Immune signatures of SARS-CoV-2 infection resolution in human lung tissues
Devin Kenney, Aoife K. O’Connell, Anna E. Tseng, Jacquelyn Turcinovic, Maegan L. Sheehan, Adam D. Nitido, Paige Montanaro, Hans P. Gertje, Maria Ericsson, John H. Connor, Vladimir Vrbanac, Nicholas A. Crossland, Christelle Harly , Alejandro B. Balazs , Florian Douam
Abstract
While human autopsy samples have provided insights into pulmonary immune mechanisms associated with severe viral respiratory diseases, the mechanisms that contribute to a clinically favorable resolution of viral respiratory infections remain unclear due to the lack of proper experimental systems. Using mice co-engrafted with a genetically matched human immune system and fetal lung xenograft (fLX), we mapped the immunological events defining successful resolution of SARS-CoV-2 infection in human lung tissues.
Introduction
Coronavirus disease 2019 (COVID-19) is a respiratory disease that has swept the world since its emergence in the Wuhan province of China in late 2019. The etiologic agent of COVID-19, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a plus-sense, enveloped RNA virus that targets the epithelium of the respiratory tract. Infection results in varying severities of COVID-19, with most cases being mild to asymptomatic.
Materials and method
Detailed descriptions of the materials and methods used for this study are available in Supporting Information.
Results
BLT-L mice effectively clear SARS-CoV-2 infection following acute viral replication
Previous work from our laboratory [23] and others [21,24,25] have shown that immunodeficient mice can successfully be engrafted with human fetal lung xenograft (fLX) alone or in combination with a human immune system (HIS). In this study, we leveraged a previously reported mouse model co-engrafted with fetal liver and thymus as well as with human hematopoietic stem cells (HSC) and fLX (BLT-L mice) [21].
Discussion
As our appreciation of the immunological differences between mice and humans continues to grow, humanized mouse models increasingly stand out as robust platforms to understand how viral pathogens interact with human tissues and the human immune system. These models are especially valuable when investigating tissue and mucosal immunity since such investigations remain impractical in human patients.
Acknowledgments
We thank the Evans Center for Interdisciplinary Biomedical Research at Boston University Chobanian and Avedisian School of Medicine for their support of the Affinity Research Collaborative on ‘Respiratory Viruses: A Focus on COVID19’.
Citation: Kenney D, O’Connell AK, Tseng AE, Turcinovic J, Sheehan ML, Nitido AD, et al. (2025) Immune signatures of SARS-CoV-2 infection resolution in human lung tissues. PLoS Pathog 21(9): e1013469. https://doi.org/10.1371/journal.ppat.1013469
Editor: Thomas E. Morrison, University of Colorado Denver, UNITED STATES OF AMERICA
Received: December 23, 2024; Accepted: August 18, 2025; Published: September 8, 2025
Copyright: © 2025 Kenney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The Genome Expression Omnibus (GEO) accession number to access the raw data of our scRNA-seq analysis is GSE255200.
Funding: This work was supported in part by funds or awards from Boston University (www.bu.edu; NEIDL start-up funds and Peter Paul Career Development Professorship to F.D.), the National Institutes of Health (www.nih.gov; K22 AI144050 to F.D.; UL1 TR001430 to F.D. and N.A.C.; R01AI174875, R01AI174276, DP1DA060607 and DP2DA040254 to A.B.B.; S10 OD026983 and S10OD030269 to N.A.C.), the U.S. Center of Disease Control (www.cdc.gov; subcontract 200-2016-91773-T.O.2 to A.B.B.), the Evergrande Massachusetts Consortium on Pathogenesis Readiness (MassCPR) (https://masscpr.hms.harvard.edu; to NEIDL as a university center, and to A.B.B.), the INSERM, CNRS and Université de Nantes (www.inserm.fr; www.cnrs.fr; www.univ-nantes.fr to C.H.), the Fondation pour la Recherche Médicale (www.frm.org; DEQ20170839118 to C.H.), and the French National Research Agency (www.anr.fr; LabEX IGO, ANR-11-LABX-0016 to C.H.). D.K. and A.E.T. were supported by a NIH (www.nih.gov) T32 training grant in immunology (T32AI007309). Salaries were supported by Boston University (F.D.), the National Institute of Health (D.K., A.E.T., A.B.B., F.D.) and CNRS (C.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: A.B.B. is a founder of Cure Systems LLC. The other authors declare no competing interests in relation to this study.
