Host C3 complement restricts bovine coronavirus infection in vitro via virus-induced IL-1β signaling.

Abstract

Bovine coronavirus (BCoV) is a major enteric and respiratory pathogen of cattle; however, its interactions with the host complement system remain poorly characterized. We previously reported that BCoV modulates host complement C3 expression. Here, we demonstrate that C3 functions as a bona fide cell-intrinsic restriction factor against BCoV infection. Using bovine C3 overexpression, recombinant human C3 supplementation, siRNA-mediated knockdown, and pharmacological inhibition with Compstatin, gain- and loss-of-function experiments consistently demonstrated that enhanced C3 activity suppresses viral replication, whereas C3 depletion or inhibition promotes it. Mechanistically, we identify a novel IL-1β-p38 MAPK-C/EBP-β signaling axis: BCoV infection induces IL-1β expression, which in turn activates p38 MAPK and drives C/EBP-β phosphorylation, leading to transcriptional upregulation of C3. This virus-triggered, cytokine-dependent induction of C3 establishes an intracellular antiviral state that restricts BCoV replication, revealing a previously unappreciated, non-canonical role for complement C3 in intrinsic immunity.