Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: The role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza

Geiss, Gary; Salvatore, Mirella; Tumpey, Terrence M.; Carter, Victoria S.; Wang, Xiuyan; Basler, Christopher F.; Taubenberger, Jeffery K.; Bumgarner, Roger E.; Palese, Peter; Katze, Michael G.; Garcı́a-Sastre, Adolfo

doi:10.1073/pnas.112338099

Cited by 326 publications

(276 citation statements)

References 38 publications

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“…It is perplexing that inhibition of virus replication within immune cells leads to such drastic defects in overall IFN-I production, given that IAV replication predominates in lung epithelia, where virus fitness is not altered. This finding may reflect a bias in the ability of IAV to subvert the innate sensing and production of IFN-I through NS1 at the site of replication (52). In this regard, the elevated expression of RLRs and antiviral signaling components in APCs may better equip these cells for the recognition of invading pathogens and provide the necessary redundancy to ensure induction of IFN-I (53, 54).…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Langlois¹,

Varble²,

Chua³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A coordinated innate and adaptive immune response, orchestrated by antigen presenting cells (APCs), is required for effective clearance of influenza A virus (IAV). Although IAV primarily infects epithelial cells of the upper respiratory tract, APCs are also susceptible. To determine if virus transcription in these cells is required to generate protective innate and adaptive immune responses, we engineered IAV to be selectively attenuated in cells of hematopoietic origin. Incorporation of hematopoietic-specific miR-142 target sites into the nucleoprotein of IAV effectively silenced virus transcription in APCs, but had no significant impact in lung epithelial cells. Here we demonstrate that inhibiting IAV replication in APCs in vivo did not alter clearance, or the generation of IAV-specific CD8 T cells, suggesting that cross-presentation is sufficient for cytotoxic T lymphocyte activation. In contrast, loss of in vivo virus infection, selectively in APCs, resulted in a significant reduction of retinoic acid-inducible gene I-dependent type I IFN (IFN-I). These data implicate the formation of virus replication intermediates in APCs as the predominant trigger of IFN-I in vivo. Taking these data together, this research describes a unique platform to study the host response to IAV and provides insights into the mechanism of antigen presentation and the induction of IFN-I.

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Section: Discussionmentioning

confidence: 99%

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Langlois¹,

Varble²,

Chua³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…1). The high virulence and pathogenesis of strains such as the H5N1 high pathogenic avian influenza (HPAI) and 1918 H1N1 viruses has been shown to be caused by the specific sequence of viral proteins (2,3) including the external surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA) (4-7), the three internal polymerase proteins (5,6,8,9), and the two nonstructural proteins PB1-F2 (10) and NS1 (11).…”

mentioning

confidence: 99%

A new influenza virus virulence determinant: The NS1 protein four C-terminal residues modulate pathogenicity

Jackson

Hossain

Hickman

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

365

306

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The virulence of influenza virus is a multigenic trait. One determinant of virulence is the multifunctional NS1 protein that functions in several ways to defeat the cellular innate immune response. Recent large-scale genome sequence analysis of avian influenza virus isolates indicated that four C-terminal residues of the NS1 protein is a PDZ ligand domain of the X-S/T-X-V type and it was speculated that it may represent a virulence determinant. To test this hypothesis, by using mice as a model system, the four Cterminal amino acid residues of a number of influenza virus strains were engineered into the

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“…Indeed, no recombinant IAV of any origin has been appraised so far for PDA treatment, and the relative small number of previous investigations concerning the use of IAV for virotherapy were focused on the human strain H1N1 A/Puerto Rico/8/34 (Bergmann et al, 2001;Muster et al, 2004;Sturlan et al, 2010;Wolschek et al, 2011). Importantly, the choice of a particular viral isolate is likely to affect its efficacy as an OV because IAVs differ in their ability to counteract host IFN response (Geiss et al, 2002;Hayman et al, 2006;Kochs et al, 2007), induce apoptosis (Kasloff et al, 2014) and in their sensitivity to host ISGs (Dittmann et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

“…The greater impact of NS1 truncation on the ability of the H7N3 virus to control IFN induction implies that this NS1 protein relies on its C-terminal ED to post-transcriptionally limit processing of host pre-mRNAs (Geiss et al, 2002;Hayman et al, 2006;Kochs et al, 2007), whereas the NS1 protein of H1N1 PR8 virus does not due to amino acid substitutions that block its interaction with the cleavage and polyadenylation specificity factor 30 (CPSF30) (Kochs et al, 2007;Steidle et al, 2010). To monitor the expression of a gene transcribed by host-cell machinery, 293T cells were transfected with pCAGGSLuc plasmid, which directs polymerase II mediated expression of firefly luciferase.…”

Section: Resultsmentioning

confidence: 99%

An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

Pizzuto

Silic-Benussi

Ciminale

et al. 2016

Journal of General Virology

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Pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer-related deaths worldwide and the development of new treatment strategies for PDA patients is of crucial importance. Virotherapy uses natural or engineered oncolytic viruses (OVs) to selectively kill tumour cells. Due to their genetic heterogeneity, PDA cells are highly variable in their permissiveness to various OVs. The avian influenza A virus (IAV) H7N3 A/turkey/Italy/2962/03 is a potent inducer of apoptosis in PDA cells previously shown to be resistant to other OVs (Kasloff et al., 2014), suggesting that it might be effective against specific subclasses of pancreatic cancer. To improve the selectivity of the avian influenza isolate for PDA cells, here confirmed deficient for IFN response, we engineered a truncation in the NS1 gene that is the major virusencoded IFN antagonist. The recombinant virus (NS1-77) replicated efficiently in PDA cells, but was attenuated in non-malignant pancreatic ductal cells, in which it induced a potent IFN response that acted upon bystander uninfected cancer cells, triggering their death. The engineered virus displayed an enhanced ability to debulk a PDA-derived tumour in xenograft mouse model. Our results highlight the possibility of selecting an IAV strain from the diverse natural avian reservoir on the basis of its inherent oncolytic potency in specific PDA subclasses and, through engineering, improve its safety, selectivity and debulking activity for cancer treatment.

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Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: The role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza

Cited by 326 publications

References 38 publications

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

A new influenza virus virulence determinant: The NS1 protein four C-terminal residues modulate pathogenicity

An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

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