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Principal Investigator: Sonja Best
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $243,355
Funding agency: National Institute of Allergy and Infectious Diseases
The emergence of SARS-CoV-2 rapidly became a global pandemic necessitating the need to understand the mechanisms of disease, and develop vaccines and therapeutics. These efforts are hampered by the fact that the most useful experimental model in these efforts, the mouse, is not susceptible to infection due to an incompatible sequence of the cellular receptor for virus entry, ACE2. Therefore we have initiated two major efforts to develop mouse models that can be utilized in the efforts to understand dysregulation of innate and adaptive immunity associated with severe viral pneumonia. The ultimate goal is to define these processes as they relate to SARS-CoV-2 to identify points of intervention of inflammatory responses that can be targeted therapeutically.
The first major initiative is to develop mouse models of severe SARS-CoV-2 infection. To achieve this, we have partnered with Jackson Laboratories to genetically engineer mice that express a humanized ACE2 gene to enable virus replication in tissues. We are currently testing 4 novel mouse models that reflect different strategies to humanize ACE2 at the endogenous locus, or as a transgene. We are also testing mouse backgrounds for susceptibility, including the 8 founder mice of the Collaborative Cross, and our preliminary data suggests that different mouse strains can reflect some aspects of human disease, including a male bias and complications from thrombosis. The ulimate goal will be to fully characterize the host responses as they relate to pathology in these models, and then utilize the models for testing biologics that block various events in inflammatory cascades.
The second major initiative is the employment of a lethal influenza infection as a model for severe viral pneumonia that can be used as a test bed for better understanding other viral pulmonary infections such COVID-19 caused by SARS-Cov2. Ongoing studies involve (i) tests of interventions in the lethal influenza model that might have clinical utility and (ii) cell and molecular studies aimed at better understanding the underlying mechanism(s) of tissue damage and why interventions that constrain viral replication or innate immunity often fail after an early point in infection but well before death of the host. Using a severe influenza infection model that bypasses early nasopharyngeal replication and leads to rapid deep lung infection, we found that only very early treatment with the anti-viral (oseltamivir phosphate - Tamiflu) could prevent death of the infected animals. No other drug or anti-inflammatory treatments tested altered the course of disease appreciably, arguing that either multiple damaging activities are involved and blunting only one is insufficient for a clinical effect, or that irreversible tissue damage occurs early and once this occurs, interfering with viral replication or host immunity does not play a major role in loss of pulmonary function. Current work utilizes the highly multiplex imaging methods developed in the Lymphocyte Biology Section, LISB, NIAID, NIH to quantitatively probe the state of key cells and structures in the lung during the critical window in which intervention affects death rates to identify possible sites of damage, while treatment strategies involving pairing of anti-virial and anti-immune drugs are being tested for synergy.
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