ABSTRACT COronaVIrus Disease 2019 (COVID-19) is caused by a human coronavirus, SARS-CoV-2. This virus caused a large outbreak in China that was associated with a high human-to-human transmission rate and mortality and subsequently led to a pandemic in the human population. SARS-CoV-2 is member of the â-coronaviruses and is highly related to SARS-CoV. In an ongoing evolutionary arms race, viruses have evolved factors that facilitate their replication while the host cell has evolved signaling networks to detect and eradicate invading viruses. The innate immune system is a conserved defense strategy critical for the initial detection and restriction of pathogens and later activation of the adaptive immune response. Activation of innate immunity relies on the recognition of pathogen-associated molecular patterns (PAMP) by pattern recognition receptors (PRRs) such as Toll-like receptors, RNA and DNA sensors. Upon activation by PAMPs, PRRs recruit adaptor proteins that initiate signaling pathways involving modifying enzymes such as kinases, phosphatases, E3 ubiquitin ligases that ultimately lead to the activation of crucial transcription factors including IRF3 and NF-êB. Synergistically, these factors promote the production of antiviral type I interferons (IFN-I), inflammatory cytokines, NK cell immunity, apoptosis, and autophagy. Thus, the pathogenicity and spread of a virus in the host is in part determined by the ability of the virus to evade host cell innate responses. The SARS-CoV-2 virion has three transmembrane proteins [envelope (E), membrane (M), and spike (S)] that are necessary for viral assembly and infectivity. They also have important immunomodulatory functions as they trigger or antagonize innate immune responses within infected cells. The E proteins from other coronaviruses have been shown to form an oligomeric structure with ion channel activity that can alter calcium homeostasis with implications on viral pathogenesis. The M protein of other coronaviruses was shown to have a range of immunomodulatory effects through TLR-dependent and independent mechanisms and the S protein can exert its effects by modulating surface signaling responses. It also causes the degradation of BST-2 (tetherin), which functions to prevent release of progeny virus. We hypothesize that the immunomodulatory properties of SARS-CoV-2 membrane proteins will determine the outcome of the infection and viral mediated pathogenesis. To test this, in Aim 1, we propose to examine E, M, and S proteins from SARS-CoV-2 and compare their impact in modulating innate immunity, proinflammatory responses, autophagy, and apoptosis with the same proteins from SARS-CoV, MERS-CoV, and HCoV-OC43. In Aim 2, we will determine the immunomodulatory effects of virus-like particles (VLPs) formed by the membrane proteins of the four viruses. We will also determine the immunoevasion capabilities of of SARS-CoV-2 and compare them with SARS-CoV, MERS and HCoV-OC43. Overall, the results of thes...