Beneficial effect of combinational methylprednisolone and remdesivir in hamster model of SARS-CoV-2 infection

Emerg Microbes Infect. 2021 Dec;10(1):291-304. doi: 10.1080/22221751.2021.1885998.

Abstract

Effective treatments for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Dexamethasone has been shown to confer survival benefits to certain groups of hospitalized patients, but whether glucocorticoids such as dexamethasone and methylprednisolone should be used together with antivirals to prevent a boost of SARS-CoV-2 replication remains to be determined. Here, we show the beneficial effect of methylprednisolone alone and in combination with remdesivir in the hamster model of SARS-CoV-2 infection. Treatment with methylprednisolone boosted RNA replication of SARS-CoV-2 but suppressed viral induction of proinflammatory cytokines in human monocyte-derived macrophages. Although methylprednisolone monotherapy alleviated body weight loss as well as nasal and pulmonary inflammation, viral loads increased and antibody response against the receptor-binding domain of spike protein attenuated. In contrast, a combination of methylprednisolone with remdesivir not only prevented body weight loss and inflammation, but also dampened viral protein expression and viral loads. In addition, the suppressive effect of methylprednisolone on antibody response was alleviated in the presence of remdesivir. Thus, combinational anti-inflammatory and antiviral therapy might be an effective, safer and more versatile treatment option for COVID-19. These data support testing of the efficacy of a combination of methylprednisolone and remdesivir for the treatment of COVID-19 in randomized controlled clinical trials.

Keywords: COVID-19; SARS-CoV-2; combination therapy; corticosteroid; remdesivir.

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives*
  • Adenosine Monophosphate / pharmacology
  • Adenosine Monophosphate / therapeutic use
  • Alanine / analogs & derivatives*
  • Alanine / pharmacology
  • Alanine / therapeutic use
  • Animals
  • Antibodies, Viral / blood
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • COVID-19 / drug therapy*
  • COVID-19 / pathology
  • COVID-19 / virology
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Female
  • Humans
  • Macrophages / immunology
  • Macrophages / virology
  • Male
  • Mesocricetus
  • Methylprednisolone / pharmacology
  • Methylprednisolone / therapeutic use*
  • RNA, Viral
  • Respiratory System / pathology
  • Respiratory System / virology
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / physiology
  • Spike Glycoprotein, Coronavirus / immunology
  • Viral Load / drug effects
  • Virus Replication / drug effects

Substances

  • Antibodies, Viral
  • Antiviral Agents
  • Cytokines
  • RNA, Viral
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • remdesivir
  • Adenosine Monophosphate
  • Alanine
  • Methylprednisolone

Supplementary concepts

  • COVID-19 drug treatment

Grant support

The work was supported by grants COVID190121 and COVID190144 from Health and Medical Research Fund of Hong Kong, grants T11-707/15-R, C5012-15E and C7142-20GF from Research Grants Council, University Grants Committee of Hong Kong, as well as grants 2020YFA0707500 and 2020YFA0707504 from the National Key Research and Development Program of China. J.F.-W.C and K.-Y.Y. were also supported by the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance of the Department of Health of Hong Kong, grant SZSM201911014 from the Sanming Project of Medicine in Shenzhen, the High Level-Hospital Program of the Health Commission of Guangdong, and donations from Richard Yu and Carol Yu, the Shaw Foundation of Hong Kong, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Hui Ming, Hui Hoy, Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, Lee Wan Keung Charity Foundation Ltd, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, the Jessie & George Ho Charitable Foundation, Perfect Shape Medical Limited, Kai Chong Tong, Kam Ming Laurence Tse, Betty Hing-Chu Lee, Ping Cham So, Foo Oi Foundation Limited, and Lo Ying Shek Chi Wai Foundation.