# Rhesus macaques model human Mayaro virus disease and transmit to Aedes aegypti mosquitoes

## TL;DR

Rhesus macaques infected with Mayaro virus show human-like symptoms and can transmit the virus to Aedes aegypti mosquitoes, but transmission is rare, which may explain why Mayaro outbreaks are uncommon.

## Contribution

This study demonstrates that rhesus macaques can model human Mayaro virus disease and transmit it to Aedes aegypti mosquitoes, revealing limited transmission potential.

## Key findings

- Rhesus macaques developed viremias that lasted 3 days and peaked 1–2 days post-inoculation.
- Aedes aegypti mosquitoes fed on viremic macaques became infected, but only 2% had infectious virus in their saliva.
- Macaques showed mild joint and muscle inflammation and transmitted MAYV to mosquitoes, but transmission rates were low.

## Abstract

Mayaro virus (MAYV) is a mosquito-borne alphavirus endemic to Latin America that causes fever and arthritis. Unlike the related chikungunya virus, MAYV has not caused widespread, human-amplified epidemics. One possible explanation is that human viremia levels are too low to support transmission to urban Aedes (Stegomyia) aegypti mosquitoes. We used rhesus macaques (RM) to model human-to-Ae. aegypti transmission and to further expand understanding of their relevance to human MAYV disease.

Twelve RM were inoculated with a genotype D lineage MAYV from an infectious clone using one of 3 dose and route combinations: 7 log10 plaque forming units (PFU) intravenously (IV), 7 log10 PFU subcutaneously (SC), or 3 log10 PFU SC. Viremia was measured daily in plasma and RM were euthanized 10- or 12-days post-inoculation (dpi). On 2, 3, 5, and 7 dpi, Ae. aegypti were allowed to bloodfeed on RM, incubated for 10 days, then dissected and tested to detect infectious MAYV in tissues and saliva. RM developed infectious MAYV viremias that lasted 3 days and peaked 1–2 dpi with titers ranging from 2-6 log10 PFU/ml. RM inoculated with 7 log10 PFU IV developed significantly higher viremias (area under the curve) than those receiving 3 log10 PFU SC. MAYV RNA was detected in muscle, lymphoid, central nervous, and cardiac tissues. RM showed no signs of fever or joint swelling but some developed mild rashes in areas distant from mosquito feeding sites and histologic inflammation was observed in joints and muscles. Only Ae. aegypti that fed on viremic RM 2 dpi became infected, with an overall infection rate of 48%. Among all mosquitoes that fed on RM 2 dpi, only 2% (4/217) had infectious MAYV in their saliva, suggesting transmission competence. Despite 11 of 12 RM transmitting MAYV to at least one mosquito, individual RM varied in infectiousness to Ae. aegypti, and mosquito cohort infection rates did not correlate with RM viremia levels.

RM exhibit short-lived MAYV viremias, broad tissue tropism, and mild joint and muscle inflammation, closely resembling human infection. While viremic RM can infect Ae. aegypti, the transmission window is narrow and transmission by Ae. aegypti is rare in this model. The combination of a short infectious period in RM and low transmissibility of Ae. aegypti infected from RM may help explain the absence of widespread urban MAYV outbreaks.

Mayaro virus (MAYV) is a mosquito-borne virus found in Latin America that causes fever and joint pain, similar to chikungunya virus (CHIKV). However, unlike CHIKV, MAYV has not led to large outbreaks. One reason may be that levels of MAYV in human blood are too low for Aedes aegypti mosquitoes—known for spreading chikungunya, dengue, and Zika viruses—to pick up and transmit the virus in cities. To better understand this, we studied rhesus macaques, a monkey species that serves as a model for how MAYV behaves in people. We tracked virus levels in their blood and tissues and observed mild joint and muscle inflammation, similar to Mayaro fever in people. Although the macaques were able to infect some Ae. aegypti mosquitoes, the transmission window was short, and only a few mosquitoes that became infected had virus in their saliva, suggesting transmission competence. This limited ability of urban mosquitoes to spread MAYV may help explain why major outbreaks have not occurred.