Fig. 3.

Life cycle of human coronavirus (HCoV) and innate immune signaling pathways in response to HCoV infection. (Left and middle) HCoV invades and infects a lung cell after cell attachment and viral entry. Then viral replication occurs, followed by viral assembly, budding and release from the infected cell. (Right) Viral RNA fragments or replication intermediates as viral pathogen-associated molecular patterns (PAMPs) are sensed by pattern recognition receptors (PRRs), thereby triggering innate immune signaling pathways. PAMP-PRR interactions activate adaptor proteins and downstream kinases. The activated innate immune signaling pathways culminate in activation of two types of critical transcription factors - interferon regulatory factors (IRFs) and NF-κB. IRF3-mediated interferon (IFN) and IFN stimulated gene (ISG) products play important roles in antiviral defense. For example, Tripartite Motif Containing 56 (TRIM56), an antiviral ISG, inhibits HCoV-OC43 propagation by targeting a later step of the viral life cycle after RNA replication [31]. Type I IFN secreted by the infected cells is responsible for establishing an “antiviral” state in neighboring cells. Whereas, NF-κB-mediated cytokines/chemokines (e.g., IL-6 and TNF-α) are indispensable for later inflammatory responses, cytokine storm and immunopathogenesis in different cell types and tissues.