Chapter 6 : Toll-Like Receptors

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This chapter focuses on examples of Toll-like receptors (TLRs) research where questions have been particularly well addressed as potential paradigms for the entire TLR system. Lipopolysaccharide (LPS) has been used for decades in immunology laboratories because of its multiple effects on innate immune cells as well as B lymphocytes and, after discovery of TLR4 as its vertebrate host counterpart receptor, has served as an important paradigm to understand the interaction and function of other TLRs with various microbial components. The malarial parasite is remarkably nonimmunogenic, both for the innate and the acquired immune systems. The early elimination of invasive microorganisms is a fundamental function of the innate immune system. Macrophages, dendritic cells (DCs), and polymorphonuclear leukocytes recognize components of invasive pathogens and orchestrate an early antimicrobial defense. Two major families of non-TLRs that have received the most attention to date are the NOD-like receptor (NLR) family of receptors and the associated inflammasomes. Recent studies indicate the existence of non-TLR pattern recognition systems that function as sensors of viral and bacterial components.

Citation: Gazzinelli R, Fitzgerald K, Golenbock D. 2009. Toll-Like Receptors, p 107-122. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch6
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Innate immunity in malaria. During the asexual portion of the cycle, merozoites are released from erythrocytes into the systemic circulation. Parasite GPI anchors and hemozoin-bound DNA trigger cytokine production. GPI anchors bind to surface TLR2 on CD14 monocytes, macrophages, and DCs. CpG-containing ODN is associated with hemozoin and triggers endosomal TLR9. Hemozoin-induced lysosomal destabilization releases DNA to access cytosolic sensors. AT-rich ODN triggers an as yet uncharacterized cytosolic DNA sensor and elicits IFN-β via NALP3, TBK1, and IRF1 to regulate IFN-β production. AT-rich ODN also elicits cytokine production (TNF, IL-6) and caspase-1-mediated processing of pro-IL-1β. These latter cytokines, still not entirely characterized, cause fever. Immune mediators also increase adhesion molecule expression on capillary endothelium. Infected erythrocytes, especially those with large schizonts, will bind to microcapillary beds in the brain.

Citation: Gazzinelli R, Fitzgerald K, Golenbock D. 2009. Toll-Like Receptors, p 107-122. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch6
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Image of FIGURE 2

Molecular and cellular steps of TLR activation. TLR4 and TLR9 are by far the best-understood surface and endosomal TLRs, respectively. TLR4 is most often located on the cell surface and it is highly specific for gram-negative derived lipid A. The recognition and sensitivity of TLR4 signaling by bacterial lipid A highly depends on the coreceptor named CD14 and MD-2. The TLR4 intracellular signaling also depends on four adapter molecules, which work in pairs, i.e., MyD88/Mal and TRIF/TRAM, which are essential for induction of IRAK/TRAF6 and TBK1/IKKe, which are then responsible for activation of NF-κB and IRF3 responses, respectively. However, TLR9 normally resides in the ER and migrates to the endolysosomal compartment in an UNCN93Bi-dependent manner, where it is activated by its agonists. TLR9 activation also depends on the MyD88 adapter molecule and results in activation of IRAK/TRAF6, culminating in stimulation of NF-κB. During activation of TLR9, MyD88 also activates IRF7- and IFN-related responses.

Citation: Gazzinelli R, Fitzgerald K, Golenbock D. 2009. Toll-Like Receptors, p 107-122. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch6
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