Toll like receptor 1 polymorphisms and susceptibility to invasive candidiasis

Introduction

Invasive candidiasis is a severe systemic fungal infection with Candida spp. affecting immunocompromised hosts, which is responsible for the highest mortality rate of all nosocomial infections. Although several clinical predisposing factors are known, the individual risk for developing invasive candidiasis varies significantly. Recognition of fungi such as Candida albicans is mediated through receptors of the innate immune system, such as Toll-like receptors (TLRs), that in turn activate innate immune system and antifungal defense.

Objective

To assess whether polymorphisms in fungal innate immune receptors such as TLRs and dectin-1 influence susceptibility to invasive candidiasis.

Methods

Frequencies of mostly nonsynonymous polymorphisms in several innate immune receptors were genotyped in a total of 331 patients that developed invasive candidiasis and compared with a total of 341 matched control patients that had the same predisposing factors. These included neutropenia, mucosal barrier injury and treatment with immunosuppressive regimens. Furthermore, in vitro studies with healthy volunteers were conducted to assess the functional consequences of these polymorphisms regarding cytokine responses.

Results

Genotyping for polymorphisms in innate immune receptor genes revealed a higher frequency of three independent non-synonymous TLR1 polymorphisms in the affected group patients that developed invasive candidiasis. These polymorphisms were also demonstrated to be associated with impaired cytokine responses upon stimulations of immune cells, including IL-1β, IL-6 and IL-8.

Conclusion

Polymorphisms in TLR1, which is known to dimerize with TLR2 and TLR6, are associated with impaired immune recognition through these receptors and predispose to invasive candidiasis in humans.