Single-nucleotide polymorphisms in Toll-like receptor (TLR)-2, TLR4 and heat shock protein 70 genes and susceptibility to scrub typhus

Abstract

Scrub typhus is a highly prevalent bacterial infection in India and South Asia that is caused by Orientia tsutsugamushi. The innate immune response to infections is modulated by Toll-like receptors (TLRs) and heat shock proteins (HSPs). This study was done to assess the prevalence and possible association of TLR and HSP polymorphisms in scrub typhus. TLR4 Asp299Gly, TLR4 Thr399Ile, TLR2 Arg753Gln and HSP70-2 A1267G are single-nucleotide polymorphisms (SNPs) that may modulate their activities, and these SNPs were assessed in 137 scrub typhus patients and 134 controls by PCR restriction fragment length polymorphism. We found that the two TLR4 mutations, TLR4 D299G and TLR4T399I, were present in 19.5% and 22% of the study population, respectively, and was in significant linkage disequilibrium with a D' of 0.8. The TLR2 mutation was found to be rare, whereas the HSP A>G mutation was very common (77.5%). Compared with the controls, the prevalence of heterozygous genotype of the TLR4D299G SNP, but not any of the other SNPs, was significantly higher among scrub typhus patients. Further studies using a larger sample size and more candidate genes may better enable in determining the role of these associations in susceptibility and severity of scrub typhus.

Dysregulated Th1 Immune and Vascular Responses in Scrub Typhus Pathogenesis

“…Since Orientia are sparse in the brains, it is speculated that inflammatory cytokines like IFN-γ and TNF-α can synergize with DAMP molecules to promote BBB opening (77). It will be important to examine the involvement of IL-1 family DAMP molecules, their receptors, and TLR2/4/9 at acute and convalescence stages via population-based genetic studies of scrub typhus patients (91) or pathway-focused studies in mouse models (33).…”

RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

“…TLR2 is expressed not only in immune cells, but is also present in pulmonary alveoli and airway epithelial cells, suggesting that it plays a role in mucosal innate immunity and infection-induced lung injury (Charles et al, 2011; Hertz et al, 2003; Hoth et al, 2012; Jiang et al, 2005). Interestingly, TLR2 deficient mice are highly susceptible to S. aureus infection (Takeuchi et al, 2000), and in humans, a loss-of-function TLR2 mutation has been linked to susceptibility to infectious and inflammatory diseases, faster disease progression, and a more severe course of sepsis in critically ill patients (Bronkhorst et al, 2013; Janardhanan et al, 2013; Nachtigall et al, 2014; Stappers et al, 2014). These studies illustrate the protective role of TLR2 in response to inflammatory insults and infectious diseases.…”

TLR9 Transcriptional Regulation in Response to Double-Stranded DNA Viruses

“…Despite the numerous data demonstrating alteration of TLR mRNA expression by ligand activation, few reports demonstrated the consequence or specific mechanism by which TLRs themselves are transcriptionally regulated. In addition, the importance of TLR transcriptional regulation is highlighted by the fact that several single nucleotide polymorphisms in TLR promoters predispose humans to several autoimmune and chronic inflammatory diseases, including asthma and Crohn's disease (44)(45)(46)(47)(48)(49)(50)(51). In this article, we provided novel insights on the transcriptional regulation of TLR9 with dsDNA viruses.…”