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

## TL;DR

Researchers developed a mouse model to study Mayaro virus infection, showing that immunodeficient mice and different sexes exhibit distinct disease symptoms.

## Contribution

The study introduces a novel murine model for Mayaro virus infection, revealing sex-specific clinical signs and potential sexual transmission.

## Key findings

- Immunodeficient mice showed more severe systemic disease symptoms compared to immunocompetent mice.
- Females exhibited more pronounced joint pain and muscle weakness, while males showed more systemic signs.
- The virus was detected in the brain and gonads, suggesting potential neuropathogenicity and sexual transmission.

## 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.

The Mayaro fever is an infectious disease transmitted by mosquitoes that causes disabling joint pain and swelling. Seventy years after the first cases were detected, the Mayaro virus (MAYV) is considered a global health issue due to the elevated risk for urban dissemination. Besides the efforts for controlling vector populations, vaccines, and antivirals must be developed to prevent and treat the Mayaro fever. This is only possible when studies are conducted to understand the disease, usually with the aid of laboratory animals. In this sense, research must be performed to identify appropriate animal models for human illness. In this work, we infected immunocompetent and immunodeficient laboratory mice with a clinical isolate of MAYV. We observed that the immunodeficient animals manifested more signs of the disease and would be appropriate for studying MAYV. Interestingly, systemic signs of infection were more evident in male mice, while females suffered more from joint pain and muscle weakness. We have also detected the virus in the brain and gonads, showing that MAYV can affect the nervous system and be sexually transmitted. Our study proposes a novel animal model that could be used to investigate MAYV biology, transmission, and possible preventive and therapeutical agents.