Dexamethasone inhibits respiratory syncytial virus-driven mucus production while increasing viral replication without altering antiviral interferon signaling

Virology. 2020 Jan 15;540:195-206. doi: 10.1016/j.virol.2019.10.007. Epub 2019 Oct 23.

Abstract

Respiratory syncytial virus (RSV) infection can cause mucus overproduction and bronchiolitis in infants leading to severe disease and hospitalization. As a therapeutic strategy, immune modulatory agents may help prevent RSV-driven immune responses that cause severe airway disease. We developed a high throughput screen to identify compounds that reduced RSV-driven mucin 5AC (Muc5AC) expression and identified dexamethasone. Despite leading to a pronounced reduction in RSV-driven Muc5AC, dexamethasone increased RSV infection in vitro and delayed viral clearance in mice. This correlated with reduced expression of a subset of immune response genes and reduced lymphocyte infiltration in vivo. Interestingly, dexamethasone increased RSV infection levels without altering antiviral interferon signaling. In summary, the immunosuppressive activities of dexamethasone had favorable inhibitory effects on RSV-driven mucus production yet prevented immune defense activities that limit RSV infection in vitro and in vivo. These findings offer an explanation for the lack of efficacy of glucocorticoids in RSV-infected patients.

Keywords: Dexamethasone; Glucocorticoid; Interferon; Muc5AC; Mucus; RSV; Respiratory syncytial virus.

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / metabolism
  • Dexamethasone / pharmacology*
  • Gene Regulatory Networks
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate
  • Interferons / metabolism*
  • Mice
  • Mucin 5AC / genetics
  • Mucin 5AC / metabolism
  • Mucus / metabolism*
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / virology
  • Respiratory Syncytial Virus Infections / genetics
  • Respiratory Syncytial Virus Infections / metabolism*
  • Respiratory Syncytial Virus Infections / virology*
  • Respiratory Syncytial Virus, Human / drug effects*
  • Signal Transduction / drug effects*
  • Virus Replication / drug effects*

Substances

  • Cytokines
  • MUC5AC protein, human
  • Mucin 5AC
  • Dexamethasone
  • Interferons