Characterizing the Role of Host's Immune Mechanisms in Coronavirus Pathogenesis

Coronaviruses are positive sense, single-stranded RNA viruses known to cause mild to severerespiratory diseases. The current COVID-19 pandemic has highlighted the need to identify the differentmolecular mechanisms and antiviral cellular host antagonists involved in the coronavirus pathogenesis.IFI16, a member of the PYHIN family, is an antiviral restriction factor known to restrict several DNAviruses like human papillomavirus, human cytomegalovirus, and herpes simplex virus type 1. Recently,its role in restricting RNA virus replication has also been established. IFI16 belongs to a PYHIN family,which is entirely lost in bats, the only mammals capable of sustained flight, and are also a naturalreservoir for several deadly viruses in the world, including coronaviruses. The evolutionary loss of thePYHIN family in bats highlights that an impaired innate immune system might be a potentialexplanation for their ability to host several pathogenic viruses without facing any casualties. IFI16 isabundantly present in other mammalian species. Thus, we proposed that IFI16 might have an antiviralrole in coronavirus pathogenesis. We used two bat-derived coronaviruses- low pathogenic (NL63) andhighly pathogenic (SARS-CoV-2) to analyze IFI16 involvement in modulating the host innate immuneresponse in IFI16 WT and IFI16 KO-HaCaT cells. We found an increase in the induction of innateimmune response in NL63-infected IFI16 KO-HaCaT cells. However, the infection rate in HaCaT cellswas insufficient to provide any conclusions. Thus, we switched to a different cell line, LLC-MK2,which is an efficient study model for studying both viruses. We noticed the induction of IFI16 uponboth NL63 and SARS-CoV-2. We also observed that NL63 dampens the innate immune response inLLC-MK2 cells. Moreover, we have identified the nuclear to cytoplasmic localization of IFI16 and itsco-localization with the NL63 nucleoprotein. However, the antiviral role of IFI16 in this context is yetto be established. We are currently working on characterizing these experiments in the newlyestablished IFI16KO-LLC-MK2. IFI16 is a crucial regulator for identifying and responding to invadingpathogens and maintaining a homeostatic balance of host cells. Deepening our understanding of IFI16'sinvolvement in triggering abnormal inflammatory reactions in hCoV-infected human epithelial cells canhelp develop novel therapeutic approaches for hCoV-related disease pathologies.