Biology subjects

Watanabe, J. K.

Publications and source records attributed to Watanabe, J. K..

3 recordsLinked to original sources

bioRxiv2025

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

BackgroundMayaro 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 FindingsTwelve RM were inoculated with a genotype D lineage MAYV strain using one of 3 doses: 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, incubated for 10 days, then dissected and tested to detect MAYV in tissues and saliva. RM developed infectious MAYV viremias lasting 3 days, peaking 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/SignificanceRM 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. 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. AUTHOR SUMMARYMayaro 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--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.

microbiology↗

bioRxiv2023

A Virus-like particle-based bivalent PCSK9 vaccine lowers LDL-cholesterol levels in Non-Human Primates

Elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor in the development of atherosclerotic cardiovascular disease (ASCVD). Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of LDL-C metabolism, have emerged as promising approaches for reducing elevated LDL-C levels. Here, we evaluated the cholesterol lowering efficacy of virus-like particle (VLP) based vaccines that target epitopes found within the LDL receptor (LDL-R) binding domain of PCSK9. In both mice and non-human primates, a bivalent VLP vaccine targeting two distinct epitopes on PCSK9 elicited strong and durable antibody responses and lowered cholesterol levels. In macaques, a VLP vaccine targeting a single PCSK9 epitope was only effective at lowering LDL-C levels in combination with statins, whereas immunization with the bivalent vaccine lowered LDL-C without requiring statin co-administration. These data highlight the efficacy of an alternative, vaccine-based approach for lowering LDL-C.

immunology↗

bioRxiv2021

Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity reduces lung inflammation

Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable levels of antiviral antibodies after infusion. In comparison to the control animals, they had similar levels of virus replication in the upper and lower respiratory tract, but had significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses. Author summaryThe results of treating SARS-CoV-2 infected hospitalized patients with COVID-19 convalescent plasma (CCP), collected from survivors of natural infection, have been disappointing. The available data from various studies indicate at best moderate clinical benefits only when CCP with high titer of neutralizing antibodies was infused early in infection. The macaque model of SARS-CoV-2 infection can be useful to gain further insights in the value of CCP therapy. In this study, animals were infected with SARS-CoV-2 and the next day, were infused with pooled human convalescent plasma, selected to have a very high titer of neutralizing antibodies. While administration of CCP did not result in a detectable reduction in virus replication in the respiratory tract, it significantly reduced lung inflammation. These data, combined with the results of monoclonal antibody studies, emphasize the need to use products with high titers of neutralizing antibodies, and guide the future development of CCP-based therapies.

immunology↗