IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes.
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Auteurs : Rudragouda Channappanavar [États-Unis] ; Anthony R. Fehr [États-Unis] ; Jian Zheng [États-Unis] ; Christine Wohlford-Lenane [États-Unis] ; Juan E. Abrahante [États-Unis] ; Matthias Mack [Allemagne] ; Ramakrishna Sompallae [États-Unis] ; Paul B. Mccray [États-Unis] ; David K. Meyerholz [États-Unis] ; Stanley Perlman [États-Unis]Source :
- The Journal of clinical investigation [ 1558-8238 ] ; 2019.
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.
DOI: 10.1172/JCI126363
PubMed: 31355779
Affiliations:
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Abrahante</name><affiliation wicri:level="2"><nlm:affiliation>University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, Minnesota, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, Minnesota</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Mack, Matthias" sort="Mack, Matthias" uniqKey="Mack M" first="Matthias" last="Mack">Matthias Mack</name><affiliation wicri:level="1"><nlm:affiliation>Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Internal Medicine, University Hospital Regensburg, Regensburg</wicri:regionArea><wicri:noRegion>Regensburg</wicri:noRegion><wicri:noRegion>Regensburg</wicri:noRegion><wicri:noRegion>Regensburg</wicri:noRegion></affiliation></author><author><name sortKey="Sompallae, Ramakrishna" sort="Sompallae, Ramakrishna" uniqKey="Sompallae R" first="Ramakrishna" last="Sompallae">Ramakrishna Sompallae</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, University of Iowa, Iowa City, Iowa, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of Iowa, Iowa City, Iowa</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Mccray, Paul B" sort="Mccray, Paul B" uniqKey="Mccray P" first="Paul B" last="Mccray">Paul B. Mccray</name><affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Meyerholz, David K" sort="Meyerholz, David K" uniqKey="Meyerholz D" first="David K" last="Meyerholz">David K. Meyerholz</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, University of Iowa, Iowa City, Iowa, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of Iowa, Iowa City, Iowa</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author></analytic><series><title level="j">The Journal of clinical investigation</title><idno type="eISSN">1558-8238</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>États-Unis</li></country><region><li>Iowa</li><li>Minnesota</li></region><settlement><li>Iowa City</li></settlement><orgName><li>Université de l'Iowa</li></orgName></list><tree><country name="États-Unis"><region name="Iowa"><name sortKey="Channappanavar, Rudragouda" sort="Channappanavar, Rudragouda" uniqKey="Channappanavar R" first="Rudragouda" last="Channappanavar">Rudragouda Channappanavar</name></region><name sortKey="Abrahante, Juan E" sort="Abrahante, Juan E" uniqKey="Abrahante J" first="Juan E" last="Abrahante">Juan E. Abrahante</name><name sortKey="Fehr, Anthony R" sort="Fehr, Anthony R" uniqKey="Fehr A" first="Anthony R" last="Fehr">Anthony R. Fehr</name><name sortKey="Mccray, Paul B" sort="Mccray, Paul B" uniqKey="Mccray P" first="Paul B" last="Mccray">Paul B. Mccray</name><name sortKey="Meyerholz, David K" sort="Meyerholz, David K" uniqKey="Meyerholz D" first="David K" last="Meyerholz">David K. Meyerholz</name><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><name sortKey="Sompallae, Ramakrishna" sort="Sompallae, Ramakrishna" uniqKey="Sompallae R" first="Ramakrishna" last="Sompallae">Ramakrishna Sompallae</name><name sortKey="Wohlford Lenane, Christine" sort="Wohlford Lenane, Christine" uniqKey="Wohlford Lenane C" first="Christine" last="Wohlford-Lenane">Christine Wohlford-Lenane</name><name sortKey="Zheng, Jian" sort="Zheng, Jian" uniqKey="Zheng J" first="Jian" last="Zheng">Jian Zheng</name></country><country name="Allemagne"><noRegion><name sortKey="Mack, Matthias" sort="Mack, Matthias" uniqKey="Mack M" first="Matthias" last="Mack">Matthias Mack</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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