Before the canonical antiviral response: How the host is fighting Zika virus

Zika virus (ZIKV) infection triggers cellular stress well before the full establishment of interferon-stimulated gene expression. Intrinsic cellular mechanisms, including adaptive processes such as antioxidant defenses, the unfolded protein response (UPR), autophagy and programmed cell death (PCD) pathways, act early to sense viral replication and constrain viral spread. Although these responses are often regarded as general stress pathways, they possess intrinsic antiviral functions and, in some cases, are subverted by the replicating ZIKV. Understanding these pre-interferon defenses uncovers new therapeutic targets that may enhance early virus control and limit tissue damage. This review summarizes current mechanistic insights into innate pro-survival and pro-death cellular defense responses, including oxidative stress regulation, UPR activation, autophagy and cell death pathways in ZIKV-infected cells.