Toll-like Receptor 1 Polymorphisms Increase Susceptibility to Candidemia

Candidemia (ie, bloodstream infection with Candida species) is the fourth most common nosocomial infection in immunocompromised patients and the systemic infections with the highest mortality rate, reaching 30%–40% in intensive care unit (ICU) patients [1, 2]. It is well established that the main risk factors for candidemia are neutropenia, mucosal barrier injury, solid organ or stem cell transplantation, treatment with immunosuppressive drugs, use of broad-spectrum antibiotics, prolonged ICU stay, and central venous catheterization [3–5]. However, among patients with similar predisposing factors, the risk of systemic Candida infection and its clinical outcome vary significantly. Several Candida species, of which C. albicans is the most prevalent, have been isolated from the bloodstream of patients with candidemia. However, in recent years there has been a trend toward increased prevalence of non-albicans species such as C. glabrata and C. krusei, with increasing reports of resistance to antifungal azoles [6, 7], which may be in part promoted by the frequent use of antifungal prophylaxis, preemptive therapeutic strategies in high-risk patients, or alteration of host status [8, 9]. Antifungal prophylaxis remains the most effective way to prevent systemic Candida infection because of the lack of specific clinical and laboratory parameters to diagnose candidemia at an early stage [10, 11]. Due to all these facts, there is urgent need to identify host factors that predispose to candidemia in order to establish a well-defined predictive profile for patients at risk for developing infection. Toll-like receptors (TLRs) are transmembrane proteins on immune cells that recognize conserved microbial molecular motifs designated as pathogen-associated molecular patterns. Toll-like receptors interact with several adaptor proteins, including myeloid differentiation primary response gene 88 (MyD88) and MyD88 adaptor–like/Toll–interleukin 1 receptor domain–containing adaptor protein (Mal/TIRAP), to activate transcription factors, leading to production of proinflammatory cytokines and subsequent induction of adaptive immunity. Recognition of Candida species by innate immune cells has been demonstrated to be mediated through several TLRs, which in turn leads to a potent host defense activation against the yeast [12]. Genetic variants of TLRs and their adaptors MyD88 and TIRAP have been associated with increased susceptibility to bacterial infections [13–17]. A number of studies have proposed associations of TLR2 and TLR4 polymorphisms with increased risk of aspergillosis and candidemia [18–21]. However, most of these studies have been performed in very small cohorts of patients, and a systematic genetic study investigating variation in pattern recognition receptors in a large cohort of patients at risk of candidemia, comprising infected patients and noninfected control patients, has not been performed to robustly interrogate the importance of this innate pathway for protection against Candida species. In the present study, we hypothesized that certain polymorphisms in TLR genes or in genes encoding their signaling adaptors may influence host susceptibility to the most common invasive fungal disease, candidemia. To test this hypothesis, we analyzed the prevalence of mostly nonsynonymous single nucleotide polymorphisms (SNPs) in 5 candidate TLR genes and genes encoding their adaptors MyD88 and TIRAP in a cohort of 338 candidemia patients and 351 noninfected controls that had similar underlying predisposing factors. The genetic study was further complemented and supported with functional assays that assessed the consequences of these specific polymorphisms on the cytokine production capacity of primary human blood mononuclear cells in order to validate the mechanistic association of the susceptibility trait.