A novel model demonstrating that human immune cells promote multiorgan SARS-CoV-2 dissemination and human T cells limit anti-viral innate immunity

Despite extensive studies, many questions remain regarding the pathology and mechanisms behind Coronavirus disease 2019 (COVID-19), and particularly on post-acute sequelae of COVID-19 (PASC). Because existing mouse models cannot recapitulate human immune responses, we developed a human immune system (HIS) mouse model with physiologic expression of hACE2. After intranasal infection, persistent viral RNA was observed in multiple organs for 8 weeks, despite the generation of human SARS-CoV-2-specific T cell responses. Human immune cells increased viral infection in the lung and non-pulmonary tissues. COVID-19-related pathology was recapitulated in the lungs, with fibrosis peaking at 14 days post-infection. Immune activation was detected in the lungs, hearts, intestines and brains of acutely infected mice and persisted at 8 weeks in the heart and lungs. The presence of human T cells correlated with attenuated innate antiviral transcriptional signatures in the lung, where a persisting cytotoxic mature CD4+ T cell population with JAK-STAT activation was enriched in infected mice. Thus, human T cells mount an antigen-specific but ultimately dysfunctional response, while paradoxically suppressing the innate interferon response, permitting chronic interferon activation and long-term viral persistence, recapitulating several immunologic and histopathologic features associated with PASC. This model will uniquely facilitate understanding of virus-human immune dynamics and therapeutic approaches to PASC.