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GOALS AND IMPACT Overview The overarching goals of DEFUSE are: • Identify and model the spillover risk of novel SARS-related CoVs in South and SE Asia • Design and demonstrate proof-of-concept that interventions to upregulate the naturally low innate immunity of bats to viruses (immune boosting) and to high risk SARSr-CoVs in particular (immune priming) will transiently reduce spillover risk. [...] The structure of the SARS-CoV spike glycoprotein has been solved and the addition of two proline residues at positions V1060P and L1061P stabilize the prefusion state of the trimer, including key neutralizing epitopes in the receptor binding domain''. [...] For SARSr-CoVs which we are not able to culture, we will construct recombinant viruses with the S gene of new bat SARSr-CoVs and the backbone of the infectious clone of SARSr-CoV WIV1 or of SARS-CoV, using the reverse genetic system described previously, and detailed below28. [...] To test this the Shi and Baric lab will structurally model and identify highly variable residue changes in the SARSr- CoV S RBD and use commercial gene blocks to introduce these changes singly and then in combination into the S glycoprotein gene of the low risk, highly abundant parental strain. [...] Using the SHC014 backbone sequence, we will sequentially and then in tandem repair the deletions in the presence and absence of the S479N.