2026 Theses Doctoral

A human immune system mouse model for the study of both acute and long-term SARS-CoV-2 infection with multiorgan dissemination of virus

Wolabaugh, Amber N.

Despite extensive studies on Coronavirus disease 2019 (COVID-19), many questions remain regarding the pathology and mechanism behind this disease, particularly in the development of post-acute sequelae of COVID-19 (PASC). Because existing mouse models cannot recapitulate human immune responses to infections, we developed a human immune system (HIS) mouse model with physiologic expression of hACE2 for the study of COVID-19 and PASC.

After intranasal infection, persistent SARS-CoV-2 infection was observed in multiple organs for 8 weeks, despite the generation of SARS-CoV-2-specific T cell responses. Human immune cells increased viral infection in the lung and non-pulmonary tissues in a T cell-independent fashion. COVID-19-related pathology was recapitulated in the lungs, with increasing fibrosis after 14 days of 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 suppressed innate immune responses 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 key features of PASC. This model will uniquely facilitate understanding of virus-human immune dynamics and therapeutic approaches to PASC.