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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.

SUBMITTER: Ho JSY

PROVIDER: S-EPMC8008343 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

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

Cell 20210330 10

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 indu ...[more]

PMID: 33836156

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide coronavirus disease 2019 (COVID-19) pandemic. Despite the high efficacy of the authorized vaccines, there may be uncertain and unknown side effects or disadvantages associated with current vaccination approaches. Live-attenuated vaccines (LAVs) have been shown to elicit robust and long-term protection by the induction of host innate and adaptive immune responses. In this study, we sought to verify an attenuation strategy by generating 3 double open reading frame (ORF)-deficient recombinant SARS-CoV-2s (rSARS-CoV-2s) simultaneously lacking two accessory ORF proteins (ORF3a/ORF6, ORF3a/ORF7a, and ORF3a/ORF7b). We report that these double ORF-deficient rSARS-CoV-2s have slower replication kinetics and reduced fitness in cultured cells compared with their parental wild-type (WT) counterpart. Importantly, these double ORF-deficient rSARS-CoV-2s showed attenuation in both K18 hACE2 transgenic mice and golden Syrian hamsters. A single intranasal dose vaccination induced high levels of neutralizing antibodies against SARS-CoV-2 and some variants of concern and activated viral component-specific T cell responses. Notably, double ORF-deficient rSARS-CoV-2s were able to protect, as determined by the inhibition of viral replication, shedding, and transmission, against challenge with SARS-CoV-2 in both K18 hACE2 mice and golden Syrian hamsters. Collectively, our results demonstrate the feasibility of implementing the double ORF-deficient strategy to develop safe, immunogenic, and protective LAVs to prevent SARS-CoV-2 infection and associated COVID-19. IMPORTANCE Live-attenuated vaccines (LAVs) are able to induce robust immune responses, including both humoral and cellular immunity, representing a very promising option to provide broad and long-term immunity. To develop LAVs for SARS-CoV-2, we engineered attenuated recombinant SARS-CoV-2 (rSARS-CoV-2) that simultaneously lacks the viral open reading frame 3a (ORF3a) in combination with either ORF6, ORF7a, or ORF7b (Δ3a/Δ6, Δ3a/Δ7a, and Δ3a/Δ7b, respectively) proteins. Among them, the rSARS-CoV-2 Δ3a/Δ7b was completely attenuated and able to provide 100% protection against an otherwise lethal challenge in K18 hACE2 transgenic mice. Moreover, the rSARS-CoV-2 Δ3a/Δ7b conferred protection against viral transmission between golden Syrian hamsters.

Dataset Information

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

Publications

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

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