A novel model demonstrating that human immune cells promote multiorgan SARS-CoV-2 dissemination and human T cells limit anti-viral innate immunity
6 affiliations
- 1Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University
- 2Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University
- 3Institute of Comparative Medicine, Columbia University Medical Center, Columbia University
- 4Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University
- 5Aaron Diamond AIDS Research Center, Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, Columbia University
- 6Department of Surgery, Columbia University Medical Center, Columbia University
Abstract
Introduction: 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).
Methods: Because existing mouse models cannot recapitulate human immune responses, we developed a human immune system (HIS) mouse model with physiologic expression of hACE2.
Results and discussion: 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 the presence of viral RNA 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 persistence of viral RNA, 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-related immunological features.
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BibTeX
@article{wolabaugh2026novel,
title = {{A novel model demonstrating that human immune cells promote multiorgan SARS-CoV-2 dissemination and human T cells limit anti-viral innate immunity}},
author = {Amber Wolabaugh and Vrushali V. Agashe and Zicheng Wang and Nichole M. Danzl and Christopher A. Parks and Mohsen Khosravi-Maharlooei and Xiaolan Ding and Hao Wei Li and Candace Castagna and Giorgia Zanetti and Katherine D. Long and Yasmeen S. Saad and Anjali Saqi and Moriya Tsuji and Megan Sykes},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1951246},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1951246/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A novel model demonstrating that human immune cells promote multiorgan SARS-CoV-2 dissemination and human T cells limit anti-viral innate immunity
AU - Amber Wolabaugh
AU - Vrushali V. Agashe
AU - Zicheng Wang
AU - Nichole M. Danzl
AU - Christopher A. Parks
AU - Mohsen Khosravi-Maharlooei
AU - Xiaolan Ding
AU - Hao Wei Li
AU - Candace Castagna
AU - Giorgia Zanetti
AU - Katherine D. Long
AU - Yasmeen S. Saad
AU - Anjali Saqi
AU - Moriya Tsuji
AU - Megan Sykes
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1951246
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1951246/full
AB - Introduction: 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). Methods: Because existing mouse models cannot recapitulate human immune responses, we developed a human immune system (HIS) mouse model with physiologic expression of hACE2. Results and discussion: 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 the presence of viral RNA 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 persistence of viral RNA, 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-related immunological features.
SN - 1664-3224
ER -