Antagonism and Evasion of Cellular Innate Immunity by SARS-CoV-2

The replication cycle of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) shares many features with other human Coronaviruses such as SARS-CoV and Middle East respiratory syndrome Coronavirus (MERS-CoV). Recent studies have elucidated the viral strategies of antagonizing the host immune response, including a multitude of mechanisms by which SARS-CoV-2 can dampen the interferon-mediated innate immunity. Furthermore, an imbalance and delay in interferon production, and exaggerated secretion of pro-inflammatory cytokines contribute to the severe immunopathology of Coronavirus disease 2019 (COVID-19). This chapter summarizes our current understanding of the intimate relationship between SARS-CoV-2 and the host innate and adaptive immune responses. The strategies that the virus utilizes to exploit cellular resources and to evade the innate immune system are described. The chapter provides a detailed discussion of interferonmediated innate immunity, interferon evasion and antagonism by SARSCoV- 2 and human Coronaviruses. © 2023 by World Scientific Publishing Co. Pte. Ltd.

Differential roles of interferons in innate responses to mucosal viral infections.

Interferons (IFNs) are among the first vertebrate immune pathways activated upon viral infection and are crucial for control of viral replication and dissemination, especially at mucosal surfaces as key locations for host exposure to pathogens. Inhibition of viral establishment and spread at and from these mucosal sites is paramount for preventing severe disease, while concomitantly limiting putative detrimental effects of inflammation. Here, we compare the roles of type I, II, and III IFNs in regulating three archetypal viruses - norovirus, herpes simplex virus, and severe acute respiratory virus coronavirus 2 (SARS-CoV-2) - which infect distinct mammalian mucosal tissues. Emerging paradigms include highly specific roles for IFNs in limiting local versus systemic infection, synergistic activities, and a spectrum of protective versus detrimental effects of IFNs during the infection response.

Transcriptional and Non-Transcriptional Activation, Posttranslational Modifications, and Antiviral Functions of Interferon Regulatory Factor 3 and Viral Antagonism by the SARS-Coronavirus.

The immune system defends against invading pathogens through the rapid activation of innate immune signaling pathways. Interferon regulatory factor 3 (IRF3) is a key transcription factor activated in response to virus infection and is largely responsible for establishing an antiviral state in the infected host. Studies in Irf3-/- mice have demonstrated the absence of IRF3 imparts a high degree of susceptibility to a wide range of viral infections. Virus infection causes the activation of IRF3 to transcribe type-I interferon (e.g., IFNß), which is responsible for inducing the interferon-stimulated genes (ISGs), which act at specific stages to limit virus replication. In addition to its transcriptional function, IRF3 is also activated to trigger apoptosis of virus-infected cells, as a mechanism to restrict virus spread within the host, in a pathway called RIG-I-like receptor-induced IRF3 mediated pathway of apoptosis (RIPA). These dual functions of IRF3 work in concert to mediate protective immunity against virus infection. These two pathways are activated differentially by the posttranslational modifications (PTMs) of IRF3. Moreover, PTMs regulate not only IRF3 activation and function, but also protein stability. Consequently, many viruses utilize viral proteins or hijack cellular enzymes to inhibit IRF3 functions. This review will describe the PTMs that regulate IRF3's RIPA and transcriptional activities and use coronavirus as a model virus capable of antagonizing IRF3-mediated innate immune responses. A thorough understanding of the cellular control of IRF3 and the mechanisms that viruses use to subvert this system is critical for developing novel therapies for virus-induced pathologies.