Fumonisin B1 aggravates inflammatory injury via mTORC1/pyroptosis, while promotes viral replication via mTORC1/apoptosis in Canine influenza virus-infected mice and A549 cells

Abstract

Canine influenza virus (CIV) has spread across the world and been a risk to canine and human. Fumonisin B1 (FB1) is a mycotoxin in feed and food, its pollution is low-level but very common. The co-occurrence of FB1 exposure and CIV infection is unavoidable. Here, we investigated the effects of low-dose FB1 exposure on CIV-induced inflammatory injury, viral replication and the underlying mechanisms in vivo and in vitro. In CIV-infected mice, low-dose FB1 (0.25, 0.5 and 0.75 mg/kg p.i.) treatment promoted systemic and lung inflammatory injury, as demonstrated by increased expressions of pro-inflammatory cytokines in serum and lung, increased occurrence of hemophagocytosis in spleen, promoted macrophage aggregation in lung, aggravated barrier damage and pathological injury of lung. In CIV-infected pulmonary epithelial model A549 cells, low-dose FB1 treatment significantly promoted the increase in pro-inflammatory cytokines expressions and the decrease in tight junction proteins expressions. Meanwhile, FB1 treatment promoted viral replication in mice and A549. Importantly, FB1 promoted CIV-inhibited mTOR/P70S6K signaling pathway and CIV-induced NLRP3-dependent pyroptosis, and inhibited CIV-induced apoptosis. Furthermore, mTORC1 inhibitor rapamycin blocked FB1-promoted pyroptosis, promoted FB1-inhibited apoptosis, and reversed FB1-promoted inflammatory injury and viral replication. NLRP3 inhibitor MCC950 attenuated FB1-aggravated inflammatory injury rather than viral replication, and apoptosis activator LY294002 reversed FB1-promoted viral replication rather than inflammatory injury. Summarily, low-dose FB1 exposure aggravated CIV-induced inflammatory injury and viral replication in vivo and in vitro via mTORC1-triggered apoptosis-pyroptosis shift. Our study provided new sights into the influence of mycotoxin on the virus-host interaction and the CIV control.