Mouse and nonhuman primate models now serve as useful platforms to study Zika virus (ZIKV) pathogenesis, candidate therapies, and vaccines, but they rely on needle inoculation of virus: the effects of mosquito-borne infection on disease outcome have not been explored in these models. Here we show that infection via mosquito bite delays ZIKV replication to peak viral loads in rhesus macaques. Importantly, in mosquito-infected animals ZIKV tissue distribution was limited to hemolymphatic tissues, female reproductive tract tissues, kidney, and liver, potentially emulating key features of human ZIKV infections, most of which are characterized by mild or asymptomatic disease. Furthermore, deep sequencing analysis reveals that ZIKV populations in mosquito-infected monkeys show greater sequence heterogeneity and lower overall diversity than in needle-inoculated animals. This newly developed system will be valuable for studying ZIKV disease because it more closely mimics human infection by mosquito bite than needle-based inoculations.
Bibliographical noteFunding Information:
The authors acknowledge Jens Kuhn and Jiro Wada for preparing silhouettes of macaques used in figures. We thank the Veterinary, Animal Care, Scientific Protocol Implementation, and the Pathology staff at the Wisconsin National Primate Research Center (WNPRC) for their contribution to this study. We also thank Emma Walker for assistance with the mouse experiments. Funding for this project came from DHHS/PHS/NIH R21AI131454 to M.T.A. and DHHS/PHS/NIH R01AI116382 to D.H.O. and from P51OD011106 awarded to the WNPRC, Madison, WI. This research was conducted in part at a facility that constructed with support from Research Facilities Improvement Program Grants RR15459-01 and RR020141-01. The publication’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or NIH.