Avian coronaviruses induce inflammatory responses by activating p38/MAPK signaling and NLRP3/caspase-1 inflammasomes through sphingosine-1-phosphate receptor 1

Infectious bronchitis virus (IBV), a member of the γ-coronavirus genus within the Coronaviridae family, is a major pathogenic threat to the global poultry industry. Most IBV infections induce severe renal pathological lesions in chickens, yet the renal metabolic perturbations triggered by IBV infection remain largely elusive. Herein, we applied a metabolomic approach to characterize the metabolic profiles of kidney tissues from IBV-infected specific-pathogen-free (SPF) chickens. IBV infection caused profound alterations in the renal metabolome, encompassing amino acids and their derivatives, energy metabolites, and lipid molecules. Most amino acids and their derivatives were significantly downregulated at 7 days post-infection (dpi), indicating that IBV usurps host amino acid pools to support its own replication in SPF chickens. In addition, the levels of L-glutamine, D-mannose 1-phosphate, and D-galacturonate were markedly elevated post-infection, implying their potential roles in mediating host energy utilization and facilitating viral replication during IBV infection. Subsequently, sphingosine-1-phosphate (S1P)-a key bioactive lipid molecule-was identified as a prominently upregulated metabolite in IBV-infected kidney tissues. Follow-up functional experiments revealed that IBV infection upregulates the S1P-S1PR1 signaling axis, and concomitantly activates the p38/JNK/MAPK pathway as well as the NLRP3/caspase-1 inflammasome. Notably, S1PR1 was found to modulate the p38/MAPK signaling pathway and NLRP3/caspase-1 inflammasome, thereby regulating the expression of the proinflammatory cytokines IL-1β and IL-18. Collectively, our study delineates the comprehensive renal metabolic landscape of chickens in response to IBV infection and identifies S1PR1 as a pivotal regulatory target of IBV-induced renal inflammation. These findings provide novel mechanistic insights for the development of preventive and therapeutic strategies targeting metabolic signaling pathways against IBV infection.