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Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer

Pro-inflammatory cytokinemia is a hallmark of highly pathogenic H5N1 influenza virus (IAV) disease yet little is known about the role of host proteins in modulating a pathogenic innate immune response. The host Interferon Induced Protein 35 (Ifi35) has been implicated in increased susceptibility to...

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Autores principales: Gounder, Anshu P., Yokoyama, Christine C., Jarjour, Nicholas N., Bricker, Traci L., Edelson, Brian T., Boon, Adrianus C. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940246/
https://www.ncbi.nlm.nih.gov/pubmed/29698474
http://dx.doi.org/10.1371/journal.ppat.1007001
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author Gounder, Anshu P.
Yokoyama, Christine C.
Jarjour, Nicholas N.
Bricker, Traci L.
Edelson, Brian T.
Boon, Adrianus C. M.
author_facet Gounder, Anshu P.
Yokoyama, Christine C.
Jarjour, Nicholas N.
Bricker, Traci L.
Edelson, Brian T.
Boon, Adrianus C. M.
author_sort Gounder, Anshu P.
collection PubMed
description Pro-inflammatory cytokinemia is a hallmark of highly pathogenic H5N1 influenza virus (IAV) disease yet little is known about the role of host proteins in modulating a pathogenic innate immune response. The host Interferon Induced Protein 35 (Ifi35) has been implicated in increased susceptibility to H5N1-IAV infection. Here, we show that Ifi35 deficiency leads to reduced morbidity in mouse models of highly pathogenic H5N1- and pandemic H1N1-IAV infection. Reduced weight loss in Ifi35(-/-) mice following H5N1-IAV challenge was associated with reduced cellular infiltration and decreased production of specific cytokines and chemokines including IL-12p40. Expression of Ifi35 by the hematopoietic cell compartment in bone-marrow chimeric mice contributed to increased immune cell recruitment and IL-12p40 production. In addition, Ifi35 deficient primary macrophages produce less IL-12p40 following TLR-3, TLR-4, and TLR-7 stimulation in vitro. Decreased levels of IL-12p40 and its homodimer, IL-12p80, were found in bronchoalveolar lavage fluid of H5N1-IAV infected Ifi35 deficient mice. Specific antibody blockade of IL-12p80 ameliorated weight loss and reduced cellular infiltration following H5N1-IAV infection in wild-type mice; suggesting that increased levels of IL-12p80 alters the immune response to promote inflammation and IAV disease. These data establish a role for Ifi35 in modulating cytokine production and exacerbating inflammation during IAV infection.
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spelling pubmed-59402462018-05-18 Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer Gounder, Anshu P. Yokoyama, Christine C. Jarjour, Nicholas N. Bricker, Traci L. Edelson, Brian T. Boon, Adrianus C. M. PLoS Pathog Research Article Pro-inflammatory cytokinemia is a hallmark of highly pathogenic H5N1 influenza virus (IAV) disease yet little is known about the role of host proteins in modulating a pathogenic innate immune response. The host Interferon Induced Protein 35 (Ifi35) has been implicated in increased susceptibility to H5N1-IAV infection. Here, we show that Ifi35 deficiency leads to reduced morbidity in mouse models of highly pathogenic H5N1- and pandemic H1N1-IAV infection. Reduced weight loss in Ifi35(-/-) mice following H5N1-IAV challenge was associated with reduced cellular infiltration and decreased production of specific cytokines and chemokines including IL-12p40. Expression of Ifi35 by the hematopoietic cell compartment in bone-marrow chimeric mice contributed to increased immune cell recruitment and IL-12p40 production. In addition, Ifi35 deficient primary macrophages produce less IL-12p40 following TLR-3, TLR-4, and TLR-7 stimulation in vitro. Decreased levels of IL-12p40 and its homodimer, IL-12p80, were found in bronchoalveolar lavage fluid of H5N1-IAV infected Ifi35 deficient mice. Specific antibody blockade of IL-12p80 ameliorated weight loss and reduced cellular infiltration following H5N1-IAV infection in wild-type mice; suggesting that increased levels of IL-12p80 alters the immune response to promote inflammation and IAV disease. These data establish a role for Ifi35 in modulating cytokine production and exacerbating inflammation during IAV infection. Public Library of Science 2018-04-26 /pmc/articles/PMC5940246/ /pubmed/29698474 http://dx.doi.org/10.1371/journal.ppat.1007001 Text en © 2018 Gounder et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Gounder, Anshu P.
Yokoyama, Christine C.
Jarjour, Nicholas N.
Bricker, Traci L.
Edelson, Brian T.
Boon, Adrianus C. M.
Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer
title Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer
title_full Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer
title_fullStr Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer
title_full_unstemmed Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer
title_short Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer
title_sort interferon induced protein 35 exacerbates h5n1 influenza disease through the expression of il-12p40 homodimer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940246/
https://www.ncbi.nlm.nih.gov/pubmed/29698474
http://dx.doi.org/10.1371/journal.ppat.1007001
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