634: Persistent changes in interferon stimulated genes associated with zika virus exposure in offspring through adolescence

Abstract

Objective: Recent evidence has demonstrated that babies born with congenital Zika syndrome (CZS) can test negative due to prenatal clearance of the virus. Conversely, among latter 2nd and 3rd trimester exposures, clinical evidence of CZS may not appear until after deliver. This is modeled in mice, where we have previously demonstrated only 4% of the offspring of ZIKV inoculated dams are positive for ZIKV despite widespread postnatal growth restriction. We therefore hypothesized that mice of these pregnancies would show lasting changes to regulatory genes of innate immunity such as interferon stimulated genes as evidence of the longer term effects of congenital ZIKV exposure and clearance. Study Design: Timed, pregnant Swiss-Webster mice immunosuppressed with anti-interferon alpha receptor were inoculated with ZIKV HN16 or control on embryonic day 8 (e8). Brain tissue of offspring was assessed at either postnatal day 1 (P1) or 6 weeks of age for the following interferon stimulated gene expression: Isg15, Ifitm3, Oas1b, SOCS1, or SOCS3. PCR was performed via gel electrophoresis as well as qPCR via SYBR Green using the delta delta CT methodology. Result(s): Mice in the mid-gestation ZIKV infected group had significantly higher rates of growth restriction compared to control (Figure 1A) (p=0.007). Within 12 ZIKV-exposed offspring brain tissue, there was decreased expression of Oas1b at birth (P1) by 22.4% (p=0.003) and SOCS1 appeared to be upregulated by 38% (p=0.055) compared to control (Figure 1B). However, at 6 weeks of age, Ifitm3 expression was 33.6% increased compared to control (p=0.029), Oas1b was trending upwards by 42% (p=0.094) and SOCS3 by 45% (p=0.057) but did not reach significance (Figure 1C). Conclusion(s): We have shown, for the first time, the persistence of dysregulation of interferon stimulated genes gene expression among congenital ZIKV-exposed, but not affected, offspring through adolescence in a murine model. IFN gene regulation changes preceded the development of clinically evident disease. Given that these same gene changes are known to be persistently altered in other congenital viral syndromes with neuropathology (i.e., HIV), these findings suggest that ISGs are active throughout development and into adolescence. We speculate that our findings may signal that ZIKV exposure during gestation, even in the absence of CZS, may have lasting neuropathic effects among offspring. [Figure presented]Copyright © 2018