immunity to microbes

Immunity to MicrobesMd. Murad Khan

Lecturer

Dept. of Microbiology

Jagannath University, Dhaka.

Introduction

The development of an infectious disease in an individual involves complex interactions between the microbe and the host. The key events during infection include: entry of the microbe

invasion and colonization of host tissues

evasion of host immunity

tissue injury or functional impairment

Microbes produce disease by: directly killing the host cells they infect, or

liberating toxins that can cause tissue damage and functional derangements in neighboring or distant cells and tissues that are not infected, or

stimulating immune responses that injure both the infected tissues and normal tissues.

General Features of Immune Responses to Microbes

Defense against microbes is mediated by the effector mechanisms of innate and adaptive immunity.

The immune system responds in specialized and distinct ways to different types of microbes to most effectively combat these infectious agents.

The survival and pathogenicity of microbes in a host are critically influenced by the ability of the microbes to evade or resist the effector mechanisms of immunity.

General Features of Immune Responses to Microbes

Many microbes establish latent, or persistent, infections in which the immune response controls but does not eliminate the microbe and the microbe survives without propagating the infection.

In many infections, tissue injury and disease may be caused by the host response to the microbe rather than by the microbe itself.

Inherited and acquired defects in innate and adaptive immunity are important causes of susceptibility to infections

Immunity to Extracellular Bacteria

Replicate outside the host cells e.g., circulation

connective tissues

in tissue spaces : lumens of the airways, gastrointestinal tract

Induce inflammation: tissue destruction at the site of infection Production toxins :diverse pathologic effects, cytotoxic and kill the cells

Endotoxin : bacterial cell wall component e.g., LPS from gram negative bacteria can activate MØ and DC

Exotoxin: bacterial secretion


Innate Immunity to Extracellular Bacteria: The principal mechanisms of innate immunity to extracellular bacteria are complement

activation, phagocytosis, and the inflammatory response. Complement activation:

Activator: Peptidoglycans in the cell walls of Gram-positive bacteria, or

LPS in Gram-negative bacteria or

Mannose on bacterial surface

Result of complement activation: Opsonization & enhanced phagocytosis of the bacteria

Membrane attack complex : lyses bacteria

Complement byproducts: stimulate inflammatory response


Activation of phagocytes and inflammation: Phagocytes (neutrophils and macrophages) use surface receptors to recognize

extracellular bacteria: Mannose receptors

Scavenger receptors

Fc receptors (opsonized bacteria)

Complement receptors (opsonized bacteria)

Microbial products activate Toll-like receptors (TLRs) and various cytoplasmic sensors in phagocytes.


Receptors function mainly to promote the phagocytosis of the microbes (e.g., mannose receptors, scavenger

receptors);

stimulate the microbicidal activities of the phagocytes (mainly TLRs); and

promote both phagocytosis and activation of the phagocytes (Fc and complement receptors)

Dendritic cells and phagocytes that are activated by the microbes secrete cytokines, which induce leukocyte infiltration into sites of infection (inflammation). The recruited leukocytes ingest and destroy the bacteria.


Adaptive Immunity to Extracellular Bacteria: Humoral immunity is a major protective immune response against extracellular

bacteria, and it functions to- block infection,

eliminate the microbes, and

neutralize their toxins.

Directed against cell wall antigens, secreted and cell-associated toxins polysaccharides : thymus independent antigens

Neutralization: high affinity IgG, IgM, IgA (mucosal lumens) Opsonization & phagocytosis : IgG Classical complement activation pathway: IgM and IgG

Immunity to Extracellular BacteriaThe protein antigens of extracellular bacteria also activate CD4+ helper T cells, which produce cytokines that induce local inflammation, enhance the phagocytic and microbicidal activities of macrophages and neutrophils, and stimulate antibody production.

FIGURE: Adaptive immune responses to extracellular microbes. Adaptive immune responses to extracellular microbes such as bacteria and their toxins consist of antibody production (A) and the activation of CD4+ helper T cells (B).

Immune Evasion by Extracellular Bacteria

The virulence of extracellular bacteria has been linked to a number of mechanisms that enable the microbes to resist innate immunity.

Evading phagocytosis: Capsule gives poor phagocyte adherence

Capsule does not adhere readily to phagocytic cells and covers carbohydrate molecules on the bacterial surface which could otherwise be recognized by phagocyte receptors.

Many pathogens evolve capsules which physically prevent access of phagocytes to C3b deposited on the bacterial cell wall.

Some microbes produce exotoxin that poisons phagocyte Some other microbe attaches to surface component to enter non-phagocytic

cell


Challenging the complement system: Poor activation of complement

Capsule provides non-stabilizing surface for alternative pathway convertase.

Accelerating breakdown of complement by action of microbial products.

Certain bacterial surface molecules, notably those rich in sialic acid, bind factor H, which then acts as a focus for the degradation of C3b by the serine protease factor I.

Some strains downregulate complement activation by interacting with C4BP; acting as a cofactor for factor I-mediated degradation of the C4b component of the classical pathway C3 convertase C4b2a.

C4BP can also inhibit activation of the alternative pathway.

Certain bacterial strains produce a C5a-ase which may act as a virulence factor by proteolytically cleaving and thereby inactivating C5a.


Challenging the complement system: Complement deviation

Some species manage to avoid lysis by deviating the complement activation site either to a secreted decoy protein or to a position on the bacterial surface distant from the cell membrane.

Resistance to insertion of terminal complement components (MAC) Gram-positive organisms have evolved thick peptidoglycan layers which prevent the

insertion of the lytic C5b-9 membrane attack complex into the bacterial cell membrane.

Many capsules do the same.

Figure: Avoidance strategies by extracellular bacteria. (a) Capsule gives poor phagocyte adherence.(b) Exotoxin poisons phagocyte. (c) Microbe attaches to surface component to enter non-phagocytic cell. (d) Capsule provides non-stabilizing surface for alternative pathway convertase. (e) Accelerating breakdown of complement by action of microbial products. (f) Complement effectors are deviated from the microbial cell wall. (g) Cell wall impervious to complement membrane attack complex (MAC).


Antigenic variations: Variation of surface lipoproteins in the lyme disease spirochete Borrelia burgdorferi

Alterations in enzymes involved in synthesizing surface structures in Campylobacter jejuni

Antigenic variation of the pili in Neisseria meningitides

Interfering with internal events in the macrophage: Enteric Gram-negative bacteria in the gut have developed a number of ways of

influencing macrophage activity, including inducing apoptosis, enhancing the production of IL-1, preventing phagosome-lysosome fusion and affecting the actin cytoskeleton.

Immunity to Intracellular Bacteria

A characteristic of facultative intracellular bacteria is their ability to survive and even to replicate within phagocytes. Because these microbes are able to find a niche where they are inaccessible to circulating antibodies, their elimination requires the mechanisms of cell-mediated immunity.

Innate Immunity to Intracellular Bacteria: The innate immune response to intracellular bacteria is mediated mainly by

phagocytes and natural killer (NK) cells. Phagocytes, initially neutrophils and later macrophages, ingest and attempt to

destroy these microbes, but pathogenic intracellular bacteria are resistant to degradation within phagocytes. Products of these bacteria are recognized by TLRs and cytoplasmic proteins of the NOD-like receptor (NLR) family, resulting in activation of the phagocytes.


Intracellular bacteria activate NK cells by inducing expression of NK cell–activating ligands on infected cells and by stimulating dendritic cell and macrophage production of IL-12 and IL-15, both of which are NK cell– activating cytokines.

The NK cells produce IFN- , which in turn activates macrophages and promotes γkilling of the phagocytosed bacteria. Thus, NK cells provide an early defense against these microbes, before the development of adaptive immunity.

However, innate immunity usually fails to eradicate the infections, and eradication requires adaptive cell-mediated immunity.


Adaptive Immunity to Intracellular Bacteria: The major protective immune response against intracellular bacteria is T cell–

mediated recruitment and activation of phagocytes (cell-mediated immunity).

T cells provide defense against infections by two types of reactions: CD4+ T cells activate phagocytes through the actions of CD40 ligand and IFN- ; these γ

two stimuli activate macrophages to produce several microbicidal substances, including reactive oxygen species, nitric oxide, and lysosomal enzymes and resulting in killing of microbes that are ingested by and survive within phagocytes. IFN- also stimulates the γproduction of antibody isotypes that activate complement and opsonize bacteria for phagocytosis, thus aiding the effector functions of macrophages.

CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells, eliminating microbes that escape the killing mechanisms of phagocytes.


Phagocytosed bacteria stimulate CD8+ T cell responses if bacterial antigens are transported from phagosomes into the cytosol or if the bacteria escape from phagosomes and enter the cytoplasm of infected cells.

In the cytosol, the microbes are no longer susceptible to the microbicidal mechanisms of phagocytes, and for eradication of the infection, the infected cells have to be killed by CTLs.

The macrophage activation that occurs in response to intracellular microbes is capable of causing tissue injury.


FIGURE: Cooperation of CD4+ and CD8+ T cells in defense against intracellular microbes.

Immunity to Intracellular Bacteria:Mycobacterium tuberculosis.

Tuberculosis (TB) is on the rampage, aided by the emergence of multidrug-resistant strains of Mycobacterium tuberculosis.

Mechanism

(a) Specific CD4 Th1 cell recognizes mycobacterial peptide associated with MHC class II and releases MØ activating IFNγ. (b) The activated MØ kills the intracellular TB, mainly through generation of toxic NO.. (c) A 'senile' MØ, unable to destroy the intracellular bacteria, is killed by CD8 and CD4 cytotoxic cells and possibly by IL-2-activated NK cells. The MØ then releases live tubercle bacilli which are taken up and killed by newly recruited MØ susceptible to IFNγ activation (d).

Figure: The 'cytokine connection': nonspecific macrophage killing of intracellular bacteria triggered by a specific T-cell-mediated immunity reaction

Immune Evasion by Intracellular Bacteria Intracellular bacteria have developed various strategies to resist elimination by

phagocytes. These include inhibiting phagolysosome fusion (Mycobacterium tuberculosis, Legionella pneumophila) or escaping into the cytosol (Listeria monocytogenes), thus hiding from the microbicidal mechanisms of lysosomes, and directly scavenging or inactivating microbicidal substances (Mycobacterium leprae) such as reactive oxygen and nitrogen species.

Immunity to Fungi

Some fungal infections are endemic, and these infections are usually caused by fungi that are present in the environment and whose spores enter humans.

Other fungal infections are said to be opportunistic because the causative agents cause mild or no disease in healthy individuals but may infect and cause severe disease in immunodeficient persons. A serious opportunistic fungal infection associated with AIDS is Pneumocystis jiroveci pneumonia.

Less is known about antifungal immunity than about immunity against bacteria and viruses.

Immunity to Fungi

Innate and Adaptive Immunity to Fungi: The principal mediators of innate immunity against fungi are neutrophils and

macrophages. Phagocytes and dendritic cells sense fungal organisms by TLRs and lectin-like

receptors called dectins. Neutrophils presumably liberate fungicidal substances, such as reactive oxygen species

and lysosomal enzymes, and phagocytose fungi for intracellular killing. Cryptococcus neoformans

inhibit production of TNF and IL-12 by macrophage and stimulate production of IL-10, thus inhibiting macrophage activation.

CD4+ and CD8+ T cells cooperate to eliminate the yeast forms of Cryptococcus neoformans, which tend to colonize the lungs and brain in immunodeficient hosts.

Immunity to Fungi

Histoplasma capsulatum facultative intracellular parasite that lives in macrophages

eliminated by the same cellular mechanisms that are effective against intracellular bacteria.

Pneumocystis jiroveci causes serious infections in individuals with defective cell-mediated immunity.

Candida mucosal surfaces and cell-mediated immunity

Fungi also elicit specific antibody responses that may be of protective value.

Immunity to Viruses

Obligatory intracellular microorganisms.

After entering host cells, viruses can cause tissue injury and disease.

Viral replication interferes with normal cellular protein synthesis and function.

Leads to injury and ultimately death of the infected cells. This result is one type of cytopathic effect of viruses, and the infection is said to be lytic because the infected cell is lysed. Viruses may also cause latent infections.

Innate and adaptive immune responses to viruses are aimed at blocking infection and eliminating infected cells.

Infection is prevented by type I interferons as part of innate immunity and neutralizing antibodies contributing to adaptive immunity.

Once infection is established, infected cells are eliminated by NK cells in the innate response and CTLs in the adaptive response.

Immunity to Viruses

Innate Immunity to Viruses: The principal mechanisms of innate immunity against viruses are inhibition of

infection by type I interferons and NK cell–mediated killing of infected cells. Type 1 IFNs are induced by pathogen-associated molecular patterns (PAMPs),

including dsRNA, ssRNA and cytosolic DNA. These lead to the activation of protein kinases, which in turn activate the IRF

transcription factors that stimulate interferon gene transcription. Type I interferons function to inhibit viral replication in both infected and uninfected

cells. Class I MHC expression is often shut off in virally infected cells as an escape mechanism

from CTLs. This enables NK cells to kill the infected cells because the absence of class I releases NK cells from a normal state of inhibition.

Immunity to Viruses Type I interferons, signaling through the type I interferon receptor, activate transcription

of several genes that confer on the cells a resistance to viral infection called an antiviral state. Type I interferon–induced genes include double-stranded RNA–activated serine/threonine protein kinase (PKR), which blocks viral transcriptional and translational events, and 2′,5′ oligoadenylate synthetase and Rnase L, which promote viral RNA degradation.

Type I interferons increase the cytotoxicity of NK cells and CD8+ CTLs and promote the differentiation of naive T cells to the TH1 subset of helper T cells. These effects of type I interferons enhance both innate and adaptive immunity.

Type I interferons upregulate expression of class I MHC molecules and thereby increase the probability that virally infected cells will be recognized and killed by CD8+ CTLs.

Protection against viruses is due, in part, to the activation of intrinsic apoptotic death pathways in infected cells and enhanced sensitivity to extrinsic inducers of apoptosis.

FIGURE: Biologic actions of type I interferons.

Immunity to Viruses Adaptive Immunity to Viruses: Adaptive immunity against viral infections is mediated by antibodies, which block virus

binding and entry into host cells, and by CTLs, which eliminate the infection by killing infected cells.

Antibodies are effective against viruses only during the extracellular stage of the lives of these microbes. Viruses may be extracellular- early in the course of infection,

before they infect host cells, or

when they are released from infected cells by virus budding or

if the infected cells die.

Immunity to Viruses Antiviral antibodies bind to viral envelope or capsid antigens and function mainly as

neutralizing antibodies to prevent virus attachment and entry into host cells. Thus, antibodies prevent both initial infection and cell to cell spread.

Antibody production resulted in virus neutralization (main function), opsonization and phagocytosis, and complement activation.

Elimination of viruses that reside within cells is mediated by CTLs, which kill the infected cells. The antiviral effects of CTLs are mainly due to killing of infected cells, but other mechanisms include activation of nucleases within infected cells that degrade viral genomes and secretion of cytokines such as IFN- , which activates phagocytes and γmay have some antiviral activity.

Immunity to Viruses

FIGURE: Innate and adaptive immune responses against viruses. A, Kinetics of innate and adaptive immune responses to a virus infection. B, Mechanisms by which innate and adaptive immunity prevent and eradicate virus infections. Innate immunity is mediated by type I interferons, which prevent infection, and NK cells, which eliminate infected cells. Adaptive immunity is mediated by antibodies and CTLs, which block infection and kill infected cells, respectively.

Immune Evasion by Viruses

Viruses have evolved numerous mechanisms for evading host immunity: Viruses can alter their antigens and are thus no longer targets of immune

responses.

Some viruses inhibit class I MHC–associated presentation of cytosolic protein antigens. Viruses make a variety of proteins that block different steps in antigen processing, transport, and presentation.

Viruses may infect and either kill or inactivate immunocompetent cells. Production of “decoy” MHC molecules to inhibit NK cells.

Production of immunosuppressive cytokine.


Inhibition of complement activation. Recruitment of factor H

Incorporation of CD59 (MAC-inhibitory protein) in viral envelope

Inhibition of innate immunity. Inhibition of access to RIG-I RNA sensor

Inhibition of PKR (signaling by IFN receptor)


FIGURE: Mechanisms by which viruses inhibit antigen processing and presentation

TABLE: Mechanisms of Immune Evasion by Viruses

Immunity to Parasites

Parasitic infection refers to infection with animal parasites such as protozoa, helminths, and ectoparasites (e.g., ticks and mites). Such parasites currently account for greater morbidity and mortality than any other class of infectious organisms, particularly in developing countries.

Innate Immunity to Parasites: The principal innate immune response to protozoa is phagocytosis, but many of these

parasites are resistant to phagocytic killing and may even replicate within macrophages. Some protozoa express surface molecules that are recognized by TLRs and activate

phagocytes. Plasmodium species (the protozoa that are responsible for malaria), Toxoplasma gondii (the agent that causes toxoplasmosis), and Cryptosporidium species (the major parasite that causes diarrhea in HIV-infected patients) all express glycosyl phosphatidylinositol lipids that can activate TLR2 and TLR4.

Immunity to Parasites

Phagocytes may also attack helminthic parasites and secrete microbicidal substances to kill organisms that are too large to be phagocytosed.

Some helminths may activate the alternative pathway of complement. Adaptive Immunity to Parasites: The principal defense mechanism against protozoa that survive within macrophages is cell-

mediated immunity, particularly macrophage activation by TH1 cell–derived cytokines.

Defense against many helminthic infections is mediated by the activation of TH2 cells, which results in production of IgE antibodies and activation of eosinophils. Helminths stimulate differentiation of naive CD4+ T cells to the TH2 subset of effector cells, which secrete IL-4 and IL-5. IL-4 stimulates the production of IgE, which binds to the Fc receptor of εeosinophils and mast cells, and IL-5 stimulates the development of eosinophils and activates eosinophils. IgE coats the parasites, and eosinophils bind to the IgE and are activated to release their granule contents, which destroy the helminths.

Immunity to Parasites: The Expulsion of Nematode Worms from the Gut.

The parasite is first damaged by IgG antibody passing into the gut lumen, perhaps as a consequence of IgE-mediated inflammation and possibly aided by accessory ADCC cells. Cytokines released by antigen-specific triggering of T cells stimulate proliferation of goblet cells and secretion of mucous materials, which coat the damaged worm and facilitate its expulsion from the body by increased gut motility induced by mast cell mediators, such as leukotriene-D4, and diarrhea resulting from inhibition of glucose dependent sodium absorption by mast cell-derived histamine. Figure: The expulsion of nematode worms from the gut.

Immune Evasion by Parasites

Parasites evade protective immunity by reducing their immunogenicity and by inhibiting host immune responses. Different parasites have developed remarkably effective ways of resisting immunity:

Parasites change their surface antigens during their life cycle in vertebrate hosts. Parasites become resistant to immune effector mechanisms during their residence in vertebrate

hosts. Protozoan parasites may conceal themselves from the immune system either by living inside host

cells or by developing cysts that are resistant to immune effectors. Parasites inhibit host immune responses by multiple mechanisms e.g.,

T cell anergy to parasite antigen,

infection of lymph nodes (deficient immunity),

immune suppression by stimulating the production of regulatory T cells,

production of immune suppressive cytokines etc.

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immunity to microbes

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