scholarly journals Equine Mx1 Restricts Influenza A Virus Replication by Targeting at Distinct Site of its Nucleoprotein

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1114 ◽  
Author(s):  
Urooj Fatima ◽  
Zhenyu Zhang ◽  
Haili Zhang ◽  
Xue-Feng Wang ◽  
Ling Xu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Substantial Reduction ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Dynamic Force ◽  
Equine Influenza Virus ◽  
Equine Influenza ◽  
Adaptive Mutations ◽  
Antiviral Activities

Interferon-mediated host factors myxovirus (Mx) proteins are key features in regulating influenza A virus (IAV) infections. Viral polymerases are essential for viral replication. The Mx1 protein has been known to interact with viral nucleoprotein (NP) and PB2, resulting in the influence of polymerase activity and providing interspecies restriction. The equine influenza virus has evolved as an independent lineage to influenza viruses from other species. We estimated the differences in antiviral activities between human MxA (huMxA) and equine Mx1 (eqMx1) against a broad range of IAV strains. We found that huMxA has antiviral potential against IAV strains from non-human species, whereas eqMx1 could only inhibit the polymerase activity of non-equine species. Here, we demonstrated that NP is the main target of eqMx1. Subsequently, we found adaptive mutations in the NP of strains A/equine/Jilin/1/1989 (H3N8JL89) and A/chicken/Zhejiang/DTID-ZJU01/2013 (H7N9ZJ13) that confer eqMx1 resistance and sensitivity respectively. A substantial reduction in Mx1 resistance was observed for the two mutations G34S and H52N in H3N8JL89 NP. Thus, eqMx1 is an important dynamic force in IAV nucleoprotein evolution. We, therefore, suggest that the amino acids responsible for Mx1 resistance should be regarded as a robust indicator for the pandemic potential of lately evolving IAVs.

scholarly journals Complete Genomic Sequences of H3N8 Equine Influenza Virus Strains Used as Vaccine Strains in Japan

2018 ◽  
Vol 6 (12) ◽  
Author(s):  
Manabu Nemoto ◽  
Takashi Yamanaka ◽  
Hiroshi Bannai ◽  
Koji Tsujimura ◽  
Hiroshi Kokado
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Animal Health ◽  
Genomic Sequences ◽  
Equine Influenza Virus ◽  
Equine Influenza ◽  
World Organization ◽  
Virus Strains ◽  
Complete Genomic

ABSTRACT We sequenced the eight segments of influenza A virus strains A/equine/Ibaraki/1/2007 and A/equine/Yokohama/aq13/2010, which are strains of the Florida sublineage clades 1 and 2 of the H3N8 subtype equine influenza virus. These strains have been used as vaccine strains in Japan since 2016 in accordance with World Organization for Animal Health (OIE) recommendations.

scholarly journals PB2 and Hemagglutinin Mutations Are Major Determinants of Host Range and Virulence in Mouse-Adapted Influenza A Virus

2010 ◽  
Vol 84 (20) ◽  
pp. 10606-10618 ◽  
Author(s):  
Jihui Ping ◽  
Samar K. Dankar ◽  
Nicole E. Forbes ◽  
Liya Keleta ◽  
Yan Zhou ◽  
...  
Keyword(s):  
Host Range ◽  
Influenza A Virus ◽  
Influenza A ◽  
Lethal Dose ◽  
Polymerase Activity ◽  
Mouse Lung ◽  
Viral Gene ◽  
Adaptive Mutations

ABSTRACT Serial mouse lung passage of a human influenza A virus, A/Hong Kong/1/68 (H3N2) (HK-wt), produced a mouse-adapted variant, MA, with nine mutations that was >103.8-fold more virulent. In this study, we demonstrate that MA mutations of the PB2 (D701N) and hemagglutinin (HA) (G218W in HA1 and T156N in HA2) genes were the most adaptive genetic determinants for increased growth and virulence in the mouse model. Recombinant viruses expressing each of the mutated MA genome segments on the HK-wt backbone showed significantly increased disease severity, whereas only the mouse-adapted PB2 gene increased virulence, as determined by the 50% lethal dose ([LD50] >101.4-fold). The converse comparisons of recombinant MA viruses expressing each of the HK-wt genome segments showed the greatest decrease in virulence due to the HA gene (102-fold), with lesser decreases due to the M1, NS1, NA, and PB1 genes (100.3- to 100.8-fold), and undetectable effects on the LD50 for the PB2 and NP genes. The HK PB2 gene did, however, attenuate MA infection, as measured by weight loss and time to death. Replication of adaptive mutations in vivo and in vitro showed both viral gene backbone and host range effects. Minigenome transcription assays showed that PB1 and PB2 mutations increased polymerase activity and that the PB2 D701N mutation was comparable in effect to the mammalian adaptive PB2 E627K mutation. Our results demonstrate that host range and virulence are controlled by multiple genes, with major roles for mutations in PB2 and HA.

scholarly journals Adaptive Mutations Resulting in Enhanced Polymerase Activity Contribute to High Virulence of Influenza A Virus in Mice

2009 ◽  
Vol 83 (13) ◽  
pp. 6673-6680 ◽  
Author(s):  
Thierry Rolling ◽  
Iris Koerner ◽  
Petra Zimmermann ◽  
Kristian Holz ◽  
Otto Haller ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Polymerase Activity ◽  
Host Cells ◽  
Mammalian Host ◽  
Avian Host ◽  
Viral Polymerase ◽  
Adaptive Mutations ◽  
High Virulence ◽  
Adaptation Experiment

ABSTRACT High virulence of influenza virus A/Puerto Rico/8/34 in mice carrying the Mx1 resistance gene was recently shown to be determined by the viral surface proteins and the viral polymerase. Here, we demonstrated high-level polymerase activity in mammalian host cells but not avian host cells and investigated which mutations in the polymerase subunits PB1, PB2, and PA are critical for increased polymerase activity and high virus virulence. Mutational analyses demonstrated that an isoleucine-to-valine change at position 504 in PB2 was the most critical and strongly enhanced the activity of the reconstituted polymerase complex. An isoleucine-to-leucine change at position 550 in PA further contributed to increased polymerase activity and high virulence, whereas all other mutations in PB1, PB2, and PA were irrelevant. To determine whether this pattern of acquired mutations represents a preferred viral strategy to gain virulence, two independent new virus adaptation experiments were performed. Surprisingly, the conservative I504V change in PB2 evolved again and was the only mutation present in an aggressive virus variant selected during the first adaptation experiment. In contrast, the virulent virus selected in the second adaptation experiment had a lysine-to-arginine change at position 208 in PB1 and a glutamate-to-glycine change at position 349 in PA. These results demonstrate that a variety of minor amino acid changes in the viral polymerase can contribute to enhanced virulence of influenza A virus. Interestingly, all virulence-enhancing mutations that we identified in this study resulted in substantially increased viral polymerase activity.

scholarly journals Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 234
Author(s):  
Sarah Al-Beltagi ◽  
Cristian Alexandru Preda ◽  
Leah V. Goulding ◽  
Joe James ◽  
Juan Pu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Respiratory Syncytial Virus ◽  
Influenza A Virus ◽  
Broad Spectrum ◽  
Influenza A ◽  
Respiratory Viruses ◽  
Influenza Viruses ◽  
Virus Challenge ◽  
2009 H1n1 ◽  
Syncytial Virus

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

scholarly journals PRESENCE OF RESPIRATORY VIRUSES IN EQUINES IN BRAZIL

2014 ◽  
Vol 56 (3) ◽  
pp. 191-195
Author(s):  
Dalva Assunção Portari Mancini ◽  
Aparecida Santo Pietro Pereira ◽  
Rita Maria Zucatelli Mendonça ◽  
Adelia Hiroko Nagamori Kawamoto ◽  
Rosely Cabette Barbosa Alves ◽  
...  
Keyword(s):  
Influenza A ◽  
Respiratory Viruses ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Equine Influenza ◽  
Hemagglutination Inhibition Test ◽  
Parainfluenza Viruses ◽  
Significant Difference ◽  
Antibody Titers ◽  
The Difference

Equines are susceptible to respiratory viruses such as influenza and parainfluenza. Respiratory diseases have adversely impacted economies all over the world. This study was intended to determine the presence of influenza and parainfluenza viruses in unvaccinated horses from some regions of the state of São Paulo, Brazil. Blood serum collected from 72 equines of different towns in this state was tested by hemagglutination inhibition test to detect antibodies for both viruses using the corresponding antigens. About 98.6% (71) and 97.2% (70) of the equines responded with antibody protective titers (≥ 80 HIU/25µL) H7N7 and H3N8 subtypes of influenza A viruses, respectively. All horses (72) also responded with protective titers (≥ 80) HIU/25µL against the parainfluenza virus. The difference between mean antibody titers to H7N7 and H3N8 subtypes of influenza A viruses was not statistically significant (p > 0.05). The mean titers for influenza and parainfluenza viruses, on the other hand, showed a statistically significant difference (p < 0.001). These results indicate a better antibody response from equines to parainfluenza 3 virus than to the equine influenza viruses. No statistically significant differences in the responses against H7N7 and H3N8 subtypes of influenza A and parainfluenza 3 viruses were observed according to the gender (female, male) or the age (≤ 2 to 20 years-old) groups. This study provides evidence of the concomitant presence of two subtypes of the equine influenza A (H7N7 and H3N8) viruses and the parainfluenza 3 virus in equines in Brazil. Thus, it is advisable to vaccinate equines against these respiratory viruses.

scholarly journals Human Cytomegalovirus Inhibitor AL18 Also Possesses Activity against Influenza A and B Viruses

2012 ◽  
Vol 56 (11) ◽  
pp. 6009-6013 ◽  
Author(s):  
Giulia Muratore ◽  
Beatrice Mercorelli ◽  
Laura Goracci ◽  
Gabriele Cruciani ◽  
Paul Digard ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Dna Polymerase ◽  
Human Cytomegalovirus ◽  
Influenza A ◽  
Molecular Model ◽  
Polymerase Activity

ABSTRACTAL18, an inhibitor of human cytomegalovirus DNA polymerase, was serendipitously found to also block the interaction between the PB1 and PA polymerase subunits of influenza A virus. Furthermore, AL18 effectively inhibited influenza A virus polymerase activity and the overall replication of influenza A and B viruses. A molecular model to explain the binding of AL18 to both cytomegalovirus and influenza targets is proposed. Thus, AL18 represents an interesting lead for the development of new antivirals.

scholarly journals Functional Analysis of PA Binding by Influenza A Virus PB1: Effects on Polymerase Activity and Viral Infectivity

2001 ◽  
Vol 75 (17) ◽  
pp. 8127-8136 ◽  
Author(s):  
Daniel R. Perez ◽  
Ruben O. Donis
Keyword(s):  
Amino Acids ◽  
Influenza Virus ◽  
Amino Acid ◽  
Viral Replication ◽  
Influenza A Virus ◽  
Influenza A ◽  
Amino Acid Sequences ◽  
Influenza Viruses ◽  
Virus Growth ◽  
Transcription And Replication

ABSTRACT Influenza A virus expresses three viral polymerase (P) subunits—PB1, PB2, and PA—all of which are essential for RNA and viral replication. The functions of P proteins in transcription and replication have been partially elucidated, yet some of these functions seem to be dependent on the formation of a heterotrimer for optimal viral RNA transcription and replication. Although it is conceivable that heterotrimer subunit interactions may allow a more efficient catalysis, direct evidence of their essentiality for viral replication is lacking. Biochemical studies addressing the molecular anatomy of the P complexes have revealed direct interactions between PB1 and PB2 as well as between PB1 and PA. Previous studies have shown that the N-terminal 48 amino acids of PB1, termed domain α, contain the residues required for binding PA. We report here the refined mapping of the amino acid sequences within this small region of PB1 that are indispensable for binding PA by deletion mutagenesis of PB1 in a two-hybrid assay. Subsequently, we used site-directed mutagenesis to identify the critical amino acid residues of PB1 for interaction with PA in vivo. The first 12 amino acids of PB1 were found to constitute the core of the interaction interface, thus narrowing the previous boundaries of domain α. The role of the minimal PB1 domain α in influenza virus gene expression and genome replication was subsequently analyzed by evaluating the activity of a set of PB1 mutants in a model reporter minigenome system. A strong correlation was observed between a functional PA binding site on PB1 and P activity. Influenza viruses bearing mutant PB1 genes were recovered using a plasmid-based influenza virus reverse genetics system. Interestingly, mutations that rendered PB1 unable to bind PA were either nonviable or severely growth impaired. These data are consistent with an essential role for the N terminus of PB1 in binding PA, P activity, and virus growth.

Broad neutralization of H1 and H3 viruses by adjuvanted influenza HA stem vaccines in nonhuman primates

2021 ◽  
Vol 13 (583) ◽  
pp. eabe5449
Author(s):  
Nicole Darricarrère ◽  
Yu Qiu ◽  
Masaru Kanekiyo ◽  
Adrian Creanga ◽  
Rebecca A. Gillespie ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Nonhuman Primates ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
Gene Families ◽  
Influenza Viruses ◽  
Public Health Importance ◽  
Water Emulsion

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus–associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.

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