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382 PARt tHREE Host Defenses to Infectious Agents

KEY CONCEPtS susceptibility to intracellular bacterial infection will continue
T Cell–Mediated Mechanisms to illuminate our understanding of how immunity is similarly
orchestrated across multiple infectious diseases.
Underlying Protection
Proinflammatory Cytokines and Phagocyte Attraction
IFN-γ- and TNF-α-mediated activation of phagocytes to kill bacteria by
means of: The recruitment of more phagocytes to the site of infection
Reactive oxygen intermediate (ROI) and reactive nitrogen intermediate represents a vital process in the resolution of infection. Phagocyte
(RNI) recruitment is achieved via the secretion by MPs and endothelial
Delivery of lysosomal hydrolytic enzymes and antimicrobial peptides cells of cytokines of the IL-1 family, TNF-α, IL-6, and chemokines.
to the bacteria-containing phagosome Signaling via IL-1 cognates is considered closely related to that
Autophagy
Formation and maintenance of granulomas of the TLRs because of the close homology of the cytoplasmic
T cell–mediated response controls but does not eradicate the domains of TLRs and IL-1 family receptors. The most studied
pathogen member is IL-1β, which, in synergy with chemokines and TNF-α,
increases the expression of adhesion molecules on the vascular
epithelium, thereby promoting extravasation of the inflammatory
cell infiltrate into infected tissues. Chemokines are a family of
listeriosis, TB, or typhoid in experimental animals. For macro- structurally related proteins. The positions of the first two cysteine
phages harboring intracellular bacteria, namely, M. tuberculosis, residues in the protein sequence have been used to divide che-
signaling with IFN-γ is a game-changer, summoning infected mokines into four subfamilies: CC (MIP-1β, MCP-1, MCP-2,
macrophages to escalate antimicrobial mechanisms. The action MCP-3), CXC (MIP-2, IL-8), C (lymphotactin), and CX3C
of TNF-α appears to augment IFN-γ and is also important in chemokines (fractalkine), where C represents cysteine and X
control of intracellular infection. This has been demonstrated represents any amino acid other than cysteine. These molecules
in humans through use of blocking of TNF-α by antibodies as are critical in controlling the migration of PMNs (IL-8) and
antiinflammatory therapy. Such treatments can activate TB in monocytes (MCP-1, also known as CCL2) from the bloodstream
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individuals with LTBI. Despite this, these potent protective effects to infected tissue. Recently, the role of chemokines in intracellular
of IFN-γ and TNF-α come at a price. The need to kill intracel- infections has been increasingly appreciated, for example, with
lular bacteria often leads to death of the host cell as collateral mice lacking the receptor for CCL2 being deficient in their ability
damage. In part, the host manages this by controlling how the to clear listeria infection. It has been suggested that in the early
cell dies. Excessive TNF-α leads to less regulated necrotic cell stages of infection, M. tuberculosis exploits a delay in the mobiliza-
death, benefiting M. tuberculosis. For this reason elaborate host tion of T-cell immunity to recruit MPs to the site of infection,
mechanisms have evolved to maintain TNF-α at optimal levels which preferentially serve as habitat because of a lack of local
to control infection. The host enzyme leukotriene A4 hydrolase IFN-γ from T cells. Moreover, M. tuberculosis is thought to infect
(LT4H) catalyzes synthesis of a highly proinflammatory lipid the relatively sterile lower airways. The lack of commensal bacteria
leukotriene B4. In the event of enzyme deficiency, an antiinflam- could mean that M. tuberculosis uses cell surface phenolic gly-
matory lipid lipotoxin A4 accumulates that counteracts effects colipid (PGL) to signal epithelial cells to produce the chemokine
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of TNF-α. Two common variant promoters control expression CCL2 in the absence of signaling via other PAMPs. This
of LT4H in humans, and homozygotes are associated with either mechanism then recruits MPs that are more permissive for
high or low inflammation. In contrast, the heterozygotes show a bacterial growth than those recruited by a more “global” MyD88-
balanced response to TNF-α associated with resistance against dependent signaling of TLRs, requiring coengagement of PAMPs
TB. Such a finding strongly suggests that genetic mechanisms on commensal bacteria that are more abundant in the upper
can maintain an optimal level of TNF-α responsiveness of cells airways. The initial macrophage infiltrates could play an important
harboring intracellular bacteria, namely, M. tuberculosis. A central role in early granuloma development.
antimicrobial mechanism stimulated by IFN-γ and TNF-α is
production of reactive nitrogen intermediates (RNIs) via the Cytokine-Induced Host-Protective Mechanisms
induction of nitric oxide synthase (NOS)2 and reactive oxygen Effector Molecules
intermediates (ROIs) via activation of nicotinamide adenine Activation of a membrane-bound NADPH oxidase by stimulation
dinucleotide phosphate (NADPH)–dependent oxidative burst. with IFN-γ or immunoglobulin G (IgG) initiates an oxidative
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− 1
IFN-γ also promotes antimicrobial effects associated with vitamin burst that generates the ROIs O 2 , H 2 O 2 , OH , O 2 , and •OH
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D and induces autophagy, a mechanism that plays an important radical (Table 26.3). In human PMNs and blood monocytes
role in host defense. It is now clear that the production of IFN-γ that possess myeloperoxidase, ROI activity is further augmented
depends on prior activation by IL-12 and/or IL-18. IL-12, in by the formation of hypochlorous acid. Oxidation and/or
concert with TNF-α, induces a cytokine loop resulting in the chlorination of bacterial lipids and proteins result in their
production of IFN-γ, which sustains the production of IL-12 inactivation and subsequent bacterial killing. The importance
and IL-18. These observations have been extended to humans, in of ROIs in antibacterial defense is underlined by recurrent
whom mutations that affect IFN-γ signaling cause susceptibility infections in patients whose phagocytes fail to generate an oxida-
to M. tuberculosis and salmonellae, as well as to BCG and com- tive burst. Nitric oxide synthase 2 (NOS2) is an inducible cytosolic
monly nonpathogenic mycobacteria, and are termed mendelian enzyme in professional phagocytes that delivers NO to the
susceptibility to mycobacterial disease (MSMD). The mutations are phagolysosome harboring bacteria while consuming O 2 and
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−
located in genes that include IL12B and IL12RB, which encode L-arginine. NO is further oxidized to NO 2 and NO 3 . Nitrification
subunit β of the IL-12 cytokine and its receptor, respectively, and/or oxidation then inactivates bacterial molecules needed
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and IFNGR1 and IFNGR2, which encode the IFN-γ receptor. for bacterial growth. The formation of •NO is catalyzed by
Further unraveling of the molecular basis of human genetic NOS2, which is promoted by both immunological stimuli, such