Immunity to Bacterial infections

Events during infection

• Entry of microbe
• Invasive 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 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
Features of immune response to bacteria
• Involve innate and adaptive immunity
• Responds in specialized and distinct ways to different types of
bacteria
• Survival and pathogenicity of bacteria in a host are influenced by
ability of the microbes to evade or resist the effective mechanisms of
immunity
• Many microbes establish latent or persistent infections
• Inherited and acquired defects in innate and adaptive immunity are
cases of susceptibility to infection
Immunity to extracellular bacteria
• Replicate outside the host cells ; Circulation, Connective tissues,
Tissue spaces such as lumen of GIT, airways
• Induce inflammation; tissue destruction at the site of infection
• Production of toxins; diverse pathologic effects, cytotoxic and kill the
cell
• Endotoxin; Bacterial cell wall components[LPS in gram negative
bacteria, Mannose on bacterial surface]
Innate Immunity to Extracellular Bacteria
• Include complement activation, Phagocytosis and inflammatory
response
Complement activation
Activators
• Peptidoglycan in the cell wall of gram positive bacteria
• LPS in gram negative bacteria surface
Results of complement activation
• Opsonization and enhanced phagocytosis of the bacteria
• Membrane attack complex; lyses bacteria
• Complement by-products- stimulate inflammatory response
Activation of Phagocytes and Inflammation
• Phagocytes use surface receptors to recognize extracellular bacterial
• 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
• Stimulate the microbicidal activities of the phagocytes [TLRs]
• 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 leucocyte infiltration into the site of
infection [inflammation]
• Recruited leucocytes ingest and destroy bacteria
Adaptive Immunity to Extracellular Bacteria
• Humoral immunity;
• Block infection
• Eliminate the microbes
• Neutralize their toxins
• Directed against cell wall antigens secreted and cell associated toxins
• Neutralize- high affinity IgG, IgM, Ig\a
• Opsonization and Phagocytosis- IgG
• Classical complement activation pathway- IgM and IgG
• Protein antigen activate CD4+ helper T cells which produce cytokines
that induce local inflammation, enhance the phagocytic and
microbiocidal activities of macrophages and neutrophils and
stimulate antibody production
Bacterial resistance to innate immunity
Evade phagocytosis
• Possess capsule- give poor adherence to phagocytic cells
• Capsules physically prevent access of phagocytes to C3b deposited on
the bacterial cell wall
• Some bacteria produce exotoxin that poison phagocytes
• Some attach to surfacet components 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 microbial products
• Sialic acid found on the bacterial surface bind factor H which then acts as a
focus for the degradation by C3b by the serine protease factor I
• Some bacterial strains downregulate complement activation by interacting
with C4BP acting as a cofactor for factor I- moderate degradation of C4b
component of the classical pathway C3 convertase C4b2a
• C4BP can also inhibit activation of the alternative pathway
• Some bacterial strains produce a C5a- ase which may act on a virulence
factor thereby inactivating C5a
Complement deviation
• Some species manage to avoid lysis by deviating the complement
activation site to a position on the bactertial surface distant to 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
Immune Evasion by Extracellular Bacteria
Antigen variations
• Variation of surface lipoproteins in the lyme disease-Spirochette- Borrelia
burgdorteri
• Alteration in enzymes involved in synthesizing surface structures in
Campylobacter jejuni
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
• Intracellular bacteria can survive and replicate within phagocytes
• They become inaccessible to circulating antibodies
• Require cell mediated immunity to be eliminated
Innate immunity to intracellular bacteria
• Mediated by phagocytes and NK cells
• Neutrophils and macrophages ingest and tend to destroy the microbes but
intracellular bacteria are resistant to degradation within phagocytes
• Products of theses bacteria are recognized by TLRs and cytoplasmic proteins of
NOD like receptors [NLR] family resulting to activation of the phagocyte
• Intracellular bacteria activate NK cells by inducing expression of NK cell
activating ligands on infected cells by stimulating dendritic cell and
macrophage production of IL-12 and IL-15 [NK activating cytokines]
• The NK cells produce IFN-Y which in turn activates macrophages and promote
killing of phagocytosed bacteria
• Innate immunity sometimes fail to eradicate the infection and therefore
requires adaptive cell mediated immunity

Adaptive immunity to intracellular Bacteria

• The major protective immune response against intracellular bactetria is T cell-
mediated recruitment and activation of phagocytes [CMI]
• CD4+ T cells activate phagocytes through CD40 ligand and IFN-ϒ
• Thus activating macrophages to produce several microbiocidal substances
such as reactive oxygen, nitric oxide and lysosomal enzymes resulting in killing
of bacteria that are ingested by and survive within the phagocytes
• IFN-ϒ also stimulates the production of antibody isotopes that activate
complement and opsonize bacteria for phagocytosis thus aiding the effector
functions of macrophages
• CD8+ cytotoxic T lymphocytes 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 the
phagosomes and enter the cytoplasm of the infected cells
• In the cytosol, the microbes are nolonger susceptible to the microbiocidal
mechanisms of the phagocytes and for eradication of the infection, the
infected cell have to be killed by the CTLs
• The macrophage activation that occurs in response to intracellular microbes
are capable of causing tissue injury