Identification of the Initial Targets of Transmission

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Summary: The current pandemic of COVID-19 has rapidly spread around the world infecting millions and killing more than 200,000 people in just months. The first wave of the pandemic is currently peaking in the United States causing almost 60,000 deaths in the past 6 weeks. This highly contagious virus with the unique features of a high percentage of asymptomatic infected and delayed severe symptoms has wreaked havoc on the population of the US. Without any other options, the US population is flattening the curve by social distancing and self-isolation. To return to normality we need an effective vaccine or therapy to protect populations around the world. Although the SARS-CoV-2 (CoV2) virus is known as a respiratory virus, it clearly has an impact beyond lung infection with increasing evidence of infection influencing multiple organ systems. Unanticipated pathologies associated with CoV2 infection such as heart attacks, loss of taste and smell, kidney failure, stroke, and COVID toe suggest possible virus dissemination beyond the respiratory tract. Such dispersed anatomical infection is possible because the CoV2 receptor ACE2 is expressed in a variety of tissues, tightly regulated by innate and adaptive immunity, and plays a key role in vascular homeostasis. High levels of ACE2 expression in the respiratory tract, liver, kidney, pancreas and cardiovascular tissues correlates with co-morbidities associated with death after extended infection. But to better define COVID-19 pathogenesis, it is essential to determine if these multiple end organ diseases leading to death are an indirect consequence of CoV2 induced inflammation and hypoxia or a consequence of direct CoV2 infection of various tissues and organs. Through the parent project and other work, we have developed the concepts of signal guided necropsies and multiscale imaging to identify and study small foci of SIV replication in the early days after mucosal transmission or rebound after cessation of antiretroviral drug treatment. The best of these methods utilizes radiolabeled and fluorescently tagged antibody- based probes to identify and in vivo fluorescently label SIVmac239 infected cells. In this emergency competitive revision application, we will adapt these novel and innovative techniques to study CoV2 infection. Critically, these state-of-the-art methods to identify active sites of CoV2 at the whole live animal method in an unbiased manner. Knowing the active anatomical sites of virus replication and inflammation will synergize with modern pathology approaches to provide an increased understanding of the natural history and pathogenesis of CoV2 infection. Based on the conceptual and technical innovation described above, combined with the more than 50 years of combined virology research expertise of Drs. Veazey and Hope, we believe the application has great potential to impact and advance the new field of COVID-19 research. This critical basic understanding will inform the field and advance strategies to stop the pandemic. There is no doubt the completion of the studies described in this application will advance the field. And we are currently the only ones in the world that can deliver the described studies at the accelerated pace of research needed for this emergency.