Modulating Toll-Like Receptor Signalling as a Novel Antiinfective Approach

Abstract

The innate immune response against invading microorganisms results in the deployment of phagocytes, including macrophages and dendritic cells to recognize pathogen-associated molecular patterns. Activation of Toll-like receptors (TLRs) expressed on these cells is a critical step in the initiation of this response, triggering the production of pro- and antiinflammatory cytokines to dampen microbial pathogenesis. Importantly, TLR activation also mediates dendritic cell maturation, a critical step in bridging the innate and adaptive arms of the immune system. Balancing the role of TLRs as central mediators of overlapping signaling pathways, whether directly through ligand interactions or via secondary adaptor molecules, mandates exquisite specificity. Further, understanding the immunopharmacology of TLR cross-talk during infection may help to provide insight into innate immunity and the mechanisms of immune-response subversion by pathogens. The continual and rapid emergence of drug resistance to traditional antimicrobial agents highlights the medical need for new treatment approaches. Herein, the discovery and development of TLR agonist and antagonist therapies for infectious diseases as adjunct to, or in place of, conventional treatment paradigms is discussed.

Expression of TLR9 and its mRNA in the lesions of lichen planus

“…So far, excitomotor and antagon of TLR9 have been found, which provides new way to precisely regulate TLR9 signal conduct and treat some diseases [8] . Artificially synthesized CpGODN can simulate CpG motif of microbial DNA to induce Th1 response, but the blockade of TLR9 pathway may be a new approach for the treatment of autoimmune diseases such as lichen planus.…”

Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease

“…During the last decade, significant research has been focused on the role of TLRs in the immune control of the airways and in the pathogenesis of airway diseases (Akira, 2003;Takeda et al, 2003;Chaudhuri et al, 2005;Sabroe et al, 2005;Pandey and Agrawal, 2006). TLRs are currently being exploited as possible targets for drug development (Mbow and Sarisky, 2005;Pandey and Agrawal, 2006;Romagne, 2007). TLR-specific treatment can be classified in three clusters (Chaudhuri et al, 2007): agonists (induce protective immunity), agonist adjuvants [antitumor treatment, T helper (Th) 1/Th2 bal-1 Abbreviations: BAL, bronchoalveolar lavage; CCL2, monocyte chemoattractant protein-1; CCL20, macrophage inflammatory protein 3-␣; CCL3, macrophage inflammatory protein-1 ␣; CD44, major cell receptor for hyaluronan; COPD, chronic obstructive pulmonary disease; CpG, cytosine-guanine repeat; CXCL8, chemoattractant interleukin-8; DAMP, damage associated molecular pattern; DC, dendritic cell; dsRNA, double-stranded RNA; ECM, extracellular matrix; GAG, glycosaminoglycan; GM-CSF, granulocyte macrophage-colony-stimulating factor; HA, hyaluronic acid or hyaluronan; HDM, house dust mite; HEK, human embryonic kidney; HMGB1, highmobility group protein B1; HSP, heat shock protein; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; LRR, leucine-rich repeat domain; MMP, matrix metalloproteinase; NK, natural killer; ODN, oligonucleotide; OVA, ovalbumin; PAMP, pathogen-associated molecular pattern; PBMC, peripheral blood derived monocyte; poly(I:C), polyinosine-polycytidylic acid; ROS, reactive oxygen species; SLIT, sublingual immunotherapy; SNP, single nucleotide polymorphism; Th, T helper; TIR, intracellular Toll/IL-1 receptor domain; TLR, Toll-like receptor; TNF, tumor necrosis factor.…”

Pattern recognition receptors in companion and farm animals – The key to unlocking the door to animal disease?

“…Recent findings suggest that there are small synthetic molecules that block TLR-adapter interaction (Ii et al, 2006). More information about TLR agonists in association with adjuvants has recently been published (Del Vecchio et al, 2005;Mbow and Sarisky, 2005).…”