scholarly journals The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis

2016 ◽  
Vol 90 (9) ◽  
pp. 4369-4382 ◽  
Author(s):  
Baoming Liu ◽  
Nan L. Li ◽  
Yang Shen ◽  
Xiaoyong Bao ◽  
Thomas Fabrizio ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Rna Synthesis ◽  
Rna Viruses ◽  
E3 Ligase ◽  
Influenza Viruses ◽  
Restriction Factor ◽  
Virus Activity ◽  
Tripartite Motif ◽  
Positive Strand Rna

ABSTRACTAccumulating data suggest that tripartite-motif-containing (TRIM) proteins participate in host responses to viral infections, either by acting as direct antiviral restriction factors or through regulating innate immune signaling of the host. Of >70 TRIMs, TRIM56 is a restriction factor of several positive-strand RNA viruses, including three members of the familyFlaviviridae(yellow fever virus, dengue virus, and bovine viral diarrhea virus) and a human coronavirus (OC43), and this ability invariably depends upon the E3 ligase activity of TRIM56. However, the impact of TRIM56 on negative-strand RNA viruses remains unclear. Here, we show that TRIM56 puts a check on replication of influenza A and B viruses in cell culture but does not inhibit Sendai virus or human metapneumovirus, two paramyxoviruses. Interestingly, the anti-influenza virus activity was independent of the E3 ligase activity, B-box, or coiled-coil domain. Rather, deletion of a 63-residue-long C-terminal-tail portion of TRIM56 abrogated the antiviral function. Moreover, expression of this short C-terminal segment curtailed the replication of influenza viruses as effectively as that of full-length TRIM56. Mechanistically, TRIM56 was found to specifically impede intracellular influenza virus RNA synthesis. Together, these data reveal a novel antiviral activity of TRIM56 against influenza A and B viruses and provide insights into the mechanism by which TRIM56 restricts these medically important orthomyxoviruses.IMPORTANCEOptions to treat influenza are limited, and drug-resistant influenza virus strains can emerge through minor genetic changes. Understanding novel virus-host interactions that alter influenza virus fitness may reveal new targets/approaches for therapeutic interventions. We show here that TRIM56, a tripartite-motif protein, is an intrinsic host restriction factor of influenza A and B viruses. Unlike its antiviral actions against positive-strand RNA viruses, the anti-influenza virus activity of TRIM56 was independent of the E3 ligase activity. Rather, expression of a short segment within the very C-terminal tail of TRIM56 inhibited the replication of influenza viruses as effectively as that of full-length TRIM56 by specifically targeting viral RNA synthesis. These data reveal the remarkable multifaceted activity of TRIM56, which has developed multiple domains to inhibit multiple viral families. They also raise the possibility of developing a broad-spectrum, TRIM56-based antiviral approach for addition to influenza prophylaxis and/or control strategies.

scholarly journals Host Protein Moloney Leukemia Virus 10 (MOV10) Acts as a Restriction Factor of Influenza A Virus by Inhibiting the Nuclear Import of the Viral Nucleoprotein

2016 ◽  
Vol 90 (8) ◽  
pp. 3966-3980 ◽  
Author(s):  
Junsong Zhang ◽  
Feng Huang ◽  
Likai Tan ◽  
Chuan Bai ◽  
Bing Chen ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Leukemia Virus ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Host Factors ◽  
Host Protein ◽  
Restriction Factor ◽  
Moloney Leukemia Virus ◽  
Importin Α

ABSTRACTThe viral ribonucleoprotein (vRNP) complex of influenza A viruses (IAVs) contains an RNA-dependent RNA polymerase complex (RdRp) and nucleoprotein (NP) and is the functional unit for viral RNA transcription and replication. The vRNP complex is an important determinant of virus pathogenicity and host adaptation, implying that its function can be affected by host factors. In our study, we identified host protein Moloney leukemia virus 10 (MOV10) as an inhibitor of IAV replication, since depletion of MOV10 resulted in a significant increase in virus yield. MOV10 inhibited the polymerase activity in a minigenome system through RNA-mediated interaction with the NP subunit of vRNP complex. Importantly, we found that the interaction between MOV10 and NP prevented the binding of NP to importin-α, resulting in the retention of NP in the cytoplasm. Both the binding of MOV10 to NP and its inhibitory effect on polymerase activity were independent of its helicase activity. These results suggest that MOV10 acts as an anti-influenza virus factor through specifically inhibiting the nuclear transportation of NP and subsequently inhibiting the function of the vRNP complex.IMPORTANCEThe interaction between the influenza virus vRNP complex and host factors is a major determinant of viral tropism and pathogenicity. Our study identified MOV10 as a novel host restriction factor for the influenza virus life cycle since it inhibited the viral growth rate. Conversely, importin-α has been shown as a determinant for influenza tropism and a positive regulator for viral polymerase activity in mammalian cells but not in avian cells. MOV10 disrupted the interaction between NP and importin-α, suggesting that MOV10 could also be an important host factor for influenza virus transmission and pathogenicity. Importantly, as an interferon (IFN)-inducible protein, MOV10 exerted a novel mechanism for IFNs to inhibit the replication of influenza viruses. Furthermore, our study potentially provides a new drug design strategy, the use of molecules that mimic the antiviral mechanism of MOV10.

scholarly journals mSphere of Influence: Resolution of the Structure of an Influenza Virus Polymerase Is a Game Changer

mSphere ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Mathilde Richard
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Rna Synthesis ◽  
Influenza Viruses ◽  
Viral Rna ◽  
Structural Insight ◽  
Rna Promoter ◽  
Insight Into ◽  
Virus Biology ◽  
Game Changer

ABSTRACT Mathilde Richard works in the field of virology, more specifically on the evolution and pathogenesis of influenza viruses. In this mSphere of Influence article, she reflects on how the two articles “Structure of Influenza A Polymerase Bound to the Viral RNA Promoter” by A. Pflug, D. Guilligay, S. Reich, and S. Cusack (Nature 516:355–360, 2014, https://doi.org/10.1038/nature14008) and “Structural Insight into Cap-Snatching and RNA Synthesis by Influenza Polymerase” by S. Reich, D. Guilligay, A. Pflug, H. Malet, I. Berger, et al. (Nature 516:361–366, 2014, https://doi.org/10.1038/nature14009) made an impact on her by providing new grounds to study the influenza virus polymerase and its role in virus biology and evolution.

scholarly journals Inhibition of Influenza Virus Replication by Nitric Oxide

1999 ◽  
Vol 73 (10) ◽  
pp. 8880-8883 ◽  
Author(s):  
Guus F. Rimmelzwaan ◽  
Marianne M. J. W. Baars ◽  
Pim de Lijster ◽  
Ron A. M. Fouchier ◽  
Albert D. M. E. Osterhaus
Keyword(s):  
Nitric Oxide ◽  
Influenza Virus ◽  
Influenza A ◽  
Rna Synthesis ◽  
Virus Production ◽  
Influenza Viruses ◽  
No Donor ◽  
Infected Cells ◽  
Influenza Virus Replication ◽  
Darby Canine Kidney

ABSTRACT Nitric oxide (NO) has been shown to contribute to the pathogenesis of influenza virus-induced pneumonia in mouse models. Here we show that replication of influenza A and B viruses in Mabin Darby canine kidney cells is severely impaired by the NO donor,S-nitroso-N-acetylpenicillamine. Reduction of productively infected cells and virus production proved to correlate with inhibition of viral RNA synthesis, indicating that NO affects an early step in the replication cycle of influenza viruses.

scholarly journals Characteristics of Seasonal Influenza Virus Activity in a Subtropical City in China, 2013–2019

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 108
Author(s):  
Aiqin Zhu ◽  
Jianhua Liu ◽  
Chuchu Ye ◽  
Jianxing Yu ◽  
Zhibing Peng ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccination ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Influenza B ◽  
Virus Activity ◽  
Epidemic Period ◽  
Positive Rate ◽  
Epidemiological Characteristics

Background: To optimize seasonal influenza vaccination programs in regions with potentially complicated seasonal patterns, the epidemiological characteristics of seasonal influenza activity in a subtropical city of China were explored. Materials and Methods: Influenza virus data of patients with influenza-like illness (ILI) during 2013–2019 were collected from two sentinel hospitals in a subtropical region of China, Yichang city. The influenza virus positive rate among sampled ILI cases served as a proxy to estimate influenza seasonal characteristics, including periodicity, duration, peaks, and predominant subtypes/lineages. Epidemiological features of different years, seasons and age groups were analyzed, and vaccine mismatches were identified. Results: In total, 8693 ILI cases were included; 1439 (16.6%) were laboratory-confirmed influenza cases. The influenza A positive rate (10.6%) was higher than the influenza B positive rate (5.9%). There were three influenza circulation patterns in Yichang: (1) annual periodicity (in 2013–2014, 2015–2016 and 2018–2019), (2) semiannual periodicity (in 2014–2015), and (3) year-round periodicity (in 2016–2017 and 2017–2018). Summer epidemics existed in two of the six years and were dominated by influenza A/H3N2. Winter and spring epidemics occurred in five of the six years, and A/H1N1, A/H3N2, B/Victoria, and B/Yamagata were codominant. During the study period, the predominant lineages, B/Victoria in 2015-16 and B/Yamagata in 2017–2018, were both mismatched with the influenza B component of the trivalent vaccine. Children 5–14 years old (26.4%) and individuals over 60 years old (16.9%) had the highest influenza positive rates. Conclusions: The seasonal epidemic period and the predominant subtype/lineage of influenza viruses in Yichang city are complex. Influenza vaccination timing and strategies need to be optimized according to the local features of influenza virus activity.

scholarly journals Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James D. Allen ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Next Generation ◽  
Virus Infections ◽  
Wild Type ◽  
Influenza Hemagglutinin ◽  
H3n2 Influenza

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

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 Influenza: An Emerging and Re-emerging Public Health Threat in Nepal

2018 ◽  
Vol 3 (2) ◽  
pp. 1-2
Author(s):  
Bishnu Prasad Upadhyay
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Winter Season ◽  
Emerging Infectious Diseases ◽  
Influenza Viruses ◽  
Influenza B ◽  
Influenza A Viruses ◽  
Influenza A H1n1 ◽  
New Variant ◽  
Seasonal Epidemics

Influenza virus type A and B are responsible for seasonal epidemics as well as pandemics in human. Influenza A viruses are further divided into two major groups namely, low pathogenic seasonal influenza (A/H1N1, A/H1N1 pdm09, A/H3N2) and highly pathogenic influenza virus (H5N1, H5N6, H7N9) on the basis of two surface antigens: hemagglutinin (HA) and neuraminidase (NA). Mutations, including substitutions, deletions, and insertions, are one of the most important mechanisms for producing new variant of influenza viruses. During the last 30 years; more than 50 viral threat has been evolved in South-East Asian countriesof them influenza is one of the major emerging and re-emerging infectious diseases of global concern. Similar to tropical and sub-tropical countries of Southeast Asia; circulation of A/H1N1 pdm09, A/H3N2 and influenza B has been circulating throughout the year with the peak during July-November in Nepal. However; the rate of infection transmission reach peak during the post-rain and winter season of Nepal.

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.

scholarly journals Haemagglutination-inhibition antibodies against influenza A and influenza B in maternal and neonatal sera

1978 ◽  
Vol 80 (1) ◽  
pp. 13-19 ◽  
Author(s):  
N. Masurel ◽  
J. I. de Bruijne ◽  
H. A. Beuningh ◽  
H. J. A. Schouten
Keyword(s):  
Influenza Virus ◽  
Maternal Age ◽  
Influenza A ◽  
Haemagglutination Inhibition ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Influenza B ◽  
B Virus ◽  
Duration Of Pregnancy ◽  
Pregnancy And Birth

SUMMARYHaemagglutination inhibition (HI) antibodies against the influenza viruses A/Hong Kong/8/68 (H3N2) and B/Nederland/77/66 were determined in 420 paired sera from mothers and newborns (umbilical cord sera), sampled in 1970–1.A higher concentration of antibodies against influenza A virus was found more frequently in neonatal than in maternal sera. By contrast, low titres against influenza B virus were more frequently observed in neonatal than in maternal sera. Maternal age, duration of pregnancy, and birth-weight did not affect the results of the tests.It is suggested that the titre of the newborn against an epidemic influenza virus can be predicted from that of the mother. Furthermore, the maternal titre may be an indication of the susceptibility of the newborn infant to influenza infections.

Equine and canine influenza: a review of current events

2010 ◽  
Vol 11 (1) ◽  
pp. 43-51 ◽  
Author(s):  
E. Paul J. Gibbs ◽  
Tara C. Anderson
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Influenza A ◽  
One Health ◽  
Control Strategies ◽  
Close Association ◽  
Companion Animals ◽  
Emerging Diseases ◽  
Influenza Viruses ◽  
Canine Influenza

AbstractIn the past decade, the pandemics of highly pathogenic avian influenza H5N1 and the novel H1N1 influenza have both illustrated the potential of influenza viruses to rapidly emerge and spread widely in animals and people. Since both of these viruses are zoonotic, these pandemics have been the driving force behind a renewed commitment by the medical and veterinary professions to practice One World, One Health for the control of infectious diseases. The discovery in 2004 that an equine origin H3N8 influenza virus was the cause of an extensive epidemic of respiratory disease in dogs in the USA came as a surprise; at that time dogs were thought to be refractory to infection with influenza viruses. In 2007, a second emerging canine influenza was confirmed in Korea, but this time the causal virus was an H3N2 avian influenza virus. This review focuses on recent events associated with equine and canine influenza viruses. While these viruses do not appear to be zoonotic, the close association between humans and dogs, and to a lesser extent horses, demands that we develop better surveillance and control strategies for emerging diseases in companion animals within the context of One World, One Health.

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