Innate immune activation and restriction of SARS CoV-2

discovery - Coronaviruses (CoVs) show striking differences in their pathogenicity, ranging from harmless colds to severe respiratory infections after viral zoonoses with fatality rates of up to 40% in the case of MERS-CoV. With death rates of ~9% and ~0.3-3.4%, respectively, SARS-CoV and the emerging SARS-CoV-2 fall between these extremes. The reasons for this different pathogenicity are poorly understood. However, host immunity and viral adaptation to humans most likely play key roles. Studies on highly pathogenic SARS-CoV and MERS-CoV revealed that they evolved various mechanisms to suppress innate immune sensing and interferon production as well as to antagonize antiviral factors. Counteraction of our immune defense impedes viral control and may be a prerequisite for high virulence. I hypothesize that counteraction of innate immunity together with untimely activation of inflammation have a major impact on CoV pathogenesis. To address this, I propose to perform comparative analyses of human CoVs, MERS-CoV, SARS-CoV, SARS-CoV-2 and their closest animal counterparts for their ability to suppress or counteract innate immunity. Initially, we will determine the expression of viral immune sensors and antiviral factors in primary lung cells. To define determinants of virus transmission and pathogenesis, we will analyze the capability of proteins from various CoVs to manipulate immune sensors, signaling molecules, and antiviral effectors. In addition, we will examine whether it is possible to modulate the innate immune response to achieve efficient control or tolerance of SARS-CoV-2.