2. 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
▶ liberating toxins that can cause tissue damage and functional derangements in
neighboring or distant cells and tissues that are not infected
▶ stimulating immune responses that injure both the infected tissues and normal tissues.
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3. 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.
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4. 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
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5. 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
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6. Immunity to Extracellular Bacteria
• 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
• ▶ LPS in Gram-negative bacteria
• ▶ Mannose on bacterial surface
Result of complement activation:
• ▶ Opsonization & enhanced phagocytosis of the bacteria
• ▶ Membrane attack complex : lyses bacteria
• ▶ Complement byproducts: stimulate inflammatory response
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7. Immunity to Extracellular Bacteria
▶ 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.
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8. Immunity to Extracellular Bacteria
of the microbes (e.g., mannose receptors, scavenger
▶ Receptors function mainly to
▶ promote the phagocytosis
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.
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9. Immunity to Extracellular 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▶
Neutralization: high affinity IgG, IgM, IgA (mucosal lumens)
Opsonization & phagocytosis : IgG
Classical complement activation pathway: IgM and IgG
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10. Immunity to Extracellular Bacteria
The protein antigens of
extracellular bacteria also
activate CD4+ helper T
cells, which produce
cytokines that induce local
inflammation, enhance the
phagocytic
microbicidal
macrophages
and
activities of
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).
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11. 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
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12. Immune Evasion by Extracellular Bacteria
▶ 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.
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13. Immune Evasion by Extracellular Bacteria
▶ 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.
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14. 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).
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15. Immune Evasion by Extracellular Bacteria
▶ 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
Apoptosis
enhancing the production of IL-1
preventing phagosome-lysosome fusion
and affecting the actin cytoskeleton.
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16. 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.
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17. Immunity to Intracellular Bacteria
▶ 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.
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18. Immunity to Intracellular Bacteria
▶ 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.
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19. Immunity to Intracellular Bacteria
▶ 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.
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20. Immunity to Intracellular Bacteria
FIGURE: Cooperation of CD4+ and CD8+ T cells in defense against intracellular microbes.
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21. 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
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22. 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.
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23. 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.
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24. 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.
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25. 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.
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