IL-22 signaling contributes to modulate the pathogenesis of Zika virus infection

Abstract

Abstract The recent outbreaks of Zika virus (ZIKV) in multiple countries are linked to increased risk of neurological disorders and congenital defects. However, host immunity and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays a role in ZIKV infection is entirely unknown. Here, we infected 3-week-old Ifnar1−/− mice with ZIKV (Cambodian isolate, 1.0×105 pfu/mouse), and found that ZIKV infection resulted in weight loss, paralysis, and mortality at 5 to 6 days post-infection (dpi). This was accompanied by tissue injuries, neutrophil influx, and CD8+ T cell expansion in multiple organs, especially in the brain. The infection significantly up-regulated gene expression of multiple inflammatory cytokines, including IL-6, IL-1β, and TNF-α. Importantly, ZIKV infection elicited a tenfold increase in IL-22 production from non-T cells compared with that of uninfected animals. To investigate the effects of IL-22 on ZIKV infection, we challenged 1-day-old WT and IL-22−/− mice with ZIKV (4.0×103 pfu/mouse). WT mice began to develop weight loss, staggered steps, bilateral hind limb paralysis, weakness at 10 dpi, and ultimately succumbed to the infection on 16–19 dpi. Surprisingly, IL-22 deficiency lessened the weight loss, moderated the systemic inflammatory response, and greatly reduced the incidence of neurological disorders and mortality. In fact, around 90% of the IL-22−/− mice recovered from the insult on the nervous system at 20 dpi. Thus, our data revealed an obvious systemic inflammation in multiple organs induced by ZIKV, and demonstrated a novel role of IL-22 in determining the disease outcome.