Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection.

TitleHumanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection.
Publication TypeJournal Article
Year of Publication2022
AuthorsKenney, DJ, O'Connell, AK, Turcinovic, J, Montanaro, P, Hekman, RM, Tamura, T, Berneshawi, AR, Cafiero, TR, Abdullatif, SAl, Blum, B, Goldstein, SI, Heller, BL, Gertje, HP, Bullitt, E, Trachtenberg, AJ, Chavez, E, Nono, ETuekam, Morrison, C, Tseng, AE, Sheikh, A, Kurnick, S, Grosz, K, Bosmann, M, Ericsson, M, Huber, BR, Saeed, M, Balazs, AB, Francis, KP, Klose, A, Paragas, N, Campbell, JD, Connor, JH, Emili, A, Crossland, NA, Ploss, A, Douam, F
JournalCell Rep
Volume39
Issue3
Pagination110714
Date Published2022 04 19
ISSN2211-1247
KeywordsAnimals, COVID-19, Disease Models, Animal, Humans, Immunity, Innate, Lung, Macrophages, Mice, SARS-CoV-2
Abstract

<p>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.</p>

DOI10.1016/j.celrep.2022.110714
Alternate JournalCell Rep
PubMed ID35421379
PubMed Central IDPMC8977517
Grant ListR01 HL139641 / HL / NHLBI NIH HHS / United States
S10 OD026983 / OD / NIH HHS / United States
R01 AI138797 / AI / NIAID NIH HHS / United States
R21 ES032882 / ES / NIEHS NIH HHS / United States
S10 OD030269 / OD / NIH HHS / United States
K22 AI144050 / AI / NIAID NIH HHS / United States
R21 AI135517 / AI / NIAID NIH HHS / United States
R01 HL141513 / HL / NHLBI NIH HHS / United States
R01 AI107301 / AI / NIAID NIH HHS / United States
R01 AI153236 / AI / NIAID NIH HHS / United States
R01 AI153613 / AI / NIAID NIH HHS / United States
UL1 TR003017 / TR / NCATS NIH HHS / United States
R01 LM013154 / LM / NLM NIH HHS / United States
R01 AI146917 / AI / NIAID NIH HHS / United States
UL1 TR001430 / TR / NCATS NIH HHS / United States