IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes

Rudragouda Channappanavar, Anthony R. Fehr, Jian Zheng, Christine Wohlford-Lenane, Juan E. Abrahante, Matthias Mack, Ramakrishna Sompallae, Paul B. McCray, David K. Meyerholz, Stanley Perlman

Research output: Contribution to journalArticle

Abstract

Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication, increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs, and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.

Original languageEnglish (US)
JournalThe Journal of clinical investigation
Volume130
DOIs
StatePublished - Jul 29 2019

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Coronavirus Infections
Virology
Virus Replication
Innate Immunity
Communicable Diseases
Monocytes
Virus Diseases
Infection
Cytokines
Neutrophil Activation
Macrophage Activation
Neutrophil Infiltration
Viral Load
Pneumonia
Vaccines
Viruses
T-Lymphocytes
Gene Expression
Lung
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. / Channappanavar, Rudragouda; Fehr, Anthony R.; Zheng, Jian; Wohlford-Lenane, Christine; Abrahante, Juan E.; Mack, Matthias; Sompallae, Ramakrishna; McCray, Paul B.; Meyerholz, David K.; Perlman, Stanley.

In: The Journal of clinical investigation, Vol. 130, 29.07.2019.

Research output: Contribution to journalArticle

Channappanavar, R, Fehr, AR, Zheng, J, Wohlford-Lenane, C, Abrahante, JE, Mack, M, Sompallae, R, McCray, PB, Meyerholz, DK & Perlman, S 2019, 'IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes', The Journal of clinical investigation, vol. 130. https://doi.org/10.1172/JCI126363
Channappanavar, Rudragouda ; Fehr, Anthony R. ; Zheng, Jian ; Wohlford-Lenane, Christine ; Abrahante, Juan E. ; Mack, Matthias ; Sompallae, Ramakrishna ; McCray, Paul B. ; Meyerholz, David K. ; Perlman, Stanley. / IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. In: The Journal of clinical investigation. 2019 ; Vol. 130.
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