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

BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.