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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.
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Research Article Infectious disease Virology

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

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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

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Figure 4

IFNAR signaling on hematopoietic cells is essential for host protection from MERS-CoV-MA infection.

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IFNAR signaling on hematopoietic cells is essential for host protection ...
(A) Percentage of initial weight and survival of BM chimeric mice after MERS-CoV-MA challenge (500 PFU, i.n.). Data were pooled from 2 independent experiments with 3 to 5 mice/group/experiment. (B) MERS-CoV gRNA levels in lungs from BM chimeric mice at 2 and 6 dpi. (C and D) mRNA levels of IFNs and ISGs (C) and inflammatory cytokines and chemokines (D) in lungs from MERS-CoV–infected BM chimeric mice (hDPP4-KI hDPP4-KI and IFNAR–/– hDPP4-KI). (A) Weight loss and survival curves show pooled data from 2 independent experiments (n = 4 to 5 mice/group/experiment). Statistical significance for survival studies in A was calculated using the log-rank (Mantel-Cox) test with a 95% CI and a P value of less than 0.05 considered significant. (B–D) Graphs show pooled data from 2 independent experiments (n = 2–3 mice/group/experiment). *P ≤ 0.05 and **P ≤ 0.01, by 2-tailed Student’s t test.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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