A sex-biased response of the adult brain to Zika virus infection: from down-regulation of neuronal IRF3 to enhanced pathology in adult female mice.

BACKGROUND

Zika virus (ZIKV) is an emerging, neurotropic flavivirus susceptible to induce brain damage and neurological disorders in adults. In human and mice adult brain tissue, ZIKV predominantly infects neurons. The host type I interferon (IFN-I) response that efficiently restricts ZIKV replication in peripheral cells is impaired in neurons through mechanisms that remain unknown. Since epidemiological studies reveal a greater susceptibility of adult females to ZIKV, investigating the influence of biological sex on the brain’s response to infection may provide new insights into this impairment.

METHODS

The impact of ZIKV infection on the expression of transcription factor IRF3, a master regulator of the IFN-I response, was investigated at the molecular and cellular level in vitro, in primary cultured neurons as compared to murine embryonic fibroblasts (MEFs) and in vivo, in the brain of male and female adult immunocompetent mice following intracranial ZIKV infection. ZIKV replication, the establishment of inflammation and the development of signs of disease were analyzed in conjunction with the level of IRF3 and the expression of the Irf1 gene.

RESULTS

We show here that ZIKV specifically down-regulates IRF3 in neurons. In vitro, in primary cultured neurons but not in MEFs and in vivo, in female hippocampal neurons that displayed higher levels of ZIKV RNA. The absence of IRF3 was compensated at late times post-infection by an increased expression of the gene coding for IRF1 capable of replacing IRF3 in its capacity to induce an IFN-I response. The down-regulation of IRF3 added to high Irf1 brain gene expression was linked to an increased recruitment of T-lymphocytes, an up-regulated pro-inflammatory response and the development of signs of disease in female but not male mice.

CONCLUSIONS

Many routes drive viruses to the brain and there is an increased gain of interest in the impact of viral infections on short and long term neurological sequelae. Results obtained here on the capacity of ZIKV to down-regulate IRF3 in neurons establishing a sex-biased pro-inflammatory response in female brains associated to the development of pathological effects constitute a major advance in understanding how the adult brain respond to viral infections.