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

Devin J. Kenney; Aoife K. O'Connell; Jacquelyn Turcinovic; Paige Montanaro; Ryan M. Hekman; Tomokazu Tamura; Andrew R. Berneshawi; Thomas R. Cafiero; Salam Al Abdullatif; Benjamin Blum; Stanley I. Goldstein; Brigitte L. Heller; Hans P. Gertje; Esther Bullitt; Alexander J. Trachtenberg; Elizabeth Chavez; Evans Tuekam Nono; Catherine Morrison; Anna E. Tseng; Amira Sheikh; Susanna Kurnick; Kyle Grosz; Markus Bosmann; Maria Ericsson; Bertrand R. Huber; Mohsan Saeed; Alejandro B. Balazs; Kevin P. Francis; Alexander Klose; Neal Paragas; Joshua D. Campbell; John H. Connor; Andrew Emili; Nicholas A. Crossland; Alexander Ploss; Florian Douam

doi:10.1016/j.celrep.2022.110714

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

Devin J. Kenney, Aoife K. O'Connell, Jacquelyn Turcinovic, Paige Montanaro, Ryan M. Hekman, Tomokazu Tamura, Andrew R. Berneshawi, Thomas R. Cafiero, Salam Al Abdullatif, Benjamin Blum, Stanley I. Goldstein, Brigitte L. Heller, Hans P. Gertje, Esther Bullitt, Alexander J. Trachtenberg, Elizabeth Chavez, Evans Tuekam Nono, Catherine Morrison, Anna E. Tseng, Amira SheikhSusanna Kurnick, Kyle Grosz, Markus Bosmann, Maria Ericsson, Bertrand R. Huber, Mohsan Saeed, Alejandro B. Balazs, Kevin P. Francis, Alexander Klose, Neal Paragas, Joshua D. Campbell, John H. Connor, Andrew Emili, Nicholas A. Crossland, Alexander Ploss, Florian Douam

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	110714
Journal	Cell Reports
Volume	39
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2022.110714
State	Published - Apr 19 2022
Externally published	Yes

Keywords

antiviral responses
COVID-19
CP: Immunology
CP: Microbiology
human immune responses to SARS-CoV-2
humanized mice
macrophage responses to SARS-CoV-2
mouse models of SARS-CoV-2
pulmonary immune responses

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.110714

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Kenney, D. J., O'Connell, A. K., Turcinovic, J., Montanaro, P., Hekman, R. M., Tamura, T., Berneshawi, A. R., Cafiero, T. R., Al Abdullatif, S., Blum, B., Goldstein, S. I., Heller, B. L., Gertje, H. P., Bullitt, E., Trachtenberg, A. J., Chavez, E., Nono, E. T., Morrison, C., Tseng, A. E., ... Douam, F. (2022). Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection. Cell Reports, 39(3), Article 110714. https://doi.org/10.1016/j.celrep.2022.110714

Kenney, DJ, O'Connell, AK, Turcinovic, J, Montanaro, P, Hekman, RM, Tamura, T, Berneshawi, AR, Cafiero, TR, Al Abdullatif, S, Blum, B, Goldstein, SI, Heller, BL, Gertje, HP, Bullitt, E, Trachtenberg, AJ, Chavez, E, Nono, ET, 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 2022, 'Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection', Cell Reports, vol. 39, no. 3, 110714. https://doi.org/10.1016/j.celrep.2022.110714

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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 = "antiviral responses, COVID-19, CP: Immunology, CP: Microbiology, 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 = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = apr,

day = "19",

doi = "10.1016/j.celrep.2022.110714",

language = "English (US)",

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T1 - Humanized mice reveal a macrophage-enriched gene signature defining human lung tissue protection during SARS-CoV-2 infection

AU - Kenney, Devin J.

AU - O'Connell, Aoife K.

AU - Turcinovic, Jacquelyn

AU - Montanaro, Paige

AU - Hekman, Ryan M.

AU - Tamura, Tomokazu

AU - Berneshawi, Andrew R.

AU - Cafiero, Thomas R.

AU - Al Abdullatif, Salam

AU - Blum, Benjamin

AU - Goldstein, Stanley I.

AU - Heller, Brigitte L.

AU - Gertje, Hans P.

AU - Bullitt, Esther

AU - Trachtenberg, Alexander J.

AU - Chavez, Elizabeth

AU - Nono, Evans Tuekam

AU - Morrison, Catherine

AU - Tseng, Anna E.

AU - Sheikh, Amira

AU - Kurnick, Susanna

AU - Grosz, Kyle

AU - Bosmann, Markus

AU - Ericsson, Maria

AU - Huber, Bertrand R.

AU - Saeed, Mohsan

AU - Balazs, Alejandro B.

AU - Francis, Kevin P.

AU - Klose, Alexander

AU - Paragas, Neal

AU - Campbell, Joshua D.

AU - Connor, John H.

AU - Emili, Andrew

AU - Crossland, Nicholas A.

AU - Ploss, Alexander

AU - Douam, Florian

PY - 2022/4/19

Y1 - 2022/4/19

N2 - 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.

AB - 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.

KW - antiviral responses

KW - COVID-19

KW - CP: Immunology

KW - CP: Microbiology

KW - human immune responses to SARS-CoV-2

KW - humanized mice

KW - macrophage responses to SARS-CoV-2

KW - mouse models of SARS-CoV-2

KW - pulmonary immune responses

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DO - 10.1016/j.celrep.2022.110714

M3 - Article

C2 - 35421379

AN - SCOPUS:85128237588

SN - 2211-1247

VL - 39

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 110714

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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