Chapter 11 : Innate Immunity to Infections

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The tasks of recognition of the invading pathogen and host defense activation are accomplished by pattern recognition receptors (PRRs) that sense conserved chemical signatures of the microorganisms called pathogen-associated molecular patterns (PAMPs). The most important cell populations involved in the phagocytosis of fungal pathogens are neutrophils and macrophages, and together with the monocytes they have been shown to represent the major producers of proinflammatory cytokines. These innate immunity cell populations have subsequently been shown to be the most important cellular component of host defense against disseminated infections. C-type lectin receptors (CLRs) are members of a large family of PRRs including dectin-1, the macrophage mannose receptor (MR), dendritic cells (DC)-specific ICAM3-grabbing nonintegrin (DC-SIGN), dectin-2, and the circulating mannose-binding lectin (MBL). Recent progress in understanding host defense against fungal infections in general, and infections in particular, has provided important novel targets for potential novel immunotherapeutic approaches. As vaccination is one of the most cost-effective treatment strategies and probably the most powerful tool to protect humans and animals against infectious disease, further vaccine development could significantly lessen the burden of infections in patients at risk.

Citation: Netea M, Gow N. 2012. Innate Immunity to Infections, p 155-170. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch11
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PRR recognition of at the membrane level. Recognition of at the level of cell membrane is mediated by TLRs and CLRs TLR4 induces mainly proinflammatory signals in monocytic cell types (monocytes, macrophages, and DCs) through the MyD88/Mal-mediated NF-κB and MAPK pathways while stimulating Th1 responses through IRF3-dependent mechanisms. TLR2 stimulates moderate amounts of proinflammatory cytokines while inducing strong IL-10 and transforming growth factor β (TGFβ) responses. On the one hand, this leads to the induction of a tolerant phenotype in DCs through an ERK/MAPK-dependent mechanism. On the other, TLR2 engagement induces proliferation of Tregs and immunosuppression. The proinflammatory effects of TLR2 can be amplified by dectin-1 and galectin-3, the latter especially in the macrophages. In addition to the amplification of TLR2 effects, the nonclassical lectin-like receptor dectin-1 induces IL-2, IL-10, and Th17 responses through a Syk/CARD9 cascade, independently of its interaction with TLR2. The classical lectin-like receptor MR induces proinflammatory effects in monocytes and macrophages, whereas chitin-dependent stimulation induces mainly Th2 responses, although this effect still has to be demonstrated for . The identity of its receptor is unknown. Other less-well characterized pathways include stimulation of TNF and IL-1Ra by dectin-2, Mincle, and CD36/Scarf lectin receptors and of synthesis of the immunosuppressive cytokine IL-10 by DC-SIGN in DCs. doi:10.1128/9781555817176.ch11.f1

Citation: Netea M, Gow N. 2012. Innate Immunity to Infections, p 155-170. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch11
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Extent of onychomycosis and dermatophytosis in a chronic mucocutaneous candidiasis patient with severe Th17 deficiency. doi:10.1128/9781555817176.ch11.f2

Citation: Netea M, Gow N. 2012. Innate Immunity to Infections, p 155-170. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch11
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Genetic susceptibility to fungal infections. Host defense against both systemic and mucosal infections relies significantly on the proper function of neutrophils, explaining the high incidence of both types of fungal infections in neutropenic patients. However, an important difference seems to be present in terms of Th cell population responsible for activation of neutrophils in systemic candidiasis (Th1 cells) or mucosal candidiasis (Th17 cells). An increased susceptibility to systemic candidiasis is seen in patients with TLR4 or TLR1 polymorphisms. In turn, defects of IL-17 production such as in patients with hyper-IgE syndrome, patients with chronic mucocutaneous candidiasis or dectin-1/CARD9 deficiency, or patients bearing polymorphisms of MBL, IL-4, or NLRP3 are associated with an increased susceptibility to mucosal forms of infections. doi:10.1128/9781555817176.ch11.f3

Citation: Netea M, Gow N. 2012. Innate Immunity to Infections, p 155-170. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch11
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Overview of the structure of cell wall and its main PAMPs. (a) Freeze-substitution electron micrograph showing the outer fibrillar mannoprotein layer and the inner amorphous skeletal layer. (b to d) Representations of the arrangement and structures of components of the cell wall. In panel c the linkages of cell wall proteins to the skeletal β-1,3 glucan–chitin layer are shown, and in panel d the structure of the -linked and -linked mannans that are attached to serine/threonine and asparagine residues (respectively) of glycosylated proteins is described. doi:10.1128/9781555817176.ch11.f4

Citation: Netea M, Gow N. 2012. Innate Immunity to Infections, p 155-170. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch11
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