albicans infection in humans. WT C57BL/6 mice or mice lacking TLR7 or TLR9 were infected i.v. with a low dose (1 × 104 CFU) of C. albicans, a challenge that was found to be sublethal for WT mice

in preliminary experiments. Survival and morbidity were monitored daily. As shown in Neratinib cell line Figure 7A, most of the mice lacking either TLR7 or TLR9 succumbed to infection while all WT mice survived. To ascertain whether increased lethality was associated with a decreased ability of these mice to control in vivo infection, we measured fungal burden in the kidney, the main target of hematogenous C. albicans dissemination, at 5 days after infection with the same C. albicans dose (1 × 104 CFU) used in the lethality experiments. In these experiments, we also tested MyD88−/−, IRF1−/−, and 3d mice in addition of TLR7−/− and TLR9−/− animals. While low CFU numbers were found in kidneys of WT mice, fungal burden was significantly increased in mice lacking

either TLR7 or TLR9 (Fig. 7B). Notably, fungal burden was even higher in 3d Wnt beta-catenin pathway or IRF1−/− mice compared with TLR7−/− or TLR9−/− mice. Mice lacking MyD88 showed the most severe phenotype of all, with colony counts that were approximately 6 orders of magnitude higher than those of WT controls. Collectively, these data indicated that the TLR7/TLR9/MyD88/IRF1 pathway has a nonredundant role in defenses against C. albicans. Moreover, 3d mice (that are unable to mobilize TLR7/9 and other intracellular TLRs to phagosomes) showed a phenotype

that was similar to that of IRF1−/− mice and intermediary between MyD88−/− (highly susceptible) and TLR9−/− or TLR7−/− (moderately susceptible). Our results, showing an increased susceptibility of TLR9−/− mice to C. albicans infection, were apparently in contrast with those of previous studies showing similar [28, 38] or even decreased [14] susceptibility Dapagliflozin of TLR9−/− mice in comparison with WT animals. We hypothesized that these discrepancies could be related to the fact that the cited studies used a higher (1–2 log) challenge doses than the one we used. Therefore, to test this hypothesis, we challenged TLR7- and TLR9- defective mice with a 20-fold higher C. albicans dose than that previously used in the experiments summarized in Fig. 7. Under these conditions, no differences were found in susceptibility to infection between TLR7-or TLR9-deficient mice and WT controls, as measured by kidney colony counts (Supporting Information Fig. 5). This data indicate that the effects of TLR7 or TLR9 deficiency on the outcome of the infection are critically dependent on the challenge dose. The identification of receptors and signal transduction pathways involved in immune responses to fungi is essential to understand the mechanisms underlying the development of mycoses and to devise alternative strategies to control these difficult to treat infections.