scholarly journals Dual R108K and G189D Mutations in the NS1 Protein of A/H1N1 Influenza Virus Counteract Host Innate Immune Responses

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 905
Author(s):  
Meng-Ting Huang ◽  
Sen Zhang ◽  
Ya-Nan Wu ◽  
Wei Li ◽  
Yu-Chang Li ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Nonstructural Protein ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Innate Immune ◽  
Ns1 Protein ◽  
H1n1 Influenza Virus ◽  
Functional Sites ◽  
Nonstructural Protein 1

Influenza A viruses (IAV) modulate host antiviral responses to promote growth and pathogenicity. Here, we examined the multifunctional IAV nonstructural protein 1 (NS1) of influenza A virus to better understand factors that contribute to viral replication efficiency or pathogenicity. In 2009, a pandemic H1N1 IAV (A/California/07/2009 pH1N1) emerged in the human population from swine. Seasonal variants of this virus are still circulating in humans. Here, we compared the sequence of a seasonal variant of this H1N1 influenza virus (A/Urumqi/XJ49/2018(H1N1), first isolated in 2018) with the pandemic strain A/California/07/2009. The 2018 virus harbored amino acid mutations (I123V and N205S) in important functional sites; however, 108R and 189G were highly conserved between A/California/07/2009 and the 2018 variant. To better understand interactions between influenza viruses and the human innate immune system, we generated and rescued seasonal 2009 H1N1 IAV mutants expressing an NS1 protein harboring a dual mutation (R108K/G189D) at these conserved residues and then analyzed its biological characteristics. We found that the mutated NS1 protein exhibited systematic and selective inhibition of cytokine responses via a mechanism that may not involve binding to cleavage and polyadenylation specificity factor 30 (CPSF30). These results highlight the complexity underlying host–influenza NS1 protein interactions.

scholarly journals Contemporary Seasonal Influenza A (H1N1) Virus Infection Primes for a More Robust Response To Split Inactivated Pandemic Influenza A (H1N1) Virus Vaccination in Ferrets

2010 ◽  
Vol 17 (12) ◽  
pp. 1998-2006 ◽  
Author(s):  
Ali H. Ellebedy ◽  
Thomas P. Fabrizio ◽  
Ghazi Kayali ◽  
Thomas H. Oguin ◽  
Scott A. Brown ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Seasonal Influenza ◽  
H1n1 Virus ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Inactivated Vaccine ◽  
H1n1 Influenza Virus ◽  
Influenza A H1n1

ABSTRACT Human influenza pandemics occur when influenza viruses to which the population has little or no immunity emerge and acquire the ability to achieve human-to-human transmission. In April 2009, cases of a novel H1N1 influenza virus in children in the southwestern United States were reported. It was retrospectively shown that these cases represented the spread of this virus from an ongoing outbreak in Mexico. The emergence of the pandemic led to a number of national vaccination programs. Surprisingly, early human clinical trial data have shown that a single dose of nonadjuvanted pandemic influenza A (H1N1) 2009 monovalent inactivated vaccine (pMIV) has led to a seroprotective response in a majority of individuals, despite earlier studies showing a lack of cross-reactivity between seasonal and pandemic H1N1 viruses. Here we show that previous exposure to a contemporary seasonal H1N1 influenza virus and to a lesser degree a seasonal influenza virus trivalent inactivated vaccine is able to prime for a higher antibody response after a subsequent dose of pMIV in ferrets. The more protective response was partially dependent on the presence of CD8+ cells. Two doses of pMIV were also able to induce a detectable antibody response that provided protection from subsequent challenge. These data show that previous infection with seasonal H1N1 influenza viruses likely explains the requirement for only a single dose of pMIV in adults and that vaccination campaigns with the current pandemic influenza vaccines should reduce viral burden and disease severity in humans.

scholarly journals Molecular basis of mammalian transmissibility of avian H1N1 influenza viruses and their pandemic potential

2017 ◽  
Vol 114 (42) ◽  
pp. 11217-11222 ◽  
Author(s):  
Mark Zanin ◽  
Sook-San Wong ◽  
Subrata Barman ◽  
Challika Kaewborisuth ◽  
Peter Vogel ◽  
...  
Keyword(s):  
Genetic Markers ◽  
Nuclear Export ◽  
Influenza A ◽  
Nonstructural Protein ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Airborne Transmission ◽  
Nonstructural Protein 1

North American wild birds are an important reservoir of influenza A viruses, yet the potential of viruses in this reservoir to transmit and cause disease in mammals is not well understood. Our surveillance of avian influenza viruses (AIVs) at Delaware Bay, USA, revealed a group of similar H1N1 AIVs isolated in 2009, some of which were airborne-transmissible in the ferret model without prior adaptation. Comparison of the genomes of these viruses revealed genetic markers of airborne transmissibility in the Polymerase Basic 2 (PB2), PB1, PB1-F2, Polymerase Acidic-X (PA-X), Nonstructural Protein 1 (NS1), and Nuclear Export Protein (NEP) genes. We studied the role of NS1 in airborne transmission and found that NS1 mutants that were not airborne-transmissible caused limited tissue pathology in the upper respiratory tract (URT). Viral maturation was also delayed, evident as strong intranuclear staining and little virus at the mucosa. Our study of this naturally occurring constellation of genetic markers has provided insights into the poorly understood phenomenon of AIV airborne transmissibility by revealing a role for NS1 and characteristics of viral replication in the URT that were associated with airborne transmission. The transmissibility of these viruses further highlights the pandemic potential of AIVs in the wild bird reservoir and the need to maintain surveillance.

scholarly journals The RNA- and TRIM25-Binding Domains of Influenza Virus NS1 Protein Are Essential for Suppression of NLRP3 Inflammasome-Mediated Interleukin-1β Secretion

2016 ◽  
Vol 90 (8) ◽  
pp. 4105-4114 ◽  
Author(s):  
Miyu Moriyama ◽  
I-Yin Chen ◽  
Atsushi Kawaguchi ◽  
Takumi Koshiba ◽  
Kyosuke Nagata ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Rna Binding ◽  
Nonstructural Protein ◽  
Binding Domain ◽  
Interleukin 1Β ◽  
Ns1 Protein ◽  
Caspase 1 ◽  
Nonstructural Protein 1

ABSTRACTInflammasomes are cytosolic multimolecular protein complexes that stimulate the activation of caspase-1 and the release of mature forms of interleukin-1β (IL-1β) and IL-18. We previously demonstrated that the influenza A virus M2 protein stimulates IL-1β secretion following activation of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. The nonstructural protein 1 (NS1) of influenza virus inhibits caspase-1 activation and IL-1β secretion. However, the precise mechanism by which NS1 inhibits IL-1β secretion remains unknown. Here, we showed that J774A.1 macrophages stably expressing the NS1 protein inhibited IL-1β secretion after infection with recombinant influenza virus lacking the NS1 gene. Coimmunoprecipitation assay revealed that the NS1 protein interacts with NLRP3. Importantly, the NS1 protein inhibited the NLRP3/ASC-induced single-speck formation required for full activation of inflammasomes. The NS1 protein of other influenza virus strains, including a recent pandemic strain, also inhibited inflammasome-mediated IL-1β secretion. The NS1 RNA-binding domain (basic residues 38 and 41) and TRIM25-binding domain (acidic residues 96 and 97) were required for suppression of NLRP3 inflammasome-mediated IL-1β secretion. These results shed light on a mechanism by which the NS1 protein of influenza virus suppresses NLRP3 inflammasome-mediated IL-1β secretion.IMPORTANCEInnate immune sensing of influenza virus via pattern recognition receptors not only plays a key role in generating type I interferons but also triggers inflammatory responses. We previously demonstrated that the influenza A virus M2 protein activates the NLRP3 inflammasome, leading to the secretion of interleukin-1β (IL-1β) and IL-18 following the activation of caspase-1. Although the nonstructural protein 1 (NS1) of influenza virus inhibits IL-1β secretion, the precise mechanism by which it achieves this remains to be defined. Here, we demonstrate that the NS1 protein interacts with NLRP3 to suppress NLRP3 inflammasome activation. J774A.1 macrophages stably expressing the NS1 protein suppressed NLRP3-mediated IL-1β secretion. The NS1 RNA-binding domain (basic residues 38 and 41) and TRIM25-binding domain (acidic residues 96 and 97) are important for suppression of NLRP3 inflammasome-mediated IL-1β secretion. These results will facilitate the development of new anti-inflammatory drugs.

scholarly journals Mammalian Adaptation of an Avian Influenza A Virus Involves Stepwise Changes in NS1

2017 ◽  
Vol 92 (5) ◽  
Author(s):  
C. Chauché ◽  
A. Nogales ◽  
H. Zhu ◽  
D. Goldfarb ◽  
A. I. Ahmad Shanizza ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Immune Evasion ◽  
Influenza A ◽  
Nonstructural Protein ◽  
Ns1 Protein ◽  
Equine Influenza Virus ◽  
Influenza A Viruses ◽  
Equine Influenza ◽  
Nonstructural Protein 1 ◽  
Avian Origin

ABSTRACT Influenza A viruses (IAVs) are common pathogens of birds that occasionally establish endemic infections in mammals. The processes and mechanisms that result in IAV mammalian adaptation are poorly understood. The viral nonstructural 1 (NS1) protein counteracts the interferon (IFN) response, a central component of the host species barrier. We characterized the NS1 proteins of equine influenza virus (EIV), a mammalian IAV lineage of avian origin. We showed that evolutionarily distinct NS1 proteins counteract the IFN response using different and mutually exclusive mechanisms: while the NS1 proteins of early EIVs block general gene expression by binding to cellular polyadenylation-specific factor 30 (CPSF30), NS1 proteins from more evolved EIVs specifically block the induction of IFN-stimulated genes by interfering with the JAK/STAT pathway. These contrasting anti-IFN strategies are associated with two mutations that appeared sequentially and were rapidly selected for during EIV evolution, highlighting the importance of evolutionary processes in immune evasion mechanisms during IAV adaptation. IMPORTANCE Influenza A viruses (IAVs) infect certain avian reservoir species and occasionally transfer to and cause epidemics of infections in some mammalian hosts. However, the processes by which IAVs gain the ability to efficiently infect and transmit in mammals remain unclear. H3N8 equine influenza virus (EIV) is an avian-origin virus that successfully established a new lineage in horses in the early 1960s and is currently circulating worldwide in the equine population. Here, we analyzed the molecular evolution of the virulence factor nonstructural protein 1 (NS1) and show that NS1 proteins from different time periods after EIV emergence counteract the host innate immune response using contrasting strategies, which are associated with two mutations that appeared sequentially during EIV evolution. The results shown here indicate that the interplay between virus evolution and immune evasion plays a key role in IAV mammalian adaptation.

scholarly journals Activation of Phosphatidylinositol 3-Kinase Signaling by the Nonstructural NS1 Protein Is Not Conserved among Type A and B Influenza Viruses

2007 ◽  
Vol 81 (21) ◽  
pp. 12097-12100 ◽  
Author(s):  
Christina Ehrhardt ◽  
Thorsten Wolff ◽  
Stephan Ludwig
Keyword(s):  
Influenza A ◽  
Nonstructural Protein ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Influenza B ◽  
Ns1 Protein ◽  
Phosphatidylinositol 3 Kinase ◽  
Nonstructural Protein 1 ◽  
Pi3k Activation ◽  
Phosphatidylinositol 3

ABSTRACT Recently it has been shown by several laboratories that the influenza A virus nonstructural protein 1 (A/NS1) binds and activates phosphatidylinositol 3-kinase (PI3K). This function of the protein is likely to prevent premature apoptosis induction during viral propagation. Here we show that the B/NS1 protein completely lacks the capacity to induce PI3K signaling. Thus, PI3K activation is another unique function of A/NS1 that is different from the action of its influenza B virus counterpart.

scholarly journals Sequential Seasonal H1N1 Influenza Virus Infections Protect Ferrets against Novel 2009 H1N1 Influenza Virus

2012 ◽  
Vol 87 (3) ◽  
pp. 1400-1410 ◽  
Author(s):  
Donald M. Carter ◽  
Chalise E. Bloom ◽  
Eduardo J. M. Nascimento ◽  
Ernesto T. A. Marques ◽  
Jodi K. Craigo ◽  
...  
Keyword(s):  
Influenza Virus ◽  
H1n1 Influenza ◽  
Cross Reactivity ◽  
Influenza Viruses ◽  
The Novel ◽  
Virus Infections ◽  
H1n1 Influenza Virus ◽  
Virus Shedding ◽  
2009 H1n1 ◽  
Novel H1n1 Influenza

ABSTRACTIndividuals <60 years of age had the lowest incidence of infection, with ∼25% of these people having preexisting, cross-reactive antibodies to novel 2009 H1N1 influenza. Many people >60 years old also had preexisting antibodies to novel H1N1. These observations are puzzling because the seasonal H1N1 viruses circulating during the last 60 years were not antigenically similar to novel H1N1. We therefore hypothesized that a sequence of exposures to antigenically different seasonal H1N1 viruses can elicit an antibody response that protects against novel 2009 H1N1. Ferrets were preinfected with seasonal H1N1 viruses and assessed for cross-reactive antibodies to novel H1N1. Serum from infected ferrets was assayed for cross-reactivity to both seasonal and novel 2009 H1N1 strains. These results were compared to those of ferrets that were sequentially infected with H1N1 viruses isolated prior to 1957 or more-recently isolated viruses. Following seroconversion, ferrets were challenged with novel H1N1 influenza virus and assessed for viral titers in the nasal wash, morbidity, and mortality. There was no hemagglutination inhibition (HAI) cross-reactivity in ferrets infected with any single seasonal H1N1 influenza viruses, with limited protection to challenge. However, sequential H1N1 influenza infections reduced the incidence of disease and elicited cross-reactive antibodies to novel H1N1 isolates. The amount and duration of virus shedding and the frequency of transmission following novel H1N1 challenge were reduced. Exposure to multiple seasonal H1N1 influenza viruses, and not to any single H1N1 influenza virus, elicits a breadth of antibodies that neutralize novel H1N1 even though the host was never exposed to the novel H1N1 influenza viruses.

scholarly journals Rewiring the RNAs of influenza virus to prevent reassortment

2009 ◽  
Vol 106 (37) ◽  
pp. 15891-15896 ◽  
Author(s):  
Qinshan Gao ◽  
Peter Palese
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Nonstructural Protein ◽  
Influenza Viruses ◽  
Ha Gene ◽  
Ns Gene ◽  
Virus Rna ◽  
Reassortant Viruses ◽  
Packaging Signals

Influenza viruses contain segmented, negative-strand RNA genomes. Genome segmentation facilitates reassortment between different influenza virus strains infecting the same cell. This phenomenon results in the rapid exchange of RNA segments. In this study, we have developed a method to prevent the free reassortment of influenza A virus RNAs by rewiring their packaging signals. Specific packaging signals for individual influenza virus RNA segments are located in the 5′ and 3′ noncoding regions as well as in the terminal regions of the ORF of an RNA segment. By putting the nonstructural protein (NS)-specific packaging sequences onto the ORF of the hemagglutinin (HA) gene and mutating the packaging regions in the ORF of the HA, we created a chimeric HA segment with the packaging identity of an NS gene. By the same strategy, we made an NS gene with the packaging identity of an HA segment. This rewired virus had the packaging signals for all eight influenza virus RNAs, but it lost the ability to independently reassort its HA or NS gene. A similar approach can be applied to the other influenza A virus segments to diminish their ability to form reassortant viruses.

Prospective Evaluation of 2009 H1N1 Influenza A in Patients Admitted with Fever to an Oncology Unit

2011 ◽  
Vol 32 (8) ◽  
pp. 815-817 ◽  
Author(s):  
Karen Seiter ◽  
Dhaval Shah ◽  
Claudio Sandoval ◽  
Delong Liu ◽  
Robert B. Nadelman ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Infection Control ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Favorable Outcome ◽  
Prospective Evaluation ◽  
H1n1 Influenza Virus ◽  
Oncology Patients ◽  
2009 H1n1 ◽  
Oncology Unit

We prospectively evaluated all oncology inpatients for 2009 H1N1 influenza virus. All patients recovered completely. Evaluating all oncology patients with fever for influenza involved overtreatment of influenza-negative patients and involved a significant infection control burden. However, early antiviral intervention could have contributed to a favorable outcome.

scholarly journals Mutations in the NS1 Protein of Swine Influenza Virus Impair Anti-Interferon Activity and Confer Attenuation in Pigs

2005 ◽  
Vol 79 (12) ◽  
pp. 7535-7543 ◽  
Author(s):  
Alicia Solórzano ◽  
Richard J. Webby ◽  
Kelly M. Lager ◽  
Bruce H. Janke ◽  
Adolfo García-Sastre ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Nonstructural Protein ◽  
Swine Influenza Virus ◽  
Swine Influenza ◽  
Influenza Viruses ◽  
Model Systems ◽  
Ns1 Protein ◽  
Wild Type ◽  
Virulence Attenuation

ABSTRACT It has been shown previously that the nonstructural protein NS1 of influenza virus is an alpha/beta interferon (IFN-α/β) antagonist, both in vitro and in experimental animal model systems. However, evidence of this function in a natural host has not yet been obtained. Here we investigated the role of the NS1 protein in the virulence of a swine influenza virus (SIV) isolate in pigs by using reverse genetics. The virulent wild-type A/Swine/Texas/4199-2/98 (TX/98) virus and various mutants encoding carboxy-truncated NS1 proteins were rescued. Growth properties of TX/98 viruses with mutated NS1, induction of IFN in tissue culture, and virulence-attenuation in pigs were analyzed and compared to those of the recombinant wild-type TX/98 virus. Our results indicate that deletions in the NS1 protein decrease the ability of the TX/98 virus to prevent IFN-α/β synthesis in pig cells. Moreover, all NS1 mutant viruses were attenuated in pigs, and this correlated with the amount of IFN-α/β induced in vitro. These data suggest that the NS1 protein of SIV is a virulence factor. Due to their attenuation, NS1-mutated swine influenza viruses might have a great potential as live attenuated vaccine candidates against SIV infections of pigs.

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