Toll-like receptor 4 polymorphisms predispose to cutaneous leishmaniasis

The clinical spectrum of cutaneous leishmaniasis (CL) is extremely variable. Studies in experimental leishmaniasis have revealed a role for TLR4 in control of infection. In the present study the associations between TLR4 mutations (Asp299Gly and Thr399Ile) with outcome of CL have been investigated. Genotyping for Asp299Gly and Thr399Ile was performed in patients with chronic (N = 22) and acute (N = 61) CL, asymptomatic (N = 45) and healthy leishmanin skin test negative individuals (N = 75). The results showed the frequency of the Asp299Gly genotype was increased in patients with chronic disease (OR 25.3, 95% CI 5.2-115.6, P < 0.001) and patients with acute disease (OR 8.03, 95% CI 1.7-37.7, P = 0.006) compared to LST negative subjects. Thr399Ileu genotype was significantly over represented among patients with chronic disease (27.3%, P < 0.001), patients with acute disease (13.1%, P = 0.016), and asymptomatic donors (15.6%, P = 0.008) in comparison with LST negative normal group (1.3%). Both variants were found together more frequently in patients with chronic disease compared to the patients with acute disease (P = 0.045), and asymptomatic donors (P = 0.045). The results provide evidence that polymorphisms of TLR4 gene may lead to the increased susceptibility to and severity of infection by Leishmania major. The concomitant carriage of both mutations increases the susceptibility of individuals to CL.