Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes
Rudragouda Channappanavar, … , David K. Meyerholz, Stanley Perlman
Rudragouda Channappanavar, … , David K. Meyerholz, Stanley Perlman
Published July 29, 2019
Citation Information: J Clin Invest. 2019;129(9):3625-3639. https://doi.org/10.1172/JCI126363.
View: Text | PDF
Research Article Infectious disease Virology

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

  • Text
  • PDF
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.

Authors

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

×

Figure 1

IFN-I signaling is protective during MERS-CoV infection.

Options: View larger image (or click on image) Download as PowerPoint
IFN-I signaling is protective during MERS-CoV infection.
(A) Percentage ...
(A) Percentage of initial weight and survival of control- and α-IFNAR–treated mice after i.n. infection with 1 × 105 PFU MERS-CoV-EMC. (B) MERS-CoV-EMC titers in the lungs determined by plaque assay at 2 and 5 dpi. (C–E) Percentage of initial weight and survival of control and α-IFNAR–treated mice after i.n. infection with 500 PFU (C) or 200–250 PFU (D, female mice; E, male mice) MERS-CoV-MA. (F and G) MERS-CoV titers as determined by plaque assays (F) and gRNA levels (G) in the lungs of control and α-IFNAR–treated mice infected with 200 to 250 PFU MERS-CoV-MA. (H) MERS-CoV-MA titers in the indicated organs at 4 dpi as determined by plaque assay. (I) Representative H&E staining of lungs collected from naive (top panel) and MERS-CoV-MA–challenged mice at 7 dpi, demonstrating lung edema and neutrophil infiltration (middle panels) and cellular proliferation (bottom panels). Original magnification, ×4 and ×20. Arrows point to neutrophils; arrowheads show cell proliferation; asterisk indicates edema. (J) Summary scores for cellular proliferation and neutrophil distribution. Data are representative of 2 independent experiments (A–C, and G–I) or were pooled from 2 independent experiments (D–F and J) (n = 3 to 5 mice/group). *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 (B, F–H, and J), by 2-tailed Student’s t test. Statistical significance for survival studies (A and C–E) was calculated using a log-rank (Mantel-Cox) test with a 95% CI and a P value of less than 0.05 considered significant.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts