Transmission of Zika Virus Through the Rectal Route Leads to Mucosal and Systemic Infection with Reduced Neuropathology in Mice

Abstract

Zika virus (ZIKV) is a mosquito‐borne flavivirus originally confined to Africa and Asia that has most recently spread to the Americas and the Caribbean. ZIKV circulates in sylvatic and urban transmission cycles and causes asymptomatic infection in most affected individuals, while the rest of the population experiences mild febrile syndrome. In some adults, ZIKV causes neurotropic Guillain–Barré syndrome. Vertical transmission of ZIKV in infected mothers causes fetal growth restriction, microcephaly, and congenital eye disease. There have been reports of infected individuals transmitting ZIKV sexually from male to female, male to male, and a suspected case of female to male. ZIKV has been detected in the semen of infected males months after symptom onset and thus, ZIKV persistence in the semen and testes can increase the risk of viral transmission for men having sex with men (MSM) and between heterosexual partners through rectal route. To further understand the risk of ZIKV acquisition through this route, we established a rectal route of infection model using immunocompromised (Ifnar1−/−) mice to investigate the sexual (rectal) and mosquito (subcutaneous) modes of transmission and their resulting systemic and mucosal responses to infection. Rectal inoculation of ZIKV results in viremia with non‐lethal infection, while establishing active rectal and testicular infection that persists for at least 21 days. We found that after one day of infection, ZIKV infects epithelial cells comprising the mucosal epithelium and dendritic cells within the lamina propria and submucosa. Significantly increased levels of the chemokine CCL2 and CD4+ T‐cell response were observed at 3 and 7 days post‐infection, respectively, relative to the subcutaneously infected group. Moreover, rectal route of infection results in reduced immune cell infiltration and inflammation in the brain with a robust CCL2 and CXCl10 response, while subcutaneous infection caused severe brain pathology and induces a more robust CD8+ T‐cell response. Lastly, at 21 days, the rectal group had specific anti‐ZIKV antiviral response suggesting the role of adaptive immune response in restricting lethal viral infection. Our studies provide comprehensive insight of ZIKV transmission through rectal route and the resulting reduced neuropathology and control of disease progression in mice due to early virological and immunological events following infection of the rectal mucosa.Support or Funding InformationThis research was funded by Cedars‐Sinai Medical Center's Institutional Research Award to V.A., the California Institute for Regenerative Medicine (CIRM) Quest – Discovery Stage Research Projects Grant (DISC2‐10188) to V.A. at UCLA, and the UCLA Interdisciplinary Postdoctoral Training Grant (T32) in Virology and Gene Therapy to L.E.M.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.