The NLRP3 inflammasome is involved with the pathogenesis of Mayaro virus

Abstract

Mayaro virus (MAYV) is an arbovirus that circulates in Latin America and is emerging as a potential threat to public health. Infected individuals develop Mayaro fever, a severe inflammatory disease characterized by high fever, rash, arthralgia, myalgia and headache. The disease is often associated with a prolonged arthralgia mediated by a chronic inflammation that can last months. Although the immune response against other arboviruses, such as chikungunya virus (CHIKV), dengue virus (DENV) and Zika virus (ZIKV), has been extensively studied, little is known about the pathogenesis of MAYV infection. In this study, we established models of MAYV infection in macrophages and in mice and found that MAYV can replicate in bone marrow-derived macrophages and robustly induce expression of inflammasome proteins, such as NLRP3, ASC, AIM2, and Caspase-1 (CASP1). Infection performed in macrophages derived from Nlrp3 ^–/– , Aim2 ^–/– , Asc ^–/– and Casp1/11 ^–/– mice indicate that the NLRP3, but not AIM2 inflammasome is essential for production of inflammatory cytokines, such as IL-1β. We also determined that MAYV triggers NLRP3 inflammasome activation by inducing reactive oxygen species (ROS) and potassium efflux. In vivo infections performed in inflammasome-deficient mice indicate that NLRP3 is involved with footpad swelling, inflammation and pain, establishing a role of the NLRP3 inflammasome in the MAYV pathogenesis. Accordingly, we detected higher levels of caspase1-p20, IL-1β and IL-18 in the serum of MAYV-infected patients as compared to healthy individuals, supporting the participation of the NLRP3-inflammasome during MAYV infection in humans.

Author summary

Viruses transmitted by mosquitoes have recently received huge attention from the media because the epidemics caused by Zika and chikungunya virus rapidly spread to new areas and infected a large number of individuals. Mayaro is a virus transmitted by mosquitoes that circulates in the Caribbean and tropical regions of Latin America. It causes a highly inflammatory disease, called Mayaro fever, and acute disease is often followed by a prolonged arthralgia mediated by chronic inflammation that can last months or years. The spread of Mayaro to urban areas is a major concern by the authorities, given that the virus has potential to cause an epidemic if spread in high-risk areas. Thus, understanding the mechanisms related to the pathogenesis of this infectious agent would be of great value to treat and prevent the disease. Here, we established an adult mouse model of Mayaro infection and demonstrated that the virus activates the NLRP3 inflammasome, which is important to regulate this viral disease. Our study provides molecular targets for a future treatment of Mayaro fever and provides an experimental model to understand the pathology caused by this emerging viral pathogen.