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 September 3, 2019; First 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

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 6

Delayed IFN treatment promotes inflammation and mortality in MERS-CoV-MA–infected mice.

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Delayed IFN treatment promotes inflammation and mortality in MERS-CoV-MA...
(A) Schematic of the experimental plan to examine the effect of delayed rIFN-β treatment. (B) Percentage of initial weight and survival of MERS-CoV-MA–infected hDPP4-KI mice treated with PBS or rIFN-β at 2 or 4 dpi. (C) MERS-CoV titers in the lungs at 3, 5, and 7 dpi in mice treated with PBS or rIFN-β (2 dpi, delayed treatment). (D and E) mRNA levels of ISGs and inflammatory cytokines and chemokines in the lungs of PBS- or rIFN-β–treated (2 dpi, delayed treatment) mice. (F and H) Frequency and number of IMMs and neutrophils in the lungs of PBS- or rIFN-β–treated mice (2 dpi). (G and I) Percentage of CD80-expressing and total number of TNF+ IMMs and neutrophils at 5 dpi in PBS- and rIFN-β–treated mice (2 dpi). (J) Percentage of initial weight and survival of MERS-CoV-MA–infected (200 PFU) hDPP4-KI mice treated with rIFN-β (2 dpi) and either α-CCR2 antibody or a control antibody (2 dpi and 4 dpi). Data were pooled from 2 separate experiments (B and F–H, left panels, I, left panel, and J) or are representative of 2 separate experiments (E, G, and I, right 2 panels) (n = 3–5 mice/group/experiment). Data were analyzed using a 2-tailed Student’s t test with *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001. Statistical significance for survival studies (B, right) was calculated using the log-rank (Mantel-Cox) test, with a 95% CI and a P value of less than 0.05 considered significant.