Chapter 2 : Cytokines and Chemokines in Infection

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Cytokines are soluble, small proteins that are produced by cells and act in a largely paracrine manner to influence the activity of other cells. Currently, the term “cytokine” describes proteins such as the tumor necrosis factor family, the interleukins, and the chemokines. Virtually every nucleated cell can produce and respond to cytokines, placing these molecules at the center of most of the body’s homeostatic mechanisms ( ). Much of our knowledge of the function of cytokines has been derived from studies wherein homeostasis has been disrupted by infection and the absence of specific cytokines results in a failure to control the disease process. In this context, infection with has proven to be very informative and has highlighted the role of cytokines in controlling infection without promoting uncontrolled and damaging inflammatory responses ( ). Herein, we focus on the key cytokine and chemokines that have been studied in the context of human TB using experimental medicine as well as infection of various animal models, including non-human primates (NHPs), mice, and rabbits. Perhaps the most important message of this review is that in a complex disease such as TB the role of any one cytokine cannot be designated either “good” or “bad” but rather that cytokines can elicit both protective and pathologic consequences depending on context.

Citation: Domingo-Gonzalez R, Prince O, Cooper A, Khader S. 2017. Cytokines and Chemokines in Infection, p 33-72. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0018-2016
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Figure 1

The role of chemokines and cytokines in the innate response to infection. Upon early infection of the lower airways, encounters alveolar macrophages and lung epithelial cells. Alveolar macrophages are a major source of proinflammatory cytokines (TNFα), although stromal cells can produce cytokines and chemokines that will also modulate immune responses. During early infection, dendritic cell trafficking from the lungs to the lymph node via CCR7 results in primed naive T cells and initiation of adaptive immune responses. Replicating bacteria generate a fulminant reaction that results in the mobilization and recruitment of both neutrophils and monocytes from the bone marrow via the induction of proinflammatory cytokines and chemokines. Regulation of cellular recruitment occurs via coordinated cytokine and chemokine induction. While initial recruitment of monocytes requires type I IFN, overexpression of this cytokine results in high levels of CCR2-expressing monocytes with limited ability to control bacterial growth. Type II IFN (IFNγ) regulates the recruitment of neutrophils, which is promoted by IL-17. CXCL5 and CXCR2 mediate the recruitment of damaging neutrophils. Mtb, .

Citation: Domingo-Gonzalez R, Prince O, Cooper A, Khader S. 2017. Cytokines and Chemokines in Infection, p 33-72. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0018-2016
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Image of Figure 2
Figure 2

The role of chemokines and cytokines in the adaptive response to infection. Following infection of the lung, migratory cells take the bacteria to the draining lymph node likely using both cytokine (IL-12p40) and chemokine (CCR2, CCR7) pathways. Antigen is then transferred to antigen-presenting cells that stimulate naïve T cells via MHC class I and class II. Antigen-presenting cells make cytokines and chemokines to potentiate T-cell proliferation and polarization. Activated T cells migrate from the draining lymph node through the vasculature to the inflamed site. Some T cells remain in the vasculature (CX3CR3) while others migrate into the parenchyma (CXCR3CCR6). Expression of CXCR5 on antigen-specific T cells allows them to respond to IL-23- and IL-17-dependent CXCL13 and locate effectively within the granuloma, where they activate -infected macrophages. T cells express a variety of cytokines in the lung including IFNγ, TNFα, IL-17, and IL-10 that have both protective and negative effects depending upon the context.

Citation: Domingo-Gonzalez R, Prince O, Cooper A, Khader S. 2017. Cytokines and Chemokines in Infection, p 33-72. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0018-2016
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