A comprehensive murine clinical model for development of countermeasures and studying mayaro virus infection

Abstract

The Mayaro virus (MAYV) is an arthropod-borne virus that causes Mayaro fever, a neglected tropical disease that produces disabling arthralgia. Given the significant threat the dissemination of MAYV poses to global public health, the development of animal models for the Mayaro fever could help elucidate its pathogenic mecha­nisms and routes of transmission and support the production of prophylactic and therapeutical agents. Thus, this work aimed to characterize a susceptible murine model for MAYV infection. Type I IFN receptor knockout (A129 KO) and wild-type 129S1 mice (A129 WT), 21 days old and from both sexes, were inoculated with the MT/SINOP/210/2011 Brazilian MAYV strain in the footpad, with phosphate-buffered saline-inoculated animals as controls. Clinical signs of infection, survival, body tem­perature, weight loss, paw swelling, hematological changes, viral load in solid organs and serum, as well as histopathological changes in the tibiotarsal joints were eval­uated. MAYV animal models have not been extensively studied using the hyperno­ciception and loss of muscle strength analysis system, therefore we also performed the Von Frey and Kondziella tests. MAYV infection triggered a systemic disease in KO male mice, while local pain and loss of muscle strength were more evident in females. Survival was lower in the KO group than in the WT animals. Both the Von Frey and Kondziella tests showed superior sensitivity in detecting local clinical signs of infection compared to footpad thickness measurements. A marked lymphocytic inflammatory response was observed in the tibiotarsal joints of KO animals, who had increased footpad thickness compared to the WT group. Higher viral titers were detected in the joints and associated muscles of KO mice compared to the WT group at 3 d.p.i., as well as in the brain and gonads of WT and KO animals at 6 d.p.i. In conclusion, we demonstrated that A129 KO mice are efficient in replicating the main clinical signs of the disease caused by Mayaro virus. The Brazilian strain might be neuropathogenic and sexually transmitted, showing that the Mayaro fever might be a serious health care concern.