tetano
Editor, Senior Moderator
Front Immunol
. 2026 Oct 22:17:1951246.
doi: 10.3389/fimmu.2026.1951246. eCollection 2026.
Amber Wolabaugh 1 2 , Vrushali V Agashe 1 , Zicheng Wang 1 , Nichole M Danzl 1 , Christopher A Parks 1 , Mohsen Khosravi-Maharlooei 1 , Xiaolan Ding 1 , Hao Wei Li 1 , Candace Castagna 3 , Giorgia Zanetti 1 , Katherine D Long 1 , Yasmeen S Saad 1 2 , Anjali Saqi 4 , Moriya Tsuji 5 , Megan Sykes 1 2 6
Affiliations Expand
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.
Keywords: COVID-19; SARS-CoV-2; T cell response; human immune system mice; humanized mice; interferon response; mouse model; post-acute sequelae of COVID-19.
. 2026 Oct 22:17:1951246.
doi: 10.3389/fimmu.2026.1951246. eCollection 2026.
A novel model demonstrating that human immune cells promote multiorgan SARS-CoV-2 dissemination and human T cells limit anti-viral innate immunity
Amber Wolabaugh 1 2 , Vrushali V Agashe 1 , Zicheng Wang 1 , Nichole M Danzl 1 , Christopher A Parks 1 , Mohsen Khosravi-Maharlooei 1 , Xiaolan Ding 1 , Hao Wei Li 1 , Candace Castagna 3 , Giorgia Zanetti 1 , Katherine D Long 1 , Yasmeen S Saad 1 2 , Anjali Saqi 4 , Moriya Tsuji 5 , Megan Sykes 1 2 6
Affiliations Expand
- PMID: 42991755
- PMCID: PMC13736727
- DOI: 10.3389/fimmu.2026.1951246
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.
Keywords: COVID-19; SARS-CoV-2; T cell response; human immune system mice; humanized mice; interferon response; mouse model; post-acute sequelae of COVID-19.