Investigating the role of SARS-CoV-2 and MERS-CoV transcription regulatory sequence (TRS) in viral gene expression and virulence

Betacoronavirus (beta-CoV) is one of four genera of coronaviruses (CoVs) that includes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV evolved in 2012 and continues to cause seasonal outbreaks in the Kingdom of Saudi Arabia (KSA), along with travel-related cases. MERS-CoV is listed by the World Health Organization (WHO) as a pandemic threat. SARS-CoV-2 emerged in December 2019 and has caused a global pandemic. MERS-CoV has a higher case fatality rate of approximately 35%, compared to a predicted 2.3% for SARS-CoV-2. Despite epidemiological data suggesting a higher death rate for MERS-CoV infections compared to SARS-CoV-2, little is known about why MERS-CoV is more lethal. CoV gene expression is mediated via viral promoters called transcription regulatory sequence (TRS). All CoV TRSs include a conserved 6-8 nucleotides core sequence (CS) plus variable 5-prime and 3-prime flanking sequences that drive viral gene expression, including expression of viral genes that inhibit antiviral innate and intrinsic host responses. We hypothesize that MERS-CoV and SARS-CoV-2 TRS differentially regulate viral gene expression, which in turn leads to differential inhibition of the type I IFN response by viral proteins. During this five-year study, we will identify differences in molecular markers of disease on infection with MERS-CoV and SARS-CoV-2. We will specifically focus on MERS-CoV and SARS-CoV-2 TRS and identify regions within these sequences that are directly responsible for differential inhibition of protective interferon (IFN) responses. Our study will establish a framework to study accessory proteins, immune response modulation, and viral TRS in CoVs that remain poorly characterized, such as SARS-CoV, porcine epidemic diarrhea virus (PEDV), swine acute diarrhea syndrome coronavirus (SADS-CoV), and pre-emergent bat borne CoVs (BANAL-236, PDF-2180, and others).