Resistance to inflammasome-mediated nitric oxide production is involved in Diffuse Cutaneous Leishmaniasis

Abstract

Abstract Leishmania amazonensis is one of the etiological agents of Cutaneous Leishmaniasis in Brazil. Infected individuals can present different forms of the disease, such as the Localized Cutaneous Leishmaniasis (LCL), characterized by round papules in the skin and the Diffuse Cutaneous Leishmanisis (DCL), a more severe form of the disease, characterized by multiple nodules in the skin, which are full of parasites. We have reported the protective function of the NLRP3 inflammasome during L. amazonensis infection in mouse, thus we aimed to evaluate if the inflammasome is involved in the determination of the LCL or DCL disease. We observed that skin biopsies of patients with DCL lesions present upregulation of inflammasome genes such as ASC, CASP1 and IL18. However, IL-1b and IL-18 levels in the plasma of LCL and DCL patients were similar. We used in vitro and mouse models to evaluate if the inflammasome is involved in the determination of the LCL or DCL. Macrophages do not differ in their ability to produce inflammasome-dependent IL-1b after infection with LCL and DCL. The inflammasome is involved in the control of LCL proliferation, but DCL isolates bypass the restrictive function of this platform both in vitro and in vivo. Further analysis showed that DCL isolates are resistant to inflammasome-mediated nitric oxide production. These data suggest that the resistance to the inflammasome effector functions may underlie the development of controlled (LCL) or disseminated (DCL) Leishmaniasis. We conclude that parasite-intrinsic factors related to resistance to the inflammasome might determine the outcome L. amazonensis infection.