Immunity to Microbes

Immunity to Microbes
Md. 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

The 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-γ, which in turn activates macrophages and promotes
killing 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-γ; these
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-γ also stimulates the
production 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-γ, which activates phagocytes and
may 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 Fcε receptor of
eosinophils 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.

Immunity to Microbes

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Editor's Notes