Editors' ChoiceInfectious Disease

Congenital Zika virus infection: More than just microcephaly

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Science Translational Medicine  07 Jun 2017:
Vol. 9, Issue 393, eaan8195
DOI: 10.1126/scitranslmed.aan8195

Abstract

A nonhuman primate model demonstrates efficient vertical transmission of Zika virus.

The spread of Zika virus (ZIKV) to the Western Hemisphere led to the discovery that congenital ZIKV infection can cause severe fetal abnormalities, including microcephaly, intrauterine growth restriction, miscarriage, and blindness. However, many babies born to ZIKV-infected mothers appear normal, without any evidence of microcephaly or growth restriction. This could mean that transplacental infection occurs only sporadically. Alternatively, congenital infection may occur frequently but cause microcephaly only in a subset of cases.

Modeling ZIKV infection in pregnant mice has certain limitations since ZIKV does not replicate efficiently in mice, which are not a natural host for ZIKV. Indeed, generation of mouse models of congenital ZIKV infection has necessitated the use of immunodeficient mice inoculated subcutaneously, or immunocompetent mice inoculated with high doses of intravenously injected virus, an artificial route of infection. Therefore, nonhuman primate models of ZIKV pathogenesis have the advantage of modeling infection in a natural, immunocompetent host. In a recent study, Nguyen et al. described the results of subcutaneous inoculation of four Indian rhesus macaques with a ZIKV isolate from French Polynesia. Two of the animals were inoculated during the first trimester, and two were inoculated in the late second/early third trimester. Maternal-fetal transmission occurred in all four animals, causing infection of the placenta and a variety of fetal tissues. Although imaging studies demonstrated that the growth rate of the fetal head was diminished in the last month of pregnancy, there was no overt microcephaly.

The findings of Nguyen et al. have two major implications: (i) transplacental transmission of ZIKV likely occurs more frequently in humans than previously thought, and (ii) many congenitally infected fetuses may appear normal, with microcephaly representing one of several potential outcomes in primates. This leaves us to wonder what may be the effects of congenital ZIKV infection in normal-appearing neonates without microcephaly. Will these newborns have more subtle neurodevelopmental or cognitive defects? Given the large numbers of potentially infected neonates from the ZIKV outbreak, epidemiological studies in humans, as well as modeling in congenitally infected animals, will be important next steps to better define more subtle consequences of congenital ZIKV infection in the absence of microcephaly.

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