TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

Jessica Sook Yuin Ho; Bobo Wing Yee Mok; Laura Campisi; Tristan Jordan; Soner Yildiz; Sreeja Parameswaran; Joseph A. Wayman; Natasha N. Gaudreault; David A. Meekins; Sabarish V. Indran; Igor Morozov; Jessie D. Trujillo; Yesai S. Fstkchyan; Raveen Rathnasinghe; Zeyu Zhu; Simin Zheng; Nan Zhao; Kris White; Helen Ray-Jones; Valeriya Malysheva; Michiel J. Thiecke; Siu Ying Lau; Honglian Liu; Anna Junxia Zhang; Andrew Chak Yiu Lee; Wen Chun Liu; Sonia Jangra; Alba Escalera; Teresa Aydillo; Betsaida Salom Melo; Ernesto Guccione; Robert Sebra; Elaine Shum; Jan Bakker; David A. Kaufman; Andre L. Moreira; Mariano Carossino; Udeni B.R. Balasuriya; Minji Byun; Randy A. Albrecht; Michael Schotsaert; Adolfo Garcia-Sastre; Sumit K. Chanda; Emily R. Miraldi; Anand D. Jeyasekharan; Benjamin R. TenOever; Mikhail Spivakov; Matthew T. Weirauch; Sven Heinz; Honglin Chen; Christopher Benner; Juergen A. Richt; Ivan Marazzi

doi:10.1016/j.cell.2021.03.051

TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

Jessica Sook Yuin Ho, Bobo Wing Yee Mok, Laura Campisi, Tristan Jordan, Soner Yildiz, Sreeja Parameswaran, Joseph A. Wayman, Natasha N. Gaudreault, David A. Meekins, Sabarish V. Indran, Igor Morozov, Jessie D. Trujillo, Yesai S. Fstkchyan, Raveen Rathnasinghe, Zeyu Zhu, Simin Zheng, Nan Zhao, Kris White, Helen Ray-Jones, Valeriya MalyshevaMichiel J. Thiecke, Siu Ying Lau, Honglian Liu, Anna Junxia Zhang, Andrew Chak Yiu Lee, Wen Chun Liu, Sonia Jangra, Alba Escalera, Teresa Aydillo, Betsaida Salom Melo, Ernesto Guccione, Robert Sebra, Elaine Shum, Jan Bakker, David A. Kaufman, Andre L. Moreira, Mariano Carossino, Udeni B.R. Balasuriya, Minji Byun, Randy A. Albrecht, Michael Schotsaert, Adolfo Garcia-Sastre, Sumit K. Chanda, Emily R. Miraldi, Anand D. Jeyasekharan, Benjamin R. TenOever, Mikhail Spivakov, Matthew T. Weirauch, Sven Heinz, Honglin Chen, Christopher Benner, Juergen A. Richt, Ivan Marazzi

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

47 Scopus citations

Abstract

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

Original language	English
Pages (from-to)	2618-2632.e17
Journal	Cell
Volume	184
Issue number	10
DOIs	https://doi.org/10.1016/j.cell.2021.03.051
State	Published - 13 May 2021

Keywords

COVID-19
SARS-CoV-2
chromatin
cytokine storm
epigenetics
inducible genes
inflammation
topoisomerase
topotecan
transcription

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10.1016/j.cell.2021.03.051

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Ho, J. S. Y., Mok, B. W. Y., Campisi, L., Jordan, T., Yildiz, S., Parameswaran, S., Wayman, J. A., Gaudreault, N. N., Meekins, D. A., Indran, S. V., Morozov, I., Trujillo, J. D., Fstkchyan, Y. S., Rathnasinghe, R., Zhu, Z., Zheng, S., Zhao, N., White, K., Ray-Jones, H., ... Marazzi, I. (2021). TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation. Cell, 184(10), 2618-2632.e17. https://doi.org/10.1016/j.cell.2021.03.051

@article{044ea0998f374a248dd16fed21ea1ba9,

title = "TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation",

abstract = "The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.",

keywords = "COVID-19, SARS-CoV-2, chromatin, cytokine storm, epigenetics, inducible genes, inflammation, topoisomerase, topotecan, transcription",

author = "Ho, {Jessica Sook Yuin} and Mok, {Bobo Wing Yee} and Laura Campisi and Tristan Jordan and Soner Yildiz and Sreeja Parameswaran and Wayman, {Joseph A.} and Gaudreault, {Natasha N.} and Meekins, {David A.} and Indran, {Sabarish V.} and Igor Morozov and Trujillo, {Jessie D.} and Fstkchyan, {Yesai S.} and Raveen Rathnasinghe and Zeyu Zhu and Simin Zheng and Nan Zhao and Kris White and Helen Ray-Jones and Valeriya Malysheva and Thiecke, {Michiel J.} and Lau, {Siu Ying} and Honglian Liu and Zhang, {Anna Junxia} and Lee, {Andrew Chak Yiu} and Liu, {Wen Chun} and Sonia Jangra and Alba Escalera and Teresa Aydillo and Melo, {Betsaida Salom} and Ernesto Guccione and Robert Sebra and Elaine Shum and Jan Bakker and Kaufman, {David A.} and Moreira, {Andre L.} and Mariano Carossino and Balasuriya, {Udeni B.R.} and Minji Byun and Albrecht, {Randy A.} and Michael Schotsaert and Adolfo Garcia-Sastre and Chanda, {Sumit K.} and Miraldi, {Emily R.} and Jeyasekharan, {Anand D.} and TenOever, {Benjamin R.} and Mikhail Spivakov and Weirauch, {Matthew T.} and Sven Heinz and Honglin Chen and Christopher Benner and Richt, {Juergen A.} and Ivan Marazzi",

note = "Funding Information: We thank the staff of KSU Biosecurity Research Institute; the histological laboratory at the Kansas State Veterinary Diagnostic Laboratory (KSVDL); members of the Histology and Immunohistochemistry sections at the Louisiana Animal Disease Diagnostic Laboratory (LADDL); the CMG staff; and Bianca Artiaga, Dashzeveg Bold, Konner Cool, Emily Gilbert-Esparza, Chester McDowell, and Yonghai Li. We thank the teams at the Icahn School of Medicine at Mount Sinai, the Genomics and Mouse facilities, and Alan Soto from the Biorepository and Pathology Dean{\textquoteright}s CoRE. We thank Cindy Beharry, Nanyi Julia Zhao, Nancy Francoeur, Nataly Fishman, Marion Dejosez, Thomas Zwaka, and Carles Martinez-Romero for their help and advice. Luis Martinez (Texas Biomedical Research Institute) and the Center for Therapeutic Antibody Development (CTAD) (Thomas Moran, Andy Duty, and Thomas Kraus) kindly provided the NP1C7C7 antibody.This work was partially supported through grants from NBAF Transition Funds and the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) under contract number HHSN 272201400006C to A.G.-S.; the Department of Homeland Security Center of Excellence for Emerging and Zoonotic Animal Diseases under grant HSHQDC-16-A-B0006 to J.A.R.; CRIP (Center for Research for Influenza Pathogenesis CEIRS, contract HHSN272201400008C ); supplements to NIAID grant U19AI135972 and DOD grant W81XWH-20-1-0270 ; the Defense Advanced Research Projects Agency ( HR0011-19-2-0020 ); and the JPB Foundation , the Open Philanthropy Project (research grant 2020-215611 [5384] ), and anonymous donors. S.Y. received funding from a Swiss National Foundation (SNF) Early Postdoc.Mobility fellowship ( P2GEP3_184202 ). This work was partially supported by funding to I. Marazzi., specifically the Burroughs Wellcome Fund (United States; 1017892 ), the Chan Zuckerberg Initiative (United States; 2018-191895 ), the Hirschl Young Investigator fellowship, and NIH grants U01AI150748 and R01AI143840 . Partial support by the AMP Core of the Center of Emerging and Zoonotic Infectious Diseases of the National Institutes of Health under award number P20GM130448 to J.R. Funding Information: We thank the staff of KSU Biosecurity Research Institute; the histological laboratory at the Kansas State Veterinary Diagnostic Laboratory (KSVDL); members of the Histology and Immunohistochemistry sections at the Louisiana Animal Disease Diagnostic Laboratory (LADDL); the CMG staff; and Bianca Artiaga, Dashzeveg Bold, Konner Cool, Emily Gilbert-Esparza, Chester McDowell, and Yonghai Li. We thank the teams at the Icahn School of Medicine at Mount Sinai, the Genomics and Mouse facilities, and Alan Soto from the Biorepository and Pathology Dean's CoRE. We thank Cindy Beharry, Nanyi Julia Zhao, Nancy Francoeur, Nataly Fishman, Marion Dejosez, Thomas Zwaka, and Carles Martinez-Romero for their help and advice. Luis Martinez (Texas Biomedical Research Institute) and the Center for Therapeutic Antibody Development (CTAD) (Thomas Moran, Andy Duty, and Thomas Kraus) kindly provided the NP1C7C7 antibody.This work was partially supported through grants from NBAF Transition Funds and the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) under contract number HHSN 272201400006C to A.G.-S.; the Department of Homeland Security Center of Excellence for Emerging and Zoonotic Animal Diseases under grant HSHQDC-16-A-B0006 to J.A.R.; CRIP (Center for Research for Influenza Pathogenesis CEIRS, contract HHSN272201400008C); supplements to NIAID grant U19AI135972 and DOD grant W81XWH-20-1-0270; the Defense Advanced Research Projects Agency (HR0011-19-2-0020); and the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 [5384]), and anonymous donors. S.Y. received funding from a Swiss National Foundation (SNF) Early Postdoc.Mobility fellowship (P2GEP3_184202). This work was partially supported by funding to I. Marazzi. specifically the Burroughs Wellcome Fund (United States; 1017892), the Chan Zuckerberg Initiative (United States; 2018-191895), the Hirschl Young Investigator fellowship, and NIH grants U01AI150748 and R01AI143840. Partial support by the AMP Core of the Center of Emerging and Zoonotic Infectious Diseases of the National Institutes of Health under award number P20GM130448 to J.R. Conceptualization, I. Marazzi; investigation: J.S.Y.H. B.W.-Y.M. L.C. T.J. S.Y. S.P. J.A.W. N.N.G. D.A.M. S.V.I. I. Morozov, J.D.T. Y.S.F. R.R. Z.Z. S.Z. N.Z. B.S.M. H.R.-.J. V.M. M.J.T. S.-Y.L. S.J. A.E. H.L. A.J.Z. A.C.-Y.L. W.-C.L. T.A. A.M. R.A.A. M. Schotsaert, and S.H.; genomics analyses (epigenetics): S.P. J.A.W. E.R.M. and M.T.W.; genomics analyses (chromatin structure), S.H. and C.B.; GSEA, J.A.W. and E.R.M.; data analyses (others), J.S.Y.H. Y.S.F. H.R.-J. V.M. and M. Spivakov; in vivo study and veterinarian analysis, J.S.Y.H. B.W.Y.M. L.C. S.Y. H.L. A.J.Z. A.C.-Y.L. H.C. N.N.G. D.A.M. S.V.I. I. Morozov, J.D.T. J.A.R. M.C. and U.B.R.B.; histology and medical consultation, E.S. D.K. A.M. J.B. and A.D.J.; writing ? original draft, I. Marazzi; resources, K.W. M.J.T. R.S. A.G.-S. B.R.T. and S.K.C.; writing ? review & editing, J.S.Y.H. Z.Z. E.G. E.S. D.A.K. M.B. E.R.M. A.G.-S. M.T.W. S.H. C.B. J.A.R. and I. Marazzi; funding acquisition, A.G.-S. H.C. C.B. J.A.R. I. Marazzi; project administration, I. Marazzi; supervision, I. Marazzi. The Garc?a-Sastre Laboratory has received research support from Pfizer, Senhwa Biosciences, 7 Hills Pharma, Pharmamar, Blade Therapuetics, Avimex, Johnson & Johnson, Dynavax, Kenall Manufacturing, and ImmunityBio. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7 Hills Pharma, Avimex, Vaxalto, Accurius, and Esperovax. M.J.T. is an employee of Enhanc3D Genomics. M. Spivakov is a co-founder of Enhanc3D Genomics. I. Marazzi is an inventor in the patent WO2017106466A1 Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = may,

day = "13",

doi = "10.1016/j.cell.2021.03.051",

language = "English",

volume = "184",

pages = "2618--2632.e17",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "10",

}

Ho, JSY, Mok, BWY, Campisi, L, Jordan, T, Yildiz, S, Parameswaran, S, Wayman, JA, Gaudreault, NN, Meekins, DA, Indran, SV, Morozov, I, Trujillo, JD, Fstkchyan, YS, Rathnasinghe, R, Zhu, Z, Zheng, S, Zhao, N, White, K, Ray-Jones, H, Malysheva, V, Thiecke, MJ, Lau, SY, Liu, H, Zhang, AJ, Lee, ACY, Liu, WC, Jangra, S, Escalera, A, Aydillo, T, Melo, BS, Guccione, E , Sebra, R, Shum, E, Bakker, J, Kaufman, DA, Moreira, AL, Carossino, M, Balasuriya, UBR, Byun, M, Albrecht, RA , Schotsaert, M , Garcia-Sastre, A, Chanda, SK, Miraldi, ER, Jeyasekharan, AD, TenOever, BR, Spivakov, M, Weirauch, MT, Heinz, S, Chen, H, Benner, C, Richt, JA & Marazzi, I 2021, 'TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation', Cell, vol. 184, no. 10, pp. 2618-2632.e17. https://doi.org/10.1016/j.cell.2021.03.051

TY - JOUR

T1 - TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

AU - Ho, Jessica Sook Yuin

AU - Mok, Bobo Wing Yee

AU - Campisi, Laura

AU - Jordan, Tristan

AU - Yildiz, Soner

AU - Parameswaran, Sreeja

AU - Wayman, Joseph A.

AU - Gaudreault, Natasha N.

AU - Meekins, David A.

AU - Indran, Sabarish V.

AU - Morozov, Igor

AU - Trujillo, Jessie D.

AU - Fstkchyan, Yesai S.

AU - Rathnasinghe, Raveen

AU - Zhu, Zeyu

AU - Zheng, Simin

AU - Zhao, Nan

AU - White, Kris

AU - Ray-Jones, Helen

AU - Malysheva, Valeriya

AU - Thiecke, Michiel J.

AU - Lau, Siu Ying

AU - Liu, Honglian

AU - Zhang, Anna Junxia

AU - Lee, Andrew Chak Yiu

AU - Liu, Wen Chun

AU - Jangra, Sonia

AU - Escalera, Alba

AU - Aydillo, Teresa

AU - Melo, Betsaida Salom

AU - Guccione, Ernesto

AU - Sebra, Robert

AU - Shum, Elaine

AU - Bakker, Jan

AU - Kaufman, David A.

AU - Moreira, Andre L.

AU - Carossino, Mariano

AU - Balasuriya, Udeni B.R.

AU - Byun, Minji

AU - Albrecht, Randy A.

AU - Schotsaert, Michael

AU - Garcia-Sastre, Adolfo

AU - Chanda, Sumit K.

AU - Miraldi, Emily R.

AU - Jeyasekharan, Anand D.

AU - TenOever, Benjamin R.

AU - Spivakov, Mikhail

AU - Weirauch, Matthew T.

AU - Heinz, Sven

AU - Chen, Honglin

AU - Benner, Christopher

AU - Richt, Juergen A.

AU - Marazzi, Ivan

N1 - Funding Information: We thank the staff of KSU Biosecurity Research Institute; the histological laboratory at the Kansas State Veterinary Diagnostic Laboratory (KSVDL); members of the Histology and Immunohistochemistry sections at the Louisiana Animal Disease Diagnostic Laboratory (LADDL); the CMG staff; and Bianca Artiaga, Dashzeveg Bold, Konner Cool, Emily Gilbert-Esparza, Chester McDowell, and Yonghai Li. We thank the teams at the Icahn School of Medicine at Mount Sinai, the Genomics and Mouse facilities, and Alan Soto from the Biorepository and Pathology Dean’s CoRE. We thank Cindy Beharry, Nanyi Julia Zhao, Nancy Francoeur, Nataly Fishman, Marion Dejosez, Thomas Zwaka, and Carles Martinez-Romero for their help and advice. Luis Martinez (Texas Biomedical Research Institute) and the Center for Therapeutic Antibody Development (CTAD) (Thomas Moran, Andy Duty, and Thomas Kraus) kindly provided the NP1C7C7 antibody.This work was partially supported through grants from NBAF Transition Funds and the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) under contract number HHSN 272201400006C to A.G.-S.; the Department of Homeland Security Center of Excellence for Emerging and Zoonotic Animal Diseases under grant HSHQDC-16-A-B0006 to J.A.R.; CRIP (Center for Research for Influenza Pathogenesis CEIRS, contract HHSN272201400008C ); supplements to NIAID grant U19AI135972 and DOD grant W81XWH-20-1-0270 ; the Defense Advanced Research Projects Agency ( HR0011-19-2-0020 ); and the JPB Foundation , the Open Philanthropy Project (research grant 2020-215611 [5384] ), and anonymous donors. S.Y. received funding from a Swiss National Foundation (SNF) Early Postdoc.Mobility fellowship ( P2GEP3_184202 ). This work was partially supported by funding to I. Marazzi., specifically the Burroughs Wellcome Fund (United States; 1017892 ), the Chan Zuckerberg Initiative (United States; 2018-191895 ), the Hirschl Young Investigator fellowship, and NIH grants U01AI150748 and R01AI143840 . Partial support by the AMP Core of the Center of Emerging and Zoonotic Infectious Diseases of the National Institutes of Health under award number P20GM130448 to J.R. Funding Information: We thank the staff of KSU Biosecurity Research Institute; the histological laboratory at the Kansas State Veterinary Diagnostic Laboratory (KSVDL); members of the Histology and Immunohistochemistry sections at the Louisiana Animal Disease Diagnostic Laboratory (LADDL); the CMG staff; and Bianca Artiaga, Dashzeveg Bold, Konner Cool, Emily Gilbert-Esparza, Chester McDowell, and Yonghai Li. We thank the teams at the Icahn School of Medicine at Mount Sinai, the Genomics and Mouse facilities, and Alan Soto from the Biorepository and Pathology Dean's CoRE. We thank Cindy Beharry, Nanyi Julia Zhao, Nancy Francoeur, Nataly Fishman, Marion Dejosez, Thomas Zwaka, and Carles Martinez-Romero for their help and advice. Luis Martinez (Texas Biomedical Research Institute) and the Center for Therapeutic Antibody Development (CTAD) (Thomas Moran, Andy Duty, and Thomas Kraus) kindly provided the NP1C7C7 antibody.This work was partially supported through grants from NBAF Transition Funds and the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) under contract number HHSN 272201400006C to A.G.-S.; the Department of Homeland Security Center of Excellence for Emerging and Zoonotic Animal Diseases under grant HSHQDC-16-A-B0006 to J.A.R.; CRIP (Center for Research for Influenza Pathogenesis CEIRS, contract HHSN272201400008C); supplements to NIAID grant U19AI135972 and DOD grant W81XWH-20-1-0270; the Defense Advanced Research Projects Agency (HR0011-19-2-0020); and the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 [5384]), and anonymous donors. S.Y. received funding from a Swiss National Foundation (SNF) Early Postdoc.Mobility fellowship (P2GEP3_184202). This work was partially supported by funding to I. Marazzi. specifically the Burroughs Wellcome Fund (United States; 1017892), the Chan Zuckerberg Initiative (United States; 2018-191895), the Hirschl Young Investigator fellowship, and NIH grants U01AI150748 and R01AI143840. Partial support by the AMP Core of the Center of Emerging and Zoonotic Infectious Diseases of the National Institutes of Health under award number P20GM130448 to J.R. Conceptualization, I. Marazzi; investigation: J.S.Y.H. B.W.-Y.M. L.C. T.J. S.Y. S.P. J.A.W. N.N.G. D.A.M. S.V.I. I. Morozov, J.D.T. Y.S.F. R.R. Z.Z. S.Z. N.Z. B.S.M. H.R.-.J. V.M. M.J.T. S.-Y.L. S.J. A.E. H.L. A.J.Z. A.C.-Y.L. W.-C.L. T.A. A.M. R.A.A. M. Schotsaert, and S.H.; genomics analyses (epigenetics): S.P. J.A.W. E.R.M. and M.T.W.; genomics analyses (chromatin structure), S.H. and C.B.; GSEA, J.A.W. and E.R.M.; data analyses (others), J.S.Y.H. Y.S.F. H.R.-J. V.M. and M. Spivakov; in vivo study and veterinarian analysis, J.S.Y.H. B.W.Y.M. L.C. S.Y. H.L. A.J.Z. A.C.-Y.L. H.C. N.N.G. D.A.M. S.V.I. I. Morozov, J.D.T. J.A.R. M.C. and U.B.R.B.; histology and medical consultation, E.S. D.K. A.M. J.B. and A.D.J.; writing ? original draft, I. Marazzi; resources, K.W. M.J.T. R.S. A.G.-S. B.R.T. and S.K.C.; writing ? review & editing, J.S.Y.H. Z.Z. E.G. E.S. D.A.K. M.B. E.R.M. A.G.-S. M.T.W. S.H. C.B. J.A.R. and I. Marazzi; funding acquisition, A.G.-S. H.C. C.B. J.A.R. I. Marazzi; project administration, I. Marazzi; supervision, I. Marazzi. The Garc?a-Sastre Laboratory has received research support from Pfizer, Senhwa Biosciences, 7 Hills Pharma, Pharmamar, Blade Therapuetics, Avimex, Johnson & Johnson, Dynavax, Kenall Manufacturing, and ImmunityBio. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7 Hills Pharma, Avimex, Vaxalto, Accurius, and Esperovax. M.J.T. is an employee of Enhanc3D Genomics. M. Spivakov is a co-founder of Enhanc3D Genomics. I. Marazzi is an inventor in the patent WO2017106466A1 Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/5/13

Y1 - 2021/5/13

N2 - The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

AB - The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

KW - COVID-19

KW - SARS-CoV-2

KW - chromatin

KW - cytokine storm

KW - epigenetics

KW - inducible genes

KW - inflammation

KW - topoisomerase

KW - topotecan

KW - transcription

UR - http://www.scopus.com/inward/record.url?scp=85103985781&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.03.051

DO - 10.1016/j.cell.2021.03.051

M3 - Article

C2 - 33836156

AN - SCOPUS:85103985781

SN - 0092-8674

VL - 184

SP - 2618-2632.e17

JO - Cell

JF - Cell

IS - 10

ER -

TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

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