Deciphering the Role of Chemokine Receptor CCR5 in Maternal Flavivirus Infections

PROJECT SUMMARY: CCR5 is a chemokine receptor involved in leukocyte trafficking. We identified a neuroprotective role for CCR5 in the context of West Nile virus (WNV) infection both in mice and humans. In mice, we found that mice lacking Ccr5 are significantly more susceptible to WNV-induced encephalitis compared to wild type (WT) mice. We translated these results using human cohorts, where we found that individuals that naturally lack CCR5 (CCR5∆32 homozygotes) develop more severe symptoms following infection with WNV. Furthermore, we and others have shown that this protective effect was not limited to WNV infection, but that the loss of CCR5 increased susceptibility to numerous other neurotropic flaviviruses, including tick-borne encephalitis virus (TBEV), and Japanese encephalitis virus (JEV). ZIKV is of particular concern because of its impact on pregnancy, with microcephaly and other congenital malformations, as well as fetal loss, stillbirth, and preterm birth among the possible outcomes. In preliminary data, we found that the loss of CCR5 increases susceptibility to ZIKV (a known teratogen) during maternal infections, resulting in poor pregnancy outcomes. This was also true for WNV, a virus not known to impact pregnancy. In this application, we will test the hypothesize that CCR5 is protective against flavivirus-induced congenital disease. This application will unravel the mechanisms involved in CCR5-mediated protection during maternal flavivirus infections.