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• W3136303338 abstract "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. 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. Influenza virus infections have caused several pandemics and pose a constant threat to humans (1Medina R.A. Garcia-Sastre A. Influenza A viruses: New research developments.Nat. Rev. Microbiol. 2011; 9: 590-603Crossref PubMed Scopus (420) Google Scholar, 2Taubenberger J.K. Morens D.M. The pathology of influenza virus infections.Annu. Rev. Pathol. 2008; 3: 499-522Crossref PubMed Scopus (706) Google Scholar, 3Krammer F. Smith G.J.D. Fouchier R.A.M. Peiris M. Kedzierska K. Doherty P.C. Palese P. Shaw M.L. Treanor J. Webster R.G. Garcia-Sastre A. Influenza.Nat. Rev. Dis. Primers. 2018; 4: 3Crossref PubMed Scopus (419) Google Scholar). Influenza A virus (IAV) infects primarily respiratory epithelial cells and causes pulmonary pathology; if uncontrolled, this infection leads to the loss of lung function and mortality (1Medina R.A. Garcia-Sastre A. Influenza A viruses: New research developments.Nat. Rev. Microbiol. 2011; 9: 590-603Crossref PubMed Scopus (420) Google Scholar, 2Taubenberger J.K. Morens D.M. The pathology of influenza virus infections.Annu. Rev. Pathol. 2008; 3: 499-522Crossref PubMed Scopus (706) Google Scholar, 4Sanders C.J. Vogel P. McClaren J.L. Bajracharya R. Doherty P.C. Thomas P.G. Compromised respiratory function in lethal influenza infection is characterized by the depletion of type I alveolar epithelial cells beyond threshold levels.Am. J. Physiol. Lung Cell. Mol. Physiol. 2013; 304: L481-L488Crossref PubMed Scopus (49) Google Scholar). IAV infection is sensed by innate immune receptors that activate type I interferons (IFNs) and proinflammatory responses (5Iwasaki A. Pillai P.S. Innate immunity to influenza virus infection.Nat. Rev. Immunol. 2014; 14: 315-328Crossref PubMed Scopus (586) Google Scholar). These responses are critical for controlling viral titers and spread in the lung and also to induce long-lasting adaptive immune responses (5Iwasaki A. Pillai P.S. Innate immunity to influenza virus infection.Nat. Rev. Immunol. 2014; 14: 315-328Crossref PubMed Scopus (586) Google Scholar, 6Lupfer C. Malik A. Kanneganti T.D. Inflammasome control of viral infection.Curr. Opin. Virol. 2015; 12: 38-46Crossref PubMed Scopus (99) Google Scholar). Acute activation of innate immune responses against IAV facilitates the recruitment of inflammatory immune cells including neutrophils and monocytes, which further establish the inflammatory milieu to clear virus-infected and dead cells to subsequently initiate lung tissue repair responses (5Iwasaki A. Pillai P.S. Innate immunity to influenza virus infection.Nat. Rev. Immunol. 2014; 14: 315-328Crossref PubMed Scopus (586) Google Scholar, 6Lupfer C. Malik A. Kanneganti T.D. Inflammasome control of viral infection.Curr. Opin. Virol. 2015; 12: 38-46Crossref PubMed Scopus (99) Google Scholar). However, excessive innate immune activation, inflammatory cytokine secretion, and immune cell recruitment have been implicated in the morbidity and mortality of the 1918 influenza pandemic and also in recent highly pathogenic avian influenza (H5N1) infections (2Taubenberger J.K. Morens D.M. The pathology of influenza virus infections.Annu. Rev. Pathol. 2008; 3: 499-522Crossref PubMed Scopus (706) Google Scholar, 7Gambotto A. Barratt-Boyes S.M. de Jong M.D. Neumann G. Kawaoka Y. Human infection with highly pathogenic H5N1 influenza virus.Lancet. 2008; 371: 1464-1475Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 8Kash J.C. Tumpey T.M. Proll S.C. Carter V. Perwitasari O. Thomas M.J. Basler C.F. Palese P. Taubenberger J.K. Garcia-Sastre A. Swayne D.E. Katze M.G. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus.Nature. 2006; 443: 578-581Crossref PubMed Scopus (457) Google Scholar, 9Brandes M. Klauschen F. Kuchen S. Germain R.N. A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection.Cell. 2013; 154: 197-212Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 10Kobasa D. Jones S.M. Shinya K. Kash J.C. Copps J. Ebihara H. Hatta Y. Kim J.H. Halfmann P. Hatta M. Feldmann F. Alimonti J.B. Fernando L. Li Y. Katze M.G. et al.Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus.Nature. 2007; 445: 319-323Crossref PubMed Scopus (766) Google Scholar). These observations indicate that robust but balanced activation of the innate immune response against IAV is crucial for host protective defense, whereas aggressive induction of these responses may compromise host lung function and ultimately lead to mortality. Thus, understanding the fundamental mechanisms orchestrating innate immune responses during IAV infection is critical to target IAV-induced pathogenesis and develop effective antiviral approaches. Type I IFNs are primarily induced by sensing of viral RNAs by innate immune receptors, including retinoic acid–inducible gene I (RIG-I) and Toll-like receptors (TLRs), to exert host-induced antiviral activities (5Iwasaki A. Pillai P.S. Innate immunity to influenza virus infection.Nat. Rev. Immunol. 2014; 14: 315-328Crossref PubMed Scopus (586) Google Scholar, 11Garcia-Sastre A. Ten strategies of interferon evasion by viruses.Cell Host Microbe. 2017; 22: 176-184Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). In addition, activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome in IAV-infected host cells promotes recruitment of monocytes and neutrophils to the site of infection, facilitates clearance of virus-infected cells, and drives lung tissue repair responses (6Lupfer C. Malik A. Kanneganti T.D. Inflammasome control of viral infection.Curr. Opin. Virol. 2015; 12: 38-46Crossref PubMed Scopus (99) Google Scholar, 12Ichinohe T. Lee H.K. Ogura Y. Flavell R. Iwasaki A. Inflammasome recognition of influenza virus is essential for adaptive immune responses.J. Exp. Med. 2009; 206: 79-87Crossref PubMed Scopus (531) Google Scholar, 13Kanneganti T.D. Body-Malapel M. Amer A. Park J.H. Whitfield J. Franchi L. Taraporewala Z.F. Miller D. Patton J.T. Inohara N. Nunez G. Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.J. Biol. Chem. 2006; 281: 36560-36568Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 14Thomas P.G. Dash P. Aldridge Jr., J.R. Ellebedy A.H. Reynolds C. Funk A.J. Martin W.J. Lamkanfi M. Webby R.J. Boyd K.L. Doherty P.C. Kanneganti T.D. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.Immunity. 2009; 30: 566-575Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 15Allen I.C. Scull M.A. Moore C.B. Holl E.K. McElvania-TeKippe E. Taxman D.J. Guthrie E.H. Pickles R.J. Ting J.P. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA.Immunity. 2009; 30: 556-565Abstract Full Text Full Text PDF PubMed Scopus (809) Google Scholar, 16Kesavardhana S. Malireddi R.K.S. Kanneganti T.D. Caspases in cell death, inflammation, and gasdermin-induced pyroptosis.Annu. Rev. Immunol. 2020; https://doi.org/10.1146/annurev-immunol-073119-095439Crossref PubMed Scopus (152) Google Scholar). Type I IFNs and inflammasome-dependent leaderless proinflammatory cytokines are the primary innate immune mediators which dominate acute host responses against IAV infection (5Iwasaki A. Pillai P.S. Innate immunity to influenza virus infection.Nat. Rev. Immunol. 2014; 14: 315-328Crossref PubMed Scopus (586) Google Scholar, 6Lupfer C. Malik A. Kanneganti T.D. Inflammasome control of viral infection.Curr. Opin. Virol. 2015; 12: 38-46Crossref PubMed Scopus (99) Google Scholar, 8Kash J.C. Tumpey T.M. Proll S.C. Carter V. Perwitasari O. Thomas M.J. Basler C.F. Palese P. Taubenberger J.K. Garcia-Sastre A. Swayne D.E. Katze M.G. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus.Nature. 2006; 443: 578-581Crossref PubMed Scopus (457) Google Scholar, 10Kobasa D. Jones S.M. Shinya K. Kash J.C. Copps J. Ebihara H. Hatta Y. Kim J.H. Halfmann P. Hatta M. Feldmann F. Alimonti J.B. Fernando L. Li Y. Katze M.G. et al.Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus.Nature. 2007; 445: 319-323Crossref PubMed Scopus (766) Google Scholar, 11Garcia-Sastre A. Ten strategies of interferon evasion by viruses.Cell Host Microbe. 2017; 22: 176-184Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Type I IFNs and the NLRP3 inflammasome responses are also key for activating adaptive immune responses, which play an essential role in controlling viral titers in later stages of infection and also subsequent IAV infections (6Lupfer C. Malik A. Kanneganti T.D. Inflammasome control of viral infection.Curr. Opin. Virol. 2015; 12: 38-46Crossref PubMed Scopus (99) Google Scholar, 12Ichinohe T. Lee H.K. Ogura Y. Flavell R. Iwasaki A. Inflammasome recognition of influenza virus is essential for adaptive immune responses.J. Exp. Med. 2009; 206: 79-87Crossref PubMed Scopus (531) Google Scholar, 13Kanneganti T.D. Body-Malapel M. Amer A. Park J.H. Whitfield J. Franchi L. Taraporewala Z.F. Miller D. Patton J.T. Inohara N. Nunez G. Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.J. Biol. Chem. 2006; 281: 36560-36568Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 14Thomas P.G. Dash P. Aldridge Jr., J.R. Ellebedy A.H. Reynolds C. Funk A.J. Martin W.J. Lamkanfi M. Webby R.J. Boyd K.L. Doherty P.C. Kanneganti T.D. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.Immunity. 2009; 30: 566-575Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 17Oslund K.L. Baumgarth N. Influenza-induced innate immunity: Regulators of viral replication, respiratory tract pathology & adaptive immunity.Future Virol. 2011; 6: 951-962Crossref PubMed Scopus (59) Google Scholar). Host defense is also mediated by ribonucleoprotein aggregates called stress granules (SGs) during IAV infection, which are formed in the absence of the IAV nonstructural protein 1 (NS1) (18Thulasi Raman S.N. Liu G. Pyo H.M. Cui Y.C. Xu F. Ayalew L.E. Tikoo S.K. Zhou Y. DDX3 interacts with influenza A virus NS1 and NP proteins and exerts antiviral function through regulation of stress granule formation.J. Virol. 2016; 90: 3661-3675Crossref PubMed Scopus (46) Google Scholar). The antiviral activity of SGs is predominantly achieved through the restriction of translation or viral protein synthesis (19Khaperskyy D.A. Hatchette T.F. McCormick C. Influenza A virus inhibits cytoplasmic stress granule formation.FASEB J. 2012; 26: 1629-1639Crossref PubMed Scopus (97) Google Scholar, 20Tsai W.C. Lloyd R.E. Cytoplasmic RNA granules and viral infection.Annu. Rev. Virol. 2014; 1: 147-170Crossref PubMed Scopus (60) Google Scholar, 21Khaperskyy D.A. Emara M.M. Johnston B.P. Anderson P. Hatchette T.F. McCormick C. Influenza a virus host shutoff disables antiviral stress-induced translation arrest.PLoS Pathog. 2014; 10e1004217Crossref PubMed Scopus (88) Google Scholar). Although type I IFNs, SGs, and the NLRP3 inflammasome are required for host defense responses during viral infections, the mechanisms regulating coordination of these responses to ultimately exert protection during IAV infection are not clear. IAV has also evolved to use immune evasion strategies to neutralize protective host defense mechanisms (11Garcia-Sastre A. Ten strategies of interferon evasion by viruses.Cell Host Microbe. 2017; 22: 176-184Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 22Hale B.G. Albrecht R.A. Garcia-Sastre A. Innate immune evasion strategies of influenza viruses.Future Microbiol. 2010; 5: 23-41Crossref PubMed Scopus (118) Google Scholar). NS1 of IAV antagonizes host defense mechanisms by interfering with type I IFN signaling and also disrupting formation of antiviral SGs (11Garcia-Sastre A. Ten strategies of interferon evasion by viruses.Cell Host Microbe. 2017; 22: 176-184Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 22Hale B.G. Albrecht R.A. Garcia-Sastre A. Innate immune evasion strategies of influenza viruses.Future Microbiol. 2010; 5: 23-41Crossref PubMed Scopus (118) Google Scholar, 23Wang X. Li M. Zheng H. Muster T. Palese P. Beg A.A. Garcia-Sastre A. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon.J. Virol. 2000; 74: 11566-11573Crossref PubMed Scopus (460) Google Scholar, 24Gack M.U. Albrecht R.A. Urano T. Inn K.S. Huang I.C. Carnero E. Farzan M. Inoue S. Jung J.U. Garcia-Sastre A. Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I.Cell Host Microbe. 2009; 5: 439-449Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar). The NS1-mediated host immune evasion suppresses antiviral defense mechanisms, which enables efficient replication of IAV (11Garcia-Sastre A. Ten strategies of interferon evasion by viruses.Cell Host Microbe. 2017; 22: 176-184Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 22Hale B.G. Albrecht R.A. Garcia-Sastre A. Innate immune evasion strategies of influenza viruses.Future Microbiol. 2010; 5: 23-41Crossref PubMed Scopus (118) Google Scholar). NS1 is also implicated in regulating NLRP3 inflammasome activation, suggesting this protein has adapted to control a variety of innate immune activation mechanisms (25Nogales A. Martinez-Sobrido L. Topham D.J. DeDiego M.L. Modulation of innate immune responses by the influenza A NS1 and PA-X proteins.Viruses. 2018; 10: 708Crossref Scopus (48) Google Scholar). It is possible that the IAV-mediated immune evasion strategies might have exerted selective pressure on the host immune system during virus–host interactions. This counter adaptation of host defense mechanisms may help fight viral immune evasion. However, the complex relationship between antiviral activities and their functional regulation in the presence of IAV-mediated immune evasion are not clear. Here, we found a critical role for the host protein DEAD-box helicase 3 X-linked (DDX3X) in regulating a complex network of host defense responses by activating the NLRP3 inflammasome, formation of SGs, and type I IFNs during IAV infection. The IAV-induced SGs inhibited activation and assembly of the NLRP3 inflammasome. DDX3X performed two mutually exclusive functions, driving IAV-induced activation of the NLRP3 inflammasome or inducing the formation of SGs, and this function was dependent on the presence of the immune-evasive NS1 protein. Lack of DDX3X expression led to severe pathology and IAV spread in the lung, compromising survival in infected mice. Thus, DDX3X is a central regulator of host defense responses against IAV infection and perhaps evolved to counteract IAV immune evasions strategies. The NLRP3 inflammasome plays a critical role in limiting IAV infection-induced lung pathology in mice (14Thomas P.G. Dash P. Aldridge Jr., J.R. Ellebedy A.H. Reynolds C. Funk A.J. Martin W.J. Lamkanfi M. Webby R.J. Boyd K.L. Doherty P.C. Kanneganti T.D. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.Immunity. 2009; 30: 566-575Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 15Allen I.C. Scull M.A. Moore C.B. Holl E.K. McElvania-TeKippe E. Taxman D.J. Guthrie E.H. Pickles R.J. Ting J.P. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA.Immunity. 2009; 30: 556-565Abstract Full Text Full Text PDF PubMed Scopus (809) Google Scholar). Host recognition of the RNA genome of IAV is important for mounting activation of both the type I IFN response and the NLRP3 inflammasome (5Iwasaki A. Pillai P.S. Innate immunity to influenza virus infection.Nat. Rev. Immunol. 2014; 14: 315-328Crossref PubMed Scopus (586) Google Scholar, 11Garcia-Sastre A. Ten strategies of interferon evasion by viruses.Cell Host Microbe. 2017; 22: 176-184Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 13Kanneganti T.D. Body-Malapel M. Amer A. Park J.H. Whitfield J. Franchi L. Taraporewala Z.F. Miller D. Patton J.T. Inohara N. Nunez G. Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.J. Biol. Chem. 2006; 281: 36560-36568Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 14Thomas P.G. Dash P. Aldridge Jr., J.R. Ellebedy A.H. Reynolds C. Funk A.J. Martin W.J. Lamkanfi M. Webby R.J. Boyd K.L. Doherty P.C. Kanneganti T.D. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.Immunity. 2009; 30: 566-575Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar). The IAV NS1 protein inhibits the type I IFN response to evade the host innate immune response and enable IAV replication and spread (22Hale B.G. Albrecht R.A. Garcia-Sastre A. Innate immune evasion strategies of influenza viruses.Future Microbiol. 2010; 5: 23-41Crossref PubMed Scopus (118) Google Scholar, 25Nogales A. Martinez-Sobrido L. Topham D.J. DeDiego M.L. Modulation of innate immune responses by the influenza A NS1 and PA-X proteins.Viruses. 2018; 10: 708Crossref Scopus (48) Google Scholar). In the absence of NS1, IAV infection leads to a stronger type I IFN response, but the NLRP3 inflammasome is not activated. The molecular mechanism underlying the interplay between these two host antiviral responses to counteract immune evasion by IAV remains poorly understood. To address this knowledge gap, we examined how IAV infection modulated the host innate immune response in the presence and absence of NS1. First, we infected primary bone marrow–derived macrophages (BMDMs) from WT and Nlrp3−/− mice with IAV/A/WSN/33/H1N1 (called IAV henceforth) and its NS1 deletion mutant (called IAV–ΔNS1 henceforth) (26Zheng M. Wang P. Song W. Lau S.Y. Liu S. Huang X. Mok B.W. Liu Y.C. Chen Y. Yuen K.Y. Chen H. An A14U substitution in the 3' noncoding region of the M segment of viral RNA supports replication of influenza virus with an NS1 deletion by modulating alternative splicing of M segment mRNAs.J. Virol. 2015; 89: 10273-10285Crossref PubMed Scopus (15) Google Scholar). Immunoblotting for NS1 protein confirmed the lack of NS1 in IAV–ΔNS1–infected BMDMs, and levels of viral nucleoprotein (NP) indicated a reduced replication or infection rate after IAV–ΔNS1 infection compared with WT IAV infection (Fig. 1A). The reduced replication rate of IAV–ΔNS1 is in line with observations from the study describing the generation of the IAV–ΔNS1 strain, which also reported a reduced replication rate (26Zheng M. Wang P. Song W. Lau S.Y. Liu S. Huang X. Mok B.W. Liu Y.C. Chen Y. Yuen K.Y. Chen H. An A14U substitution in the 3' noncoding region of the M segment of viral RNA supports replication of influenza virus with an NS1 deletion by modulating alternative splicing of M segment mRNAs.J. Virol. 2015; 89: 10273-10285Crossref PubMed Scopus (15) Google Scholar). We then assessed the effect of the ΔNS1 mutation on immune activation. IAV infection in BMDMs induced cleavage of caspase-1 (CASP1), which is a measure of IAV-induced NLRP3 inflammasome activation. This cleavage was observed in WT BMDMs but not in Nlrp3−/− BMDMs, suggesting activation of the NLRP3 inflammasome specifically (Fig. 1A). IAV–ΔNS1 infection, however, did not lead to CASP1 activation in WT BMDMs, suggesting that the lack of NS1 protein in IAV abolished activation of the NLRP3 inflammasome (Fig. 1A). Release of NLRP3 inflammasome-dependent proinflammatory cytokines, interleukin (IL)-1β and IL-18, was also significantly reduced in IAV–ΔNS1–infected WT BMDMs compared with IAV-infected cells (Fig. 1B). This further indicates that the deletion of NS1 results in a loss of NLRP3 inflammasome activation in BMDMs. The protein expression levels of inflammasome components (NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain [ASC]) were comparable in BMDMs infected with IAV and IAV–ΔNS1, suggesting that reduced NLRP3 activation in IAV–ΔNS1–infected BMDMs was not due to defects in priming of the inflammasome (Fig. 1C). To further investigate the role of priming in the reduced NLRP3 activation in response to IAV–ΔNS1, we infected BMDMs with IAV–ΔNS1 and then stimulated the BMDMs with TLR ligands (Pam3Csk4 or poly(I:C)) or IFN-β. None of these stimulations rescued NLRP3 inflammasome activation in IAV–ΔNS1–infected cells (Fig. S1A), which further suggests that inhibition of NLRP3 activation by IAV–ΔNS1 was not due to defects in the priming of inflammasome activation. Finally, we used IAV infection as the priming signal followed by ATP or nigericin treatment for NLRP3 inflammasome activation to test the effect of NS1 loss (Fig. S1, B and C). We observed decreased CASP1 cleavage in IAV–ΔNS1–infected BMDMs, suggesting that loss of NS1 was inhibiting the NLRP3 inflammasome even with canonical triggers. In addition, the IAV NS1 protein is a robust type I IFN antagonist (22Hale B.G. Albrecht R.A. Garcia-Sastre A. Innate immune evasion strategies of influenza viruses.Future Microbiol. 2010; 5: 23-41Crossref PubMed Scopus (118) Google Scholar). IAV–ΔNS1 infection in BMDMs induced elevated IFN-β secretion compared with that induced by IAV, further confirming the role of NS1 in restricting type I IFN responses (Fig. 1B). These results indicate that the expression of NS1 promotes both IAV replication and NLRP3 inflammasome activation and inhibits the type I IFN response. SGs are membraneless cytoplasmic aggregates of RNA–protein complexes which arrest translation and also carry out other cellular functions during stress conditions (20Tsai W.C. Lloyd R.E. Cytoplasmic RNA granules and viral infection.Annu. Rev. Virol. 2014; 1: 147-170Crossref PubMed Scopus (60) Google Scholar, 27Protter D.S.W. Parker R. Principles and properties of stress granules.Trends Cell Biol. 2016; 26: 668-679Abstract Full Text Full Text PDF PubMed Scopus (666) Google Scholar). SGs play an important role in virus–host interactions by driving antiviral responses or promoting viral replication in some cases (20Tsai W.C. Lloyd R.E. Cytoplasmic RNA granules and viral infection.Annu. Rev. Virol. 2014; 1: 147-170Crossref PubMed Scopus (60) Google Scholar, 28Onomoto K. Yoneyama M. Fung G. Kato H. Fujita T. Antiviral innate immunity and stress granule responses.Trends Immunol. 2014; 35: 420-428Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). IAV infection efficiently inhibits formation of SGs via its NS1 protein to promote translation of viral mRNAs (19Khaperskyy D.A. Hatchette T.F. McCormick C. Influenza A virus inhibits cytoplasmic stress granule formation.FASEB J. 2012; 26: 1629-1639Crossref PubMed Scopus (97) Google Scholar, 20Tsai W.C. Lloyd R.E. Cytoplasmic RNA granules and viral infection.Annu. Rev. Virol. 2014; 1: 147-170Crossref PubMed Scopus (60) Google Scholar, 21Khaperskyy D.A. Emara M.M. Johnston B.P. Anderson P. Hatchette T.F. McCormick C. Influenza a virus host shutoff disables antiviral stress-induced translation arrest.PLoS Pathog. 2014; 10e1004217Crossref PubMed Scopus (88) Google Scholar). Specifically, the IAV NS1 protein inhibits dsRNA binding by protein kinase R and further phosphorylation of eIF2α (P-eIF2α), which are essential for SG assembly (20Tsai W.C. Lloyd R.E. Cytoplasmic RNA granules and viral infection.Annu. Rev. Virol. 2014; 1: 147-170Crossref PubMed Scopus (60) Google Scholar). We observed increased amounts of P-eIF2α and robust induction of SGs in BMDMs infected with IAV–ΔNS1 compared with WT IAV infection (Fig. 1, C and D). In addition, the dramatic increase in NP expression observed with WT IAV from 6 to 9 h after infection was much less notable with IAV–ΔNS1, suggesting that in addition to the replication defect of this virus, SGs were also exerting antiviral effects (Fig. 1C). Phosphorylation of signal transducer and activator of transcription 1 (STAT1), which is a measure of its activation by type I IFN signaling, was also increased in BMDMs infected with IAV–ΔNS1 compared with WT IAV, suggesting NS1 plays a role in restricting both SGs and type I IFN responses (Fig. 1C). However, in spite of high IFN-β levels, there was reduced NLRP3 inflammasome activation in cells infected with IAV–ΔNS1 (Fig. 1, A and B). Previous studies have reported both inhibition and promotion of NLRP3 inflammasome activation mediated by type I IFN signaling (5Iwasaki A. Pillai P.S. Innate immunity to influenza virus infection.Nat. Rev. Immunol. 2014; 14: 315-328Crossref PubMed Scopus (586) Google Scholar, 29Kuriakose T. Man S.M. Malireddi R.K. Karki R. Kesavardhana S. Place D.E. Neale G. Vogel P. Kanneganti T.D. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways.Sci. Immunol. 2016; 1aag2045Crossref PubMed Scopus (274) Google Scholar, 30Pothlichet J. Meunier I. Davis B.K. Ting J.P. Skamene E. von Messling V. Vidal S.M. Type I IFN triggers RIG-I/TLR3/NLRP3-dependent inflammasome activation in influenza A virus infected cells.PLoS Pathog. 2013; 9e1003256Crossref PubMed Scopus (167) Google Scholar, 31Kesavardhana S. Kuriakose T. Guy C.S. Samir P. Malireddi R.K.S. Mishra A. Kanneganti T.D. ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death.J. Exp. Med. 2017; 214: 2217-2229Crossref PubMed Scopus (83) Google Scholar, 32Guarda G. Braun M. Staehli F. Tardivel A. Mattmann C. Förster I. Farlik M. Decker T. Du Pasquier R.A. Romero P. Tschopp J. Type I interferon inhibits interleukin-1 production and inflammasome activation.Immunity. 2011; 34: 213-223Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar). To test whether the reduced NLRP3 inflammasome activation was due to the increased production of IFN-β that occurs after IAV–ΔNS1 infection, we analyzed the effect of IFN-β supplementation on NLRP3 inflammasome activation in response to IAV infection. Exogenous IFN-β supplementation enhanced NLRP3 inflammasome activation in" @default.
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• W3136303338 title "DDX3X coordinates host defense against influenza virus by activating the NLRP3 inflammasome and type I interferon response" @default.
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