Pathogen-Associated Molecular Patterns, PAMPS) through Pattern Recognition Receptors (PRRs) on host cells & molecules that are part of the innate immune system Lipotechoic acid (Gram +ve) and Lipopolysaccharide (Gram –ve) bacterial cell walls recognized by Toll-like receptors on macrophages leading to macrophage activation & cytokine production Double-stranded RNA of replicating viruses recognized by toll-like receptors on NK cells leading to interferon production

Summary of TLR ligands recognized by TLR family

Adaptive Immune System Initially slow to respond i.e. involved in clearing an infection Subsequently prevents re-infection with the same pathogen Specific components produced in response to a particular invader Memory (faster, more vigorous immunological response on re-exposure) (A) Humoral mediated– antibodies produced by plasma cells (transformed B-lymphocytes) (B) Cell-mediated – T lymphocytes

Adaptive Immune Response & Immunological Memory

Host Response vs. Infection Antibody (humoral mediated immunity) defends against viruses when outside cells, bacteria, toxins, fungi, parasites Cell-mediated immunity defends against pathogens (all viruses, some bacteria, fungi and protozoa) that have entered into our own cells. Thus much more destructive as destroys both pathogen and host cell

Bacteria Prokaryotes (without a membrane-bound nucleus) Mostly free living Reproduce by binary fission Usually have a cell wall Size 0.5 - 10  Classified by shape, size, staining characteristics but nowadays by genome sequencing Can be killed by a vast array of antimicrobials

Bacterial Diseases Many Infectious agents and many diseases Bacteria can Infect any part of the body Cause disease due to – Growth of the microbe in a tissue – Produce Bacterial factors that are harmful to host – Elicite an inflammatory response that causes damage But also leads to acquired immunity

Steps of Bacterial Infection 1. Attachment of bacterium to host tissue • Persistence and growth called colonization

Steps of Bacterial Infection 2 2. Invasion into deeper host tissues and production of toxins • Results in host cell and tissue injury

Steps of Bacterial Infection 3 3. Inflammation at site of invasion • Initiated by antibody binding to bacterium • Initiated by complement activation at bacterial surface • Initiated by wound healing mechanisms • All can activate complement pathways that alters vascular permeability and activates local macrophage and neutrophils (PMNs)

Inflammation at site of invasion

Factors that promote colonization, entry, and progression to disease

Factors that promote colonization, entry, and progression to disease • Bacterial Aliginate – Promotes adherence to host tissue • Bacterial LPS and pilus – Promote persistence by resisting complement and phagocytosis • Bacterial Type III secretion system – Deliver enzymes and toxins that • injure host tissues or • diminish host immune responses • Includes signaling proteins, proteases, and superantigens

The defence mechanisms used depend on:- Immunity to bacteria The defence mechanisms used depend on:- - Site of infection - Structure of the invading bacteria - How they cause damage - Intracellular vs. extracellular location

How Can Bacteria Cause Damage? Toxin production Tissue invasion Both Clostridium tetani Mycobacteria Most bacteria

Immunity to bacteria Innate and adaptive immune systems work together. In general, the innate response is important in preventing an infection becoming established, the adaptive subsequently in combating an established infection

Innate immune system can recognise and respond to common bacterial components Not antigen specific but are protective responses generated by common often conserved bacterial components Pathogen associated molecular patterns, (PAMS) recognised by cells of the innate immune system. eg:-Lipopolysaccharide (LPS) produced by gram negative bacteria.

Innate Immune Effectors and Bacterial Infection

Adaptive Immune Response: Antibacterial Roles of Antibody Action How Block adhesion Ab to surface proteins Block proliferation Ab to surface receptors eg. iron Cause phagocytosis Bind bacterial surface and allow phagocytes to bind bacteria Lysis, phagocytosis and inflammation Activate complement Neutralise toxic products Bind toxins Prevent tissue invasion and damage Neutralise bacterial products and proteases

Immunity to extracellular bacteria by antibodies: Antibodies and complement result in opsonization via FcReceptors (FcR) or Complement Receptors (CR) on M! and PMN. Antibody can activate classical complement pathway resulting membrane attack complex (MAC) and opsonization via CR. Antibodies can also trigger antibody-dependent cell mediated cytotoxicity (ADCC) by PMN with FcR and CR release proteases, nucleases, lipases.

Immunity to extracellular bacteria by antibodies

Immune System Function and Resistance to Bacterial Infection Major mediators of resistance to extracellular bacterial infections is ANTIBODIES Provide protective immunity by Killing live organisms through: Opsonophagocytosis = promotion of complement mediated phagocytosis Neutralizing bacterial toxins to prevent damage and intense damaging inflammatory responses

Mechanisms of Immunity to intracellular bacteria by CMI

Immunity to intracellular bacteria by cell mediated immunity (CMI) Bacterial antigens present in the cytoplasm of infected host cell – Processed via endogenous pathway and presented to CD8+ T cells (cytotoxic T lymphocytes or CTLs) on MHC class I. Bacterial antigens present in the endosomes of infected host cell – Processed via the exogenous pathway and presented to CD4+ helper T cells (TH) on MHC class II. Bacterial antigens present on the surface of the infected host cell can be bound by antibodies and targeted for killing by NK cells using ADCC

Do T Lymphocytes Have a Role in the Response to Bacteria? T cytotoxic lymphocytes can kill infected cells intracellular pathogens eg Mycobacterium tuberculosis T helper cells produce cytokines or interleukins more antibody production Interferon  activates macrophages and increases bacterial killing, increases production of IgG used by phagocytes, increases cytotoxicity and CD8 T cell activity

Bacterial Virulence Factors: How they Thwart Host Immunity • Virulence factors are anything that bacteria use to cause disease Examples: – Proteins, glycolipids, carbohydrates, teichoic acids, peptidoglycan, metabolites, enzymes, toxins • Impede the function of lymphocytes and granulocytes – Proteins, enzymes, and toxins • Overstimulate inflammation so normal defenses do not work – Glycolipids like LPS, cell wall structures like teichoic acids ad peptidoglycan, also enterotoxins and bacterial superantigens • Prevent phagocytosis – Carbohydrates like LPS side chains and capsular polysaccharides • Evade Complement mediated killing – Lots of ways..