Inactivated Wild-Type Human Coronavirus (OC43)

Seasonal coronaviruses, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cause severe respiratory symptoms in only a small subset of infected individuals. However, host factors that determine differential responses to coronavirus infections remain unclear. Here, researchers used seasonal human coronavirus OC43 (HCoV-OC43) infection as an asymptomatic model that triggers both innate and adaptive immune responses in mice. Interestingly, innate sensing pathways and adaptive immune cells were not essential for protection against HCoV-OC43. Instead, deficiency in mouse alveolar macrophages (AMΦ) resulted in severe COVID-19-like pneumonia after HCoV-OC43 infection, with massive neutrophil infiltration, neutrophil extracellular trap (NET) release, and excessive production of proinflammatory cytokines. Mechanistically, AMΦ efficiently phagocytosed HCoV-OC43, effectively blocking viral transmission, while in the absence of AMΦ, HCoV-OC43 triggered Toll-like receptor (TLR)-dependent chemokine production, leading to pneumonia. These findings reveal a central role for AMΦ in protection against seasonal HCoV-OC43 and have clinical implications for coronavirus infection-associated human immunopathology.

There was no difference in the induction of Tnfa, Il1b, and Il6 in mice treated with activated and inactivated HCoV-OC43 (Figure 1A), indicating that the induction of inflammatory genes is independent of signaling triggered by viral RNA. Next, the researchers investigated the role of cell surface PRRs TLR2 and TLR4 by using TLR2 (C29) and TLR4 (resatorvid) inhibitors in in vitro culture. Treatment with C29, but not resatorvid, significantly reduced HCoV-OC43-induced Tnfa, Il1b, and Il6 in mouse BMDM and human PBMC (Figures 1A and 1B), indicating that the induction of inflammatory genes is dependent on TLR2 signaling. To confirm the role of TLR2, the researchers induced bone marrow mesenchymal stem cells (BMDM) using bone marrow from wild-type (WT), Tlr2-/-, and Tlr4-/- mice and co-cultured them with inactivated or activated HCoV-OC43. Tlr2 deficiency blocked virus-induced Tnfa, Il1b, and Il6 (Figure 1C), but Tlr4 deficiency did not. Tlr2 deficiency also consistently blocked p65 phosphorylation and IκBα degradation in BMDMs induced by both inactivated and activated HCoV-OC43. These results strongly suggest that non-nucleic acid components of HCoV-OC43 induce transcription of inflammatory genes by activating TLR2.

Figure 1. TLR2 signaling pathways are not required for protecting mice from severe symptoms in response to HCoV-OC43. (Zhong X, et al., 2025)