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DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response
Viruses and hosts have coevolved for millions of years, leading to the development of complex host–pathogen interactions. Influenza A virus (IAV) causes severe pulmonary pathology and is a recurrent threat to human health. Innate immune sensing of IAV triggers a complex chain of host responses. IAV...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081917/ https://www.ncbi.nlm.nih.gov/pubmed/33766561 http://dx.doi.org/10.1016/j.jbc.2021.100579 |
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author | Kesavardhana, Sannula Samir, Parimal Zheng, Min Malireddi, R.K. Subbarao Karki, Rajendra Sharma, Bhesh Raj Place, David E. Briard, Benoit Vogel, Peter Kanneganti, Thirumala-Devi |
author_facet | Kesavardhana, Sannula Samir, Parimal Zheng, Min Malireddi, R.K. Subbarao Karki, Rajendra Sharma, Bhesh Raj Place, David E. Briard, Benoit Vogel, Peter Kanneganti, Thirumala-Devi |
author_sort | Kesavardhana, Sannula |
collection | PubMed |
description | Viruses and hosts have coevolved for millions of years, leading to the development of complex host–pathogen interactions. Influenza A virus (IAV) causes severe pulmonary pathology and is a recurrent threat to human health. Innate immune sensing of IAV triggers a complex chain of host responses. IAV has adapted to evade host defense mechanisms, and the host has coevolved to counteract these evasion strategies. However, the molecular mechanisms governing the balance between host defense and viral immune evasion is poorly understood. Here, we show that the host protein DEAD-box helicase 3 X-linked (DDX3X) is critical to orchestrate a multifaceted antiviral innate response during IAV infection, coordinating the activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, assembly of stress granules, and type I interferon (IFN) responses. DDX3X activated the NLRP3 inflammasome in response to WT IAV, which carries the immune evasive nonstructural protein 1 (NS1). However, in the absence of NS1, DDX3X promoted the formation of stress granules that facilitated efficient activation of type I IFN signaling. Moreover, induction of DDX3X-containing stress granules by external stimuli after IAV infection led to increased type I IFN signaling, suggesting that NS1 actively inhibits stress granule–mediated host responses and DDX3X-mediated NLRP3 activation counteracts this action. Furthermore, the loss of DDX3X expression in myeloid cells caused severe pulmonary pathogenesis and morbidity in IAV-infected mice. Together, our findings show that DDX3X orchestrates alternate modes of innate host defense which are critical to fight against NS1-mediated immune evasion strategies during IAV infection. |
format | Online Article Text |
id | pubmed-8081917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-80819172021-05-06 DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response Kesavardhana, Sannula Samir, Parimal Zheng, Min Malireddi, R.K. Subbarao Karki, Rajendra Sharma, Bhesh Raj Place, David E. Briard, Benoit Vogel, Peter Kanneganti, Thirumala-Devi J Biol Chem Research Article Viruses and hosts have coevolved for millions of years, leading to the development of complex host–pathogen interactions. Influenza A virus (IAV) causes severe pulmonary pathology and is a recurrent threat to human health. Innate immune sensing of IAV triggers a complex chain of host responses. IAV has adapted to evade host defense mechanisms, and the host has coevolved to counteract these evasion strategies. However, the molecular mechanisms governing the balance between host defense and viral immune evasion is poorly understood. Here, we show that the host protein DEAD-box helicase 3 X-linked (DDX3X) is critical to orchestrate a multifaceted antiviral innate response during IAV infection, coordinating the activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, assembly of stress granules, and type I interferon (IFN) responses. DDX3X activated the NLRP3 inflammasome in response to WT IAV, which carries the immune evasive nonstructural protein 1 (NS1). However, in the absence of NS1, DDX3X promoted the formation of stress granules that facilitated efficient activation of type I IFN signaling. Moreover, induction of DDX3X-containing stress granules by external stimuli after IAV infection led to increased type I IFN signaling, suggesting that NS1 actively inhibits stress granule–mediated host responses and DDX3X-mediated NLRP3 activation counteracts this action. Furthermore, the loss of DDX3X expression in myeloid cells caused severe pulmonary pathogenesis and morbidity in IAV-infected mice. Together, our findings show that DDX3X orchestrates alternate modes of innate host defense which are critical to fight against NS1-mediated immune evasion strategies during IAV infection. American Society for Biochemistry and Molecular Biology 2021-03-23 /pmc/articles/PMC8081917/ /pubmed/33766561 http://dx.doi.org/10.1016/j.jbc.2021.100579 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Kesavardhana, Sannula Samir, Parimal Zheng, Min Malireddi, R.K. Subbarao Karki, Rajendra Sharma, Bhesh Raj Place, David E. Briard, Benoit Vogel, Peter Kanneganti, Thirumala-Devi DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response |
title | DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response |
title_full | DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response |
title_fullStr | DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response |
title_full_unstemmed | DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response |
title_short | DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response |
title_sort | ddx3x coordinates host defense against influenza virus by activating the nlrp3 inflammasome and type i interferon response |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081917/ https://www.ncbi.nlm.nih.gov/pubmed/33766561 http://dx.doi.org/10.1016/j.jbc.2021.100579 |
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