@article{a8219ca57ce9429787ae4e465d69e90c,
title = "Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection",
abstract = "The human immunological mechanisms defining the clinical outcome of SARS-CoV-2 infection remain elusive. This knowledge gap is mostly driven by the lack of appropriate experimental platforms recapitulating human immune responses in a controlled human lung environment. Here, we report a mouse model (i.e., HNFL mice) co-engrafted with human fetal lung xenografts (fLX) and a myeloid-enhanced human immune system to identify cellular and molecular correlates of lung protection during SARS-CoV-2 infection. Unlike mice solely engrafted with human fLX, HNFL mice are protected against infection, severe inflammation, and histopathological phenotypes. Lung tissue protection from infection and severe histopathology associates with macrophage infiltration and differentiation and the upregulation of a macrophage-enriched signature composed of 11 specific genes mainly associated with the type I interferon signaling pathway. Our work highlights the HNFL model as a transformative platform to investigate, in controlled experimental settings, human myeloid immune mechanisms governing lung tissue protection during SARS-CoV-2 infection.",
keywords = "COVID-19, CP: Immunology, CP: Microbiology, antiviral responses, human immune responses to SARS-CoV-2, humanized mice, macrophage responses to SARS-CoV-2, mouse models of SARS-CoV-2, pulmonary immune responses",
author = "Kenney, {Devin J.} and O'Connell, {Aoife K.} and Jacquelyn Turcinovic and Paige Montanaro and Hekman, {Ryan M.} and Tomokazu Tamura and Berneshawi, {Andrew R.} and Cafiero, {Thomas R.} and {Al Abdullatif}, Salam and Benjamin Blum and Goldstein, {Stanley I.} and Heller, {Brigitte L.} and Gertje, {Hans P.} and Esther Bullitt and Trachtenberg, {Alexander J.} and Elizabeth Chavez and Nono, {Evans Tuekam} and Catherine Morrison and Tseng, {Anna E.} and Amira Sheikh and Susanna Kurnick and Kyle Grosz and Markus Bosmann and Maria Ericsson and Huber, {Bertrand R.} and Mohsan Saeed and Balazs, {Alejandro B.} and Francis, {Kevin P.} and Alexander Klose and Neal Paragas and Campbell, {Joshua D.} and Connor, {John H.} and Andrew Emili and Crossland, {Nicholas A.} and Alexander Ploss and Florian Douam",
note = "Funding Information: This work was supported by a start-up fund and the Peter Paul Career Development Professorship from Boston University (to F.D.), grants from the National Institutes of Health ( R01 AI138797 , R01 AI107301 , R01 AI146917 , R01 AI153236 to A.P.; R21 ES032882 , K22 AI144050 to F.D.; R01 HL141513 , R01 HL139641 , R01 AI153613 , UL1 TR001430 to M.B.; R01 502088946 , R21 AI135517 to J.H.C.), awards from the National Center for Advancing Translational Sciences of the National Institutes of Health ( UL1TR001430 to F.D., N.A.C., and A.E.; UL1TR003017 to A.P.), a grant from the National Library of Medicine ( R01 LM013154-01 to J.D.C.), the Deutsche Forschungsgemeinschaft ( BO3482/3-3 , BO3482/4-1 to M.B.), a Research Scholar Award from the American Cancer Society ( RSG-15-048-01-MPC to A.P.), a Burroughs Wellcome Fund Award for Investigators in Pathogenesis ( 101539 to A.P.), Princeton COVID-19 research funds through the Office of the Dean for Research , and Boston University start-up funds and an Evergrande MassCPR award (to M.S.). T.T. is a recipient of postdoctoral fellowship awards from the Uehara Memorial Foundation and the JSPS Research Fellowships for young scientists. We thank the Evans Center for Interdisciplinary Biomedical Research at Boston University School of Medicine for their support of the Affinity Research Collaborative on “Respiratory Viruses: A Focus on COVID-19.” This work utilized a Ventana Discovery Ultra and a Vectra Polaris that were purchased with funding from National Institutes of Health SIG grants ( S10 OD026983 and S10OD030269 ). We thank the Boston University Animal Science Center and the NEIDL animal core staff for their outstanding support. We thank Robert LeDesma and Emily Mesev for their critical review of the manuscript. We also thank all the Douam, Ploss, Crossland, Connor, and Emili lab members; NEIDL members; and members of the Department of Microbiology, Pathology, Biochemistry, and Medicine at Boston University for their constant support and advice. Funding Information: This work was supported by a start-up fund and the Peter Paul Career Development Professorship from Boston University (to F.D.), grants from the National Institutes of Health (R01 AI138797, R01 AI107301, R01 AI146917, R01 AI153236 to A.P.; R21 ES032882, K22 AI144050 to F.D.; R01 HL141513, R01 HL139641, R01 AI153613, UL1 TR001430 to M.B.; R01 502088946, R21 AI135517 to J.H.C.), awards from the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001430 to F.D. N.A.C. and A.E.; UL1TR003017 to A.P.), a grant from the National Library of Medicine (R01 LM013154-01 to J.D.C.), the Deutsche Forschungsgemeinschaft (BO3482/3-3, BO3482/4-1 to M.B.), a Research Scholar Award from the American Cancer Society (RSG-15-048-01-MPC to A.P.), a Burroughs Wellcome Fund Award for Investigators in Pathogenesis (101539 to A.P.), Princeton COVID-19 research funds through the Office of the Dean for Research, and Boston University start-up funds and an Evergrande MassCPR award (to M.S.). T.T. is a recipient of postdoctoral fellowship awards from the Uehara Memorial Foundation and the JSPS Research Fellowships for young scientists. We thank the Evans Center for Interdisciplinary Biomedical Research at Boston University School of Medicine for their support of the Affinity Research Collaborative on “Respiratory Viruses: A Focus on COVID-19.” This work utilized a Ventana Discovery Ultra and a Vectra Polaris that were purchased with funding from National Institutes of Health SIG grants (S10 OD026983 and S10OD030269). We thank the Boston University Animal Science Center and the NEIDL animal core staff for their outstanding support. We thank Robert LeDesma and Emily Mesev for their critical review of the manuscript. We also thank all the Douam, Ploss, Crossland, Connor, and Emili lab members; NEIDL members; and members of the Department of Microbiology, Pathology, Biochemistry, and Medicine at Boston University for their constant support and advice. D.K. and F.D. conceptualized the study. D.K. A.K.O. J.T. P.M. R.M.H. T.T. J.H.C. A.E. N.A.C. A.P. and F.D. designed the experiments. D.K. A.K.O. J.T. P.M. R.M.H. T.T. A.R.B. T.R.C. B.B. S.I.G. B.L.H. H.P.G. A.T. A.J.T. E.C. E.T.N. C.M. A.E.T. A.S. S.K. K.G. M.S. A.B.B. N.A.C. A.P. and F.D. performed experiments. D.K. A.K.O. J.T. P.M. R.M.H. T.T. S.A.A. B.B. E.B. M.E. M.S. K.P.F. A.K. N.P. J.D.C. J.H.C. A.E. N.A.C. A.P. and F.D. analyzed the data. J.T. R.M.H. S.A.A. and J.D.C. carried out computational analysis. K.P.F. A.K. and N.P. carried out bioluminescence imaging analysis. M.E. carried out electron microscopy analysis. B.R.H. M.B. K.P.F. A.K. and N.P provided access to key resources. E.B. M.B. M.E. M.S. K.P.F. A.K. and N.P. provided conceptual and technical inputs and/or helped with data interpretation. D.K. N.A.C. A.P. and F.D. wrote the manuscript with contributions from all authors. K.P.F. is an employee of PerkinElmer, Inc. and a technology advisor of InVivo Analytics. N.P. and A.K. are shareholders of InVivo Analytics with issued patents. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = apr,
day = "19",
doi = "10.1016/j.celrep.2022.110714",
language = "English (US)",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}