Chikungunya Virus Exposure Partially Cross-Protects against Mayaro Virus Infection in Mice

Chikungunya virus (CHIKV) and Mayaro virus (MAYV) are closely related members of the Semliki Forest virus antigenic complex classified as belonging to the genus Alphavirus of the family Togaviridae. These viruses cause human disease, with sudden fever and joint inflammation that can persist for long periods. CHIKV is the causative agent of large outbreaks worldwide, and MAYV infection represents a growing public health concern in Latin America, causing sporadic cases and geographically limited outbreaks. Considering the relationship between CHIKV and MAYV, the present study aimed to evaluate if preexisting CHIKV immunity protects against MAYV infection. Immunocompetent C57BL/6 mice were intraperitoneally infected with CHIKV and, 4 weeks later, they were infected with MAYV in their hind paw. We observed that the preexistence of CHIKV immunity conferred partial cross-protection against secondary MAYV infection, reducing disease severity, tissue viral load, and histopathological scores. Interestingly, CHIKV antibodies from humans and mice showed low cross-neutralization to MAYV, but neutralizing activity significantly increased after secondary infection. Furthermore, depletion of adaptive immune cells (CD4⁺ T, CD8⁺ T, and CD19⁺ B cells) did not alter the cross-protection phenotype, suggesting that distinct cell subsets or a combination of adaptive immune cells stimulated by CHIKV are responsible for the partial cross-protection against MAYV. The reduction of proinflammatory cytokines, such as interferon gamma (IFN-γ), in animals secondarily infected by MAYV, suggests a role for innate immunity in cross-protection. Our findings shed light on how preexisting immunity to arthritogenic alphaviruses may affect secondary infection, which may further develop relevant influence in disease outcome and viral transmission. IMPORTANCE Mosquito-borne viruses have a worldwide impact, especially in tropical climates. Chikungunya virus has been present mostly in developing countries, causing millions of infections, while Mayaro virus, a close relative, has been limited to the Caribbean and tropical regions of Latin America. The potential emergence and spread of Mayaro virus to other high-risk areas have increased the scientific community's attention to an imminent worldwide epidemic. Here, we designed an experimental protocol of chikungunya and Mayaro virus mouse infection, which develops a measurable and quantifiable disease that allows us to make inferences about potential immunological effects during secondary virus infection. Our results demonstrate that previous chikungunya virus infection is able to reduce the severity of clinical outcomes during secondary Mayaro infection. We provide scientific understanding of immunological features during secondary infection with the closely related virus, thus assisting in better comprehending viral transmission and the pathological outcome of these diseases.