W168 - Human Immune Cells Promote SARS-CoV-2 Dissemination and T Cells Promote Lung Pathology

Nichole Danzl – Columbia University; Vrushali Agashe – Columbia University; Mohsen Khosravi Maharlooei – Columbia University; Yasmeen Saad – Columbia University; Katherine Long – Columbia University; Christopher Parks – Columbia University; Moriya Tsuji – Columbia University; Anjali Saqi – Columbia University; Megan Sykes – Columbia University

Abstract Text: We have developed a novel human immune system (HIS) mouse model in NOD/LtSz-scid IL2R gamma null (NSG) mice engineered to express hACE2 under physiologic control. Using CRISPR, the hACE2 gene was knocked into the endogenous murine ACE2 locus in NSG zygotes. hACE2-specific qPCR revealed hACE2 expression in 14 different tissues of these mice, mirroring hACE2 expression in humans. Upon short-term (1- 2 weeks) intranasal infection with SARS-CoV-2, the virus disseminated to at least eight different tissues, including the brain, heart, and intestine. This spread of infection was not dependent on the presence of T cells but was markedly enhanced by the presence of human immune cells. Histology of the native mouse lung after infection revealed thickened interstitium and inflammation around the airways, reminiscent of human COVID-19 patient histology, and the presence of SARS-CoV-2 N protein. Nanostring analysis also revealed an active immune response to virus in multiple tissues, including brain and intestine. Human innate immune activation was greater in mice lacking T cells compared to mice with T cell reconstitution. This mouse model is also amenable to the study of post-acute sequelae of SARS-CoV-2 infection (PASC), as long-term (8-week) infection resulted in marked lung pathology with more inflammation present in mice with T cells, the persistence of viral proteins, and intrapulmonary T cell responses to a broad range of SARS-CoV-2 peptides. This model will permit long-term SARS-CoV-2 studies and further investigation of the role of T cells and other human immune components in the pathogenesis of acute COVID-19 and PASC.