Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

Timothy N. Hoang; Maria Pino; Arun K. Boddapati; Elise G. Viox; Carly E. Starke; Amit A. Upadhyay; Sanjeev Gumber; Michael Nekorchuk; Kathleen Busman-Sahay; Zachary Strongin; Justin L. Harper; Gregory K. Tharp; Kathryn L. Pellegrini; Shannon Kirejczyk; Keivan Zandi; Sijia Tao; Tristan R. Horton; Elizabeth N. Beagle; Ernestine A. Mahar; Michelle Y.H. Lee; Joyce Cohen; Sherrie M. Jean; Jennifer S. Wood; Fawn Connor-Stroud; Rachelle L. Stammen; Olivia M. Delmas; Shelly Wang; Kimberly A. Cooney; Michael N. Sayegh; Lanfang Wang; Peter D. Filev; Daniela Weiskopf; Guido Silvestri; Jesse Waggoner; Anne Piantadosi; Sudhir P. Kasturi; Hilmi Al-Shakhshir; Susan P. Ribeiro; Rafick P. Sekaly; Rebecca D. Levit; Jacob D. Estes; Thomas H. Vanderford; Raymond F. Schinazi; Steven E. Bosinger; Mirko Paiardini

doi:10.1016/j.cell.2020.11.007

Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

Timothy N. Hoang, Maria Pino, Arun K. Boddapati, Elise G. Viox, Carly E. Starke, Amit A. Upadhyay, Sanjeev Gumber, Michael Nekorchuk, Kathleen Busman-Sahay, Zachary Strongin, Justin L. Harper, Gregory K. Tharp, Kathryn L. Pellegrini, Shannon Kirejczyk, Keivan Zandi, Sijia Tao, Tristan R. Horton, Elizabeth N. Beagle, Ernestine A. Mahar, Michelle Y.H. LeeJoyce Cohen, Sherrie M. Jean, Jennifer S. Wood, Fawn Connor-Stroud, Rachelle L. Stammen, Olivia M. Delmas, Shelly Wang, Kimberly A. Cooney, Michael N. Sayegh, Lanfang Wang, Peter D. Filev, Daniela Weiskopf, Guido Silvestri, Jesse Waggoner, Anne Piantadosi, Sudhir P. Kasturi, Hilmi Al-Shakhshir, Susan P. Ribeiro, Rafick P. Sekaly, Rebecca D. Levit, Jacob D. Estes, Thomas H. Vanderford, Raymond F. Schinazi, Steven E. Bosinger, Mirko Paiardini

Vaccine and Gene Therapy Institute

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

93 Scopus citations

Abstract

Using a rhesus macaque infection model, it is shown that baricitinib treatment started early after infection effectively resolves inflammatory signatures in airway macrophages, with decreased lung pathology and neutrophil infiltration.

Original language	English (US)
Pages (from-to)	460-475.e21
Journal	Cell
Volume	184
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2020.11.007
State	Published - Jan 21 2021

Keywords

COVID-19
SARS-CoV-2
baricitinib
immune activation
immunology
inflammation
nonhuman primate
pathogenesis

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2020.11.007

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Hoang, T. N., Pino, M., Boddapati, A. K., Viox, E. G., Starke, C. E., Upadhyay, A. A., Gumber, S., Nekorchuk, M., Busman-Sahay, K., Strongin, Z., Harper, J. L., Tharp, G. K., Pellegrini, K. L., Kirejczyk, S., Zandi, K., Tao, S., Horton, T. R., Beagle, E. N., Mahar, E. A., ... Paiardini, M. (2021). Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell, 184(2), 460-475.e21. https://doi.org/10.1016/j.cell.2020.11.007

Hoang, TN, Pino, M, Boddapati, AK, Viox, EG, Starke, CE, Upadhyay, AA, Gumber, S, Nekorchuk, M, Busman-Sahay, K, Strongin, Z, Harper, JL, Tharp, GK, Pellegrini, KL, Kirejczyk, S, Zandi, K, Tao, S, Horton, TR, Beagle, EN, Mahar, EA, Lee, MYH, Cohen, J, Jean, SM, Wood, JS, Connor-Stroud, F, Stammen, RL, Delmas, OM, Wang, S, Cooney, KA, Sayegh, MN, Wang, L, Filev, PD, Weiskopf, D, Silvestri, G, Waggoner, J, Piantadosi, A, Kasturi, SP, Al-Shakhshir, H, Ribeiro, SP, Sekaly, RP, Levit, RD, Estes, JD, Vanderford, TH, Schinazi, RF, Bosinger, SE & Paiardini, M 2021, 'Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques', Cell, vol. 184, no. 2, pp. 460-475.e21. https://doi.org/10.1016/j.cell.2020.11.007

@article{a5c9ae9eaa9a4e32a2b2ae3c78c1e559,

title = "Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques",

abstract = "Using a rhesus macaque infection model, it is shown that baricitinib treatment started early after infection effectively resolves inflammatory signatures in airway macrophages, with decreased lung pathology and neutrophil infiltration.",

keywords = "COVID-19, SARS-CoV-2, baricitinib, immune activation, immunology, inflammation, nonhuman primate, pathogenesis",

author = "Hoang, {Timothy N.} and Maria Pino and Boddapati, {Arun K.} and Viox, {Elise G.} and Starke, {Carly E.} and Upadhyay, {Amit A.} and Sanjeev Gumber and Michael Nekorchuk and Kathleen Busman-Sahay and Zachary Strongin and Harper, {Justin L.} and Tharp, {Gregory K.} and Pellegrini, {Kathryn L.} and Shannon Kirejczyk and Keivan Zandi and Sijia Tao and Horton, {Tristan R.} and Beagle, {Elizabeth N.} and Mahar, {Ernestine A.} and Lee, {Michelle Y.H.} and Joyce Cohen and Jean, {Sherrie M.} and Wood, {Jennifer S.} and Fawn Connor-Stroud and Stammen, {Rachelle L.} and Delmas, {Olivia M.} and Shelly Wang and Cooney, {Kimberly A.} and Sayegh, {Michael N.} and Lanfang Wang and Filev, {Peter D.} and Daniela Weiskopf and Guido Silvestri and Jesse Waggoner and Anne Piantadosi and Kasturi, {Sudhir P.} and Hilmi Al-Shakhshir and Ribeiro, {Susan P.} and Sekaly, {Rafick P.} and Levit, {Rebecca D.} and Estes, {Jacob D.} and Vanderford, {Thomas H.} and Schinazi, {Raymond F.} and Bosinger, {Steven E.} and Mirko Paiardini",

note = "Funding Information: We thank the Yerkes National Primate Research Center (YNPRC) Division of Animal Resources, especially Stephanie Ehnert, Stacey Weissman, Denise Bonenberger, John M. Wambua, Dominic M. D'Urso, Racquel Sampson-Harley, and Kalpana Patel in Research Resources for providing support in animal care. We thank Nichole Arnett for assistance with clinical pathology assays and Kevin Nguyen for additional laboratory processing. We thank Dr. Vincent Marconi for discussions and critical reading of the manuscript. Pharmaceutical-grade baricitinib was commercially obtained, provided free of charge by Dr. Schinazi, and it was found to be >99% pure by LC-MS-MS. This study was supported by an Emory University COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant to M. Paiardini, A.P. and R.F.S.; by YNPRC Coronavirus Pilot Research Project Program grant to M. Paiardini under award P51 OD11132; and by Fast Grants Award #2144 to M. Paiardini. This work was additionally funded by the National Institute of Allergy and Infectious Diseases (NIAID, NIH) under awards R37AI141258 and R01AI116379 to M. Paiardini, R01MH116695 to R.F.S, R01AI143411, R01HL140223 to R.D.L. and R01AI149672 to J.D.E. and U24AI120134 to S.E.B. Support for this work was also provided by award NIH Office of Research Infrastructure Programs (ORIP) P51OD11132 to YNPRC, P51OD011092 to ONPRC, 1S10OD025002-01 to the Integrated Pathology Core/ONPRC, NIAID award P30 AI050409 to the Center for AIDS Research (CFAR) at Emory University, and contract Nr. 75N9301900065 (to D.W.). Next-generation sequencing services were provided by the Yerkes NHP Genomics Core, which is supported in part by NIH P51OD011132. Sequencing data were acquired on an Illumina NovaSeq6000 funded by NIH S10OD026799 to S.E.B. Pictorial illustrations were created with BioRender.com. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services nor does it imply endorsement of organizations or commercial products. Conceptualization, T.N.H. M. Pino, J.L.H. G.S. A.P. S.E.B. R.F.S. and M. Paiardini; Methodology, T.N.H. M. Pino, A.K.B. E.G.V. N.K. K.B.-S. A.A.U. Z.S. G.K.T. K.L.P. S.G. S.K. S.T. O.M.D. K.A.C. M.N.S. L.W. P.D.F. J.W. A.P. S.P.K. C.E.S. S.W. H.A. E.A.M. M.Y.H.L. K.Z. S.T. T.R.H. E.N.B. S.P.R. and T.H.V.; Formal Analysis, T.N.H. M. Pino, Z.S. E.G.V. A.K.B. K.B.-S. A.A.U. G.K.T. S.G. S.K. S.T. P.D.F. J.W. A.P. S.P.K. S.P.R. and T.H.V; Investigation, T.N.H. M. Pino, E.G.V. J.C. S.M.J. J.S.W. F.C.-S. R.L.S. R.D.L. A.P. S.P.R. R.P.S. and T.H.V.; Resources, D.W. R.F.S. S.E.B. and M. Paiardini; Writing – Original Draft, T.N.H. M. Pino, J.L.H. and M. Paiardini; Writing – Review & Editing, T.N.H. M. Pino, J.L.H. S.E.B. and M. Paiardini; Visualization, T.N.H. M. Pino, A.K.B. A.A.U. G.K.T. Z.S. and E.G.V.; Supervision, R.F.S. S.E.B. and M. Paiardini; Funding Acquisition, A.P. S.E.B. R.F.S. and M. Paiardini. R.F.S. served as an unpaid consultant for Eli Lilly whose drugs are being evaluated in the research described in this paper. In addition, R.F.S. owns shares in Eli Lilly. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Eli Lilly had no role in the design of this study and did not have any role during its execution, analyses, interpretation of the data, or decision to submit results. All other authors do not have any conflicts to declare. Funding Information: We thank the Yerkes National Primate Research Center (YNPRC) Division of Animal Resources, especially Stephanie Ehnert, Stacey Weissman, Denise Bonenberger, John M. Wambua, Dominic M. D{\textquoteright}Urso, Racquel Sampson-Harley, and Kalpana Patel in Research Resources for providing support in animal care. We thank Nichole Arnett for assistance with clinical pathology assays and Kevin Nguyen for additional laboratory processing. We thank Dr. Vincent Marconi for discussions and critical reading of the manuscript. Pharmaceutical-grade baricitinib was commercially obtained, provided free of charge by Dr. Schinazi, and it was found to be >99% pure by LC-MS-MS. This study was supported by an Emory University COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant to M. Paiardini, A.P., and R.F.S.; by YNPRC Coronavirus Pilot Research Project Program grant to M. Paiardini under award P51 OD11132 ; and by Fast Grants Award #2144 to M. Paiardini. This work was additionally funded by the National Institute of Allergy and Infectious Diseases (NIAID, NIH) under awards R37AI141258 and R01AI116379 to M. Paiardini, R01MH116695 to R.F.S, R01AI143411 , R01HL140223 to R.D.L., and R01AI149672 to J.D.E., and U24AI120134 to S.E.B. Support for this work was also provided by award NIH Office of Research Infrastructure Programs (ORIP) P51OD11132 to YNPRC, P51OD011092 to ONPRC, 1S10OD025002-01 to the Integrated Pathology Core/ONPRC , NIAID award P30 AI050409 to the Center for AIDS Research (CFAR) at Emory University, and contract Nr. 75N9301900065 (to D.W.). Next-generation sequencing services were provided by the Yerkes NHP Genomics Core, which is supported in part by NIH P51OD011132 . Sequencing data were acquired on an Illumina NovaSeq6000 funded by NIH S10OD026799 to S.E.B. Pictorial illustrations were created with BioRender.com . The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services nor does it imply endorsement of organizations or commercial products. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2021",

month = jan,

day = "21",

doi = "10.1016/j.cell.2020.11.007",

language = "English (US)",

volume = "184",

pages = "460--475.e21",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

AU - Hoang, Timothy N.

AU - Pino, Maria

AU - Boddapati, Arun K.

AU - Viox, Elise G.

AU - Starke, Carly E.

AU - Upadhyay, Amit A.

AU - Gumber, Sanjeev

AU - Nekorchuk, Michael

AU - Busman-Sahay, Kathleen

AU - Strongin, Zachary

AU - Harper, Justin L.

AU - Tharp, Gregory K.

AU - Pellegrini, Kathryn L.

AU - Kirejczyk, Shannon

AU - Zandi, Keivan

AU - Tao, Sijia

AU - Horton, Tristan R.

AU - Beagle, Elizabeth N.

AU - Mahar, Ernestine A.

AU - Lee, Michelle Y.H.

AU - Cohen, Joyce

AU - Jean, Sherrie M.

AU - Wood, Jennifer S.

AU - Connor-Stroud, Fawn

AU - Stammen, Rachelle L.

AU - Delmas, Olivia M.

AU - Wang, Shelly

AU - Cooney, Kimberly A.

AU - Sayegh, Michael N.

AU - Wang, Lanfang

AU - Filev, Peter D.

AU - Weiskopf, Daniela

AU - Silvestri, Guido

AU - Waggoner, Jesse

AU - Piantadosi, Anne

AU - Kasturi, Sudhir P.

AU - Al-Shakhshir, Hilmi

AU - Ribeiro, Susan P.

AU - Sekaly, Rafick P.

AU - Levit, Rebecca D.

AU - Estes, Jacob D.

AU - Vanderford, Thomas H.

AU - Schinazi, Raymond F.

AU - Bosinger, Steven E.

AU - Paiardini, Mirko

N1 - Funding Information: We thank the Yerkes National Primate Research Center (YNPRC) Division of Animal Resources, especially Stephanie Ehnert, Stacey Weissman, Denise Bonenberger, John M. Wambua, Dominic M. D'Urso, Racquel Sampson-Harley, and Kalpana Patel in Research Resources for providing support in animal care. We thank Nichole Arnett for assistance with clinical pathology assays and Kevin Nguyen for additional laboratory processing. We thank Dr. Vincent Marconi for discussions and critical reading of the manuscript. Pharmaceutical-grade baricitinib was commercially obtained, provided free of charge by Dr. Schinazi, and it was found to be >99% pure by LC-MS-MS. This study was supported by an Emory University COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant to M. Paiardini, A.P. and R.F.S.; by YNPRC Coronavirus Pilot Research Project Program grant to M. Paiardini under award P51 OD11132; and by Fast Grants Award #2144 to M. Paiardini. This work was additionally funded by the National Institute of Allergy and Infectious Diseases (NIAID, NIH) under awards R37AI141258 and R01AI116379 to M. Paiardini, R01MH116695 to R.F.S, R01AI143411, R01HL140223 to R.D.L. and R01AI149672 to J.D.E. and U24AI120134 to S.E.B. Support for this work was also provided by award NIH Office of Research Infrastructure Programs (ORIP) P51OD11132 to YNPRC, P51OD011092 to ONPRC, 1S10OD025002-01 to the Integrated Pathology Core/ONPRC, NIAID award P30 AI050409 to the Center for AIDS Research (CFAR) at Emory University, and contract Nr. 75N9301900065 (to D.W.). Next-generation sequencing services were provided by the Yerkes NHP Genomics Core, which is supported in part by NIH P51OD011132. Sequencing data were acquired on an Illumina NovaSeq6000 funded by NIH S10OD026799 to S.E.B. Pictorial illustrations were created with BioRender.com. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services nor does it imply endorsement of organizations or commercial products. Conceptualization, T.N.H. M. Pino, J.L.H. G.S. A.P. S.E.B. R.F.S. and M. Paiardini; Methodology, T.N.H. M. Pino, A.K.B. E.G.V. N.K. K.B.-S. A.A.U. Z.S. G.K.T. K.L.P. S.G. S.K. S.T. O.M.D. K.A.C. M.N.S. L.W. P.D.F. J.W. A.P. S.P.K. C.E.S. S.W. H.A. E.A.M. M.Y.H.L. K.Z. S.T. T.R.H. E.N.B. S.P.R. and T.H.V.; Formal Analysis, T.N.H. M. Pino, Z.S. E.G.V. A.K.B. K.B.-S. A.A.U. G.K.T. S.G. S.K. S.T. P.D.F. J.W. A.P. S.P.K. S.P.R. and T.H.V; Investigation, T.N.H. M. Pino, E.G.V. J.C. S.M.J. J.S.W. F.C.-S. R.L.S. R.D.L. A.P. S.P.R. R.P.S. and T.H.V.; Resources, D.W. R.F.S. S.E.B. and M. Paiardini; Writing – Original Draft, T.N.H. M. Pino, J.L.H. and M. Paiardini; Writing – Review & Editing, T.N.H. M. Pino, J.L.H. S.E.B. and M. Paiardini; Visualization, T.N.H. M. Pino, A.K.B. A.A.U. G.K.T. Z.S. and E.G.V.; Supervision, R.F.S. S.E.B. and M. Paiardini; Funding Acquisition, A.P. S.E.B. R.F.S. and M. Paiardini. R.F.S. served as an unpaid consultant for Eli Lilly whose drugs are being evaluated in the research described in this paper. In addition, R.F.S. owns shares in Eli Lilly. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Eli Lilly had no role in the design of this study and did not have any role during its execution, analyses, interpretation of the data, or decision to submit results. All other authors do not have any conflicts to declare. Funding Information: We thank the Yerkes National Primate Research Center (YNPRC) Division of Animal Resources, especially Stephanie Ehnert, Stacey Weissman, Denise Bonenberger, John M. Wambua, Dominic M. D’Urso, Racquel Sampson-Harley, and Kalpana Patel in Research Resources for providing support in animal care. We thank Nichole Arnett for assistance with clinical pathology assays and Kevin Nguyen for additional laboratory processing. We thank Dr. Vincent Marconi for discussions and critical reading of the manuscript. Pharmaceutical-grade baricitinib was commercially obtained, provided free of charge by Dr. Schinazi, and it was found to be >99% pure by LC-MS-MS. This study was supported by an Emory University COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant to M. Paiardini, A.P., and R.F.S.; by YNPRC Coronavirus Pilot Research Project Program grant to M. Paiardini under award P51 OD11132 ; and by Fast Grants Award #2144 to M. Paiardini. This work was additionally funded by the National Institute of Allergy and Infectious Diseases (NIAID, NIH) under awards R37AI141258 and R01AI116379 to M. Paiardini, R01MH116695 to R.F.S, R01AI143411 , R01HL140223 to R.D.L., and R01AI149672 to J.D.E., and U24AI120134 to S.E.B. Support for this work was also provided by award NIH Office of Research Infrastructure Programs (ORIP) P51OD11132 to YNPRC, P51OD011092 to ONPRC, 1S10OD025002-01 to the Integrated Pathology Core/ONPRC , NIAID award P30 AI050409 to the Center for AIDS Research (CFAR) at Emory University, and contract Nr. 75N9301900065 (to D.W.). Next-generation sequencing services were provided by the Yerkes NHP Genomics Core, which is supported in part by NIH P51OD011132 . Sequencing data were acquired on an Illumina NovaSeq6000 funded by NIH S10OD026799 to S.E.B. Pictorial illustrations were created with BioRender.com . The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services nor does it imply endorsement of organizations or commercial products. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2021/1/21

Y1 - 2021/1/21

N2 - Using a rhesus macaque infection model, it is shown that baricitinib treatment started early after infection effectively resolves inflammatory signatures in airway macrophages, with decreased lung pathology and neutrophil infiltration.

AB - Using a rhesus macaque infection model, it is shown that baricitinib treatment started early after infection effectively resolves inflammatory signatures in airway macrophages, with decreased lung pathology and neutrophil infiltration.

KW - COVID-19

KW - SARS-CoV-2

KW - baricitinib

KW - immune activation

KW - immunology

KW - inflammation

KW - nonhuman primate

KW - pathogenesis

UR - http://www.scopus.com/inward/record.url?scp=85097217128&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85097217128&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.11.007

DO - 10.1016/j.cell.2020.11.007

M3 - Article

C2 - 33278358

AN - SCOPUS:85097217128

VL - 184

SP - 460-475.e21

JO - Cell

JF - Cell

SN - 0092-8674

IS - 2

ER -

Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

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