Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here, we offer an indepth analysis of the transcriptional response to SARS-CoV-2 as it compares to other respiratory viruses. Cell and animal models of SARS-CoV-2 infections, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of
Type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. Taken together, we propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving feature of COVID-19.