Journal article
IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes
The Journal of Clinical Investigation, Vol.129(9), pp.3625-3639
2019
DOI: 10.1172/JCI126363
PMCID: PMC6715373
PMID: 31355779
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.
Details
- Title: Subtitle
- IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes
- Creators
- Rudragouda Channappanavar - State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaAnthony R Fehr - State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaJian Zheng - University of Iowa, Microbiology and ImmunologyChristine Wohlford-Lenane - University of Iowa, Stead Family Department of PediatricsJuan E Abrahante - State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaMatthias Mack - State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaRamakrishna Sompallae - University of Iowa, PathologyPaul B McCray - University of Iowa, Internal MedicineDavid K Meyerholz - University of Iowa, PathologyStanley Perlman - University of Iowa, Stead Family Department of Pediatrics
- Resource Type
- Journal article
- Publication Details
- The Journal of Clinical Investigation, Vol.129(9), pp.3625-3639
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI126363
- PMID
- 31355779
- PMCID
- PMC6715373
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- PO1AI060699 / ;\r\nRO1AI129269 / ;\r\nR21AG060222 / ;
- Language
- English
- Date published
- 2019
- Academic Unit
- Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
- Record Identifier
- 9983782098902771
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