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cluster of confirmed COVID-19 cases arose in Wuhan, China, in late 2019, but we lack insight—and may never have it—on where the first SARS-CoV-2 infection occurred. Although all of the earliest confirmed cases of COVID-19 were documented in China’s Hubei Province, where Wuhan is located, according to Western and China’s press reports, it is plausible that a traveler came in contact with the virus elsewhere and then went to Wuhan. · We continue to monitor scientific publications and discuss these issues with experts. Even if the virus is found to have existed outside China before the Wuhan outbreak, credible evidence of human infection would also be necessary to determine if the first COVID-19 outbreak began there. [ 15 ] The NIC collaborated closely with the National Counterproliferation Center (NCPC), the National Intelligence Management Council (NIMC), IC agencies, and other USG entities and departments on this assessment. The IC kicked off the 90-day study by outlining the core intelligence questions that would be addressed over lines of effort—collection and analysis. These questions included: · Did the outbreak begin through contact with infected domestic or wild animals or was it the result of a laboratory-associated incident? · Was the virus genetically engineered? · Is SARS-CoV-2 a biological weapon? Collection: At the kick-off meeting for the 90-day study, the IC discussed core intelligence gaps to drive collection moving forward. Analysis: The NIC had two separate structured analytic exercises to discuss both the underlying reporting and to strengthen argumentation moving into the drafting phase. Analysts at individual agencies also pursued various structured analytic techniques to build their own assessments. · During a two-day-long in-person IC-wide Analysis of Competing Hypothesis (ACH) analytic exercise in June, analysts determined whether existing reporting was consistent or inconsistent with information in individual reports. This exercise allowed analysts to determine that most reporting was consistent with both hypotheses and the reporting that was inconsistent was deemed to be not credible. · Before the start of drafting, the NIC hosted an ICwide Team A/Team B analytic exercise to explore how the IC could strengthen either hypothesis through a debate style format. Agencies pulled from these conversations—along with the work conducted during and before the study—to solidify their consensus positions. Mechanisms of SARS-CoV-2 Transmission and Pathogenesis Andrew G. Harrison,1,2 Tao Lin,1,2 and Penghua Wang1,* The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marks the third highly pathogenic coronavirus to spill over into the human population. SARS-CoV-2 is highly transmissible with a broad tissue tropism that is likely perpetuating the pandemic. However, important questions remain regarding its transmissibility and pathogenesis. In this review, we summarize current SARSCoV-2 research, with an emphasis on transmission, tissue tropism, viral pathogenesis, and immune antagonism. We further present advances in animal models that are important for understanding the pathogenesis of SARS-CoV-2, vaccine development, and therapeutic testing. When necessary, comparisons are made from studies with SARS to provide further perspectives on coronavirus infectious disease 2019 (COVID-19), as well as draw inferences for future investigations. The Emergence of a Third, Novel Coronavirus Current State of the COVID-19 Pandemic CoVs have caused three large-scale outbreaks over the past two decades: severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome (MERS), and now COVID-19. The origin of the COVID-19 pandemic was traced back to a cluster of pneumonia cases connected to a wet seafood market in Wuhan City, Hubei Province, China [1]. Following the likely spillover of a zoonotic disease (see Glossary), further work confirmed the etiological agent to be a novel Betacoronavirus related to SARS-CoV [1,2]. The first patients developed symptoms on December 1, 2019 after which rapid human-to-human transmission and intercontinental spread later ensued, being declared a pandemic by the WHO in March 2020 [3]. Since then, ~35 million people have been infected with SARS-CoV-2, with >1 million deaths in 235 countries, areas, or territories.