scholarly journals Inhibition of Interferon-Mediated Antiviral Responses by Influenza A Viruses and Other Negative-Strand RNA Viruses

Virology ◽  
2001 ◽  
Vol 279 (2) ◽  
pp. 375-384 ◽  
Author(s):  
Adolfo García-Sastre
Keyword(s):  
Influenza A ◽  
Rna Viruses ◽  
Influenza A Viruses ◽  
Negative Strand ◽  
Antiviral Responses

scholarly journals Upstream translation initiation expands the coding capacity of segmented negative-strand RNA viruses

2019 ◽  
Author(s):  
Elizabeth Sloan ◽  
Marta Alenquer ◽  
Liliane Chung ◽  
Sara Clohisey ◽  
Adam M. Dinan ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Influenza A ◽  
Viral Infections ◽  
Rna Viruses ◽  
Influenza Viruses ◽  
Open Reading Frames ◽  
Viral Gene ◽  
Influenza A Viruses ◽  
Negative Strand ◽  
Coding Potential

AbstractSegmented negative-strand RNA viruses (sNSVs) include the influenza viruses, the bunyaviruses, and other major pathogens of humans, other animals and plants. The genomes of these viruses are extremely short. In response to this severe genetic constraint, sNSVs use a variety of strategies to maximise their coding potential. Because the eukaryotic hosts parasitized by sNSVs can regulate gene expression through low levels of translation initiation upstream of their canonical open reading frames (ORFs), we asked whether sNSVs could use upstream translation initiation to expand their own genetic repertoires. Consistent with this hypothesis, we showed that influenza A viruses (IAVs) and bunyaviruses were capable of upstream translation initiation. Using a combination of reporter assays and viral infections, we found that upstream translation in IAVs can initiate in two unusual ways: through non-AUG initiation in virally encoded ‘untranslated’ regions, and through the appropriation of an AUG-containing leader sequence from host mRNAs through viral cap-snatching, a process we termed ‘start-snatching.’ Finally, while upstream translation of cellular genes is mainly regulatory, for sNSVs it also has the potential to create novel viral gene products. If in frame with a viral ORF, this creates N-extensions of canonical viral proteins. If not, it allows the expression of cryptic overlapping ORFs, which we found were highly conserved in IAV and widely distributed in peribunyaviruses. Thus, by exploiting their host’s capacity for upstream translation initiation, sNSVs can expand still further the coding potential of their extremely compact RNA genomes.

scholarly journals A synergistic effect between 3′ terminal noncoding and adjacent coding regions of influenza A virus HA segment on template preference

2021 ◽  
Author(s):  
Yue Xiao ◽  
Wenyu Zhang ◽  
Minglei Pan ◽  
David L. V. Bauer ◽  
Yuhai Bi ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Influenza A Virus ◽  
Influenza A ◽  
Rna Viruses ◽  
Nucleotide Position ◽  
Virus Growth ◽  
Noncoding Regions ◽  
Negative Strand ◽  
Coding Regions ◽  
Growth Phenotype

The influenza A virus genome is comprised of eight single-stranded negative-sense viral RNA (vRNA) segments. Each of the eight vRNA segments contains segment-specific nonconserved noncoding regions (NCRs) of similar sequence and length in different influenza A virus strains. However, in the subtype-determinant segments, encoding haemagglutinin (HA) and neuraminidase (NA), the segment-specific noncoding regions are subtype-specific, varying significantly in sequence and length at both the 3´ and 5´ termini among different subtypes. The significance of these subtype-specific noncoding regions (ssNCR) in the influenza virus replication cycle is not fully understood. In this study, we show that truncations of the 3´-end H1-subtype-specific noncoding region (H1-ssNCR) resulted in recombinant viruses with decreased HA vRNA replication and attenuated growth phenotype, although the vRNA replication was not affected in single-template RNP reconstitution assays. The attenuated viruses were unstable and point mutations at nucleotide position 76 or 56 in the adjacent coding region of HA vRNA were found after serial passage. The mutations restored the HA vRNA replication and reversed the attenuated virus growth phenotype. We propose that the terminal noncoding and adjacent coding regions act synergistically to ensure optimal levels of HA vRNA replication in a multi-segment environment. These results, provide novel insights into the role of the 3´-end nonconserved noncoding regions and adjacent coding regions on template preference in multiple-segmented negative-strand RNA viruses. IMPORTANCE While most influenza A virus vRNA segments contain segment-specific nonconserved noncoding regions of similar length and sequence, these regions vary considerably both in length and sequence in the segments encoding HA and NA, the two major antigenic determinants of influenza A viruses. In this study, we investigated the function of the 3´-end H1-ssNCR and observed a synergistic effect between the 3´-end H1-ssNCR nucleotides and adjacent coding nucleotide(s) of HA segment on template preference in a multi-segment environment. The results unravel an additional level of complexity in the regulation of RNA replication in multiple-segmented negative-strand RNA viruses.

scholarly journals Natural Selection of H5N1 Avian Influenza A Viruses with Increased PA-X and NS1 Shutoff Activity

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1760
Author(s):  
Aitor Nogales ◽  
Laura Villamayor ◽  
Sergio Utrilla-Trigo ◽  
Javier Ortego ◽  
Luis Martinez-Sobrido ◽  
...  
Keyword(s):  
Amino Acid ◽  
Virulence Factors ◽  
Influenza A ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Influenza A Viruses ◽  
Antiviral Responses ◽  
H5n1 Avian Influenza ◽  
Inhibit Gene Expression ◽  
Important Challenge

Influenza A viruses (IAV) can infect a broad range of mammalian and avian species. However, the host innate immune system provides defenses that restrict IAV replication and infection. Likewise, IAV have evolved to develop efficient mechanisms to counteract host antiviral responses to efficiently replicate in their hosts. The IAV PA-X and NS1 non-structural proteins are key virulence factors that modulate innate immune responses and virus pathogenicity during infection. To study the determinants of IAV pathogenicity and their functional co-evolution, we evaluated amino acid differences in the PA-X and NS1 proteins of early (1996–1997) and more recent (since 2016) H5N1 IAV. H5N1 IAV have zoonotic and pandemic potential and represent an important challenge both in poultry farming and human health. The results indicate that amino acid changes occurred over time, affecting the ability of these two non-structural H5N1 IAV proteins to inhibit gene expression and affecting virus pathogenicity. These results highlight the importance to monitor the evolution of these two virulence factors of IAV, which could result in enhanced viral replication and virulence.

scholarly journals RIG-I from waterfowl and mammals differ in their abilities to induce antiviral responses against influenza A viruses

2015 ◽  
Vol 96 (2) ◽  
pp. 277-287 ◽  
Author(s):  
Qiang Shao ◽  
Wenping Xu ◽  
Qiang Guo ◽  
Li Yan ◽  
Lei Rui ◽  
...  
Keyword(s):  
Influenza A ◽  
Influenza A Viruses ◽  
Antiviral Responses

scholarly journals Randomly primed, strand-switching, MinION-based sequencing for the detection and characterization of cultured RNA viruses

2020 ◽  
pp. 104063872098101
Author(s):  
Kelsey T. Young ◽  
Kevin K. Lahmers ◽  
Holly S. Sellers ◽  
David E. Stallknecht ◽  
Rebecca L. Poulson ◽  
...  
Keyword(s):  
Influenza A ◽  
Rna Viruses ◽  
False Negative ◽  
Molecular Techniques ◽  
Detection Methods ◽  
Hemorrhagic Disease ◽  
Coverage Depth ◽  
Influenza A Viruses ◽  
Culture Methods ◽  
Diarrhea Virus

RNA viruses rapidly mutate, which can result in increased virulence, increased escape from vaccine protection, and false-negative detection results. Targeted detection methods have a limited ability to detect unknown viruses and often provide insufficient data to detect coinfections or identify antigenic variants. Random, deep sequencing is a method that can more fully detect and characterize RNA viruses and is often coupled with molecular techniques or culture methods for viral enrichment. We tested viral culture coupled with third-generation sequencing for the ability to detect and characterize RNA viruses. Cultures of bovine viral diarrhea virus, canine distemper virus (CDV), epizootic hemorrhagic disease virus, infectious bronchitis virus, 2 influenza A viruses, and porcine respiratory and reproductive syndrome virus were sequenced on the MinION platform using a random, reverse primer in a strand-switching reaction, coupled with PCR-based barcoding. Reads were taxonomically classified and used for reference-based sequence building using a stock personal computer. This method accurately detected and identified complete coding sequence genomes with a minimum of 20× coverage depth for all 7 viruses, including a sample containing 2 viruses. Each lineage-typing region had at least 26× coverage depth for all viruses. Furthermore, analyzing the CDV sample through a pipeline devoid of CDV reference sequences modeled the ability of this protocol to detect unknown viruses. Our results show the ability of this technique to detect and characterize dsRNA, negative- and positive-sense ssRNA, and nonsegmented and segmented RNA viruses.

scholarly journals Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway

2015 ◽  
Vol 90 (5) ◽  
pp. 2372-2387 ◽  
Author(s):  
Sowmya Pattabhi ◽  
Courtney R. Wilkins ◽  
Ran Dong ◽  
Megan L. Knoll ◽  
Jeffrey Posakony ◽  
...  
Keyword(s):  
Small Molecule ◽  
Influenza A ◽  
Ebola Virus ◽  
Rna Viruses ◽  
Nipah Virus ◽  
Innate Immune ◽  
Lassa Virus ◽  
Content Type ◽  
Antiviral Responses ◽  
Syncytial Virus

ABSTRACTThe cellular response to virus infection is initiated when pathogen recognition receptors (PRR) engage viral pathogen-associated molecular patterns (PAMPs). This process results in induction of downstream signaling pathways that activate the transcription factor interferon regulatory factor 3 (IRF3). IRF3 plays a critical role in antiviral immunity to drive the expression of innate immune response genes, including those encoding antiviral factors, type 1 interferon, and immune modulatory cytokines, that act in concert to restrict virus replication. Thus, small molecule agonists that can promote IRF3 activation and induce innate immune gene expression could serve as antivirals to induce tissue-wide innate immunity for effective control of virus infection. We identified small molecule compounds that activate IRF3 to differentially induce discrete subsets of antiviral genes. We tested a lead compound and derivatives for the ability to suppress infections caused by a broad range of RNA viruses. Compound administration significantly decreased the viral RNA load in cultured cells that were infected with viruses of the familyFlaviviridae, including West Nile virus, dengue virus, and hepatitis C virus, as well as viruses of the familiesFiloviridae(Ebola virus),Orthomyxoviridae(influenza A virus),Arenaviridae(Lassa virus), andParamyxoviridae(respiratory syncytial virus, Nipah virus) to suppress infectious virus production. Knockdown studies mapped this response to the RIG-I-like receptor pathway. This work identifies a novel class of host-directed immune modulatory molecules that activate IRF3 to promote host antiviral responses to broadly suppress infections caused by RNA viruses of distinct genera.IMPORTANCEIncidences of emerging and reemerging RNA viruses highlight a desperate need for broad-spectrum antiviral agents that can effectively control infections caused by viruses of distinct genera. We identified small molecule compounds that can selectively activate IRF3 for the purpose of identifying drug-like molecules that can be developed for the treatment of viral infections. Here, we report the discovery of a hydroxyquinoline family of small molecules that can activate IRF3 to promote cellular antiviral responses. These molecules can prophylactically or therapeutically control infection in cell culture by pathogenic RNA viruses, including West Nile virus, dengue virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, Nipah virus, Lassa virus, and Ebola virus. Our study thus identifies a class of small molecules with a novel mechanism to enhance host immune responses for antiviral activity against a variety of RNA viruses that pose a significant health care burden and/or that are known to cause infections with high case fatality rates.

scholarly journals Double-Stranded RNA Is Detected by Immunofluorescence Analysis in RNA and DNA Virus Infections, Including Those by Negative-Stranded RNA Viruses

2015 ◽  
Vol 89 (18) ◽  
pp. 9383-9392 ◽  
Author(s):  
Kyung-No Son ◽  
Zhiguo Liang ◽  
Howard L. Lipton
Keyword(s):  
Influenza A ◽  
Rna Viruses ◽  
Rna Virus ◽  
Immunofluorescence Staining ◽  
Virus Infections ◽  
Double Stranded Rna ◽  
Negative Strand ◽  
Animal Virus ◽  
Rna And Dna ◽  
Dsrna Species

ABSTRACTEarly biochemical studies of viral replication suggested that most viruses produce double-stranded RNA (dsRNA), which is essential for the induction of the host immune response. However, it was reported in 2006 that dsRNA could be detected by immunofluorescence antibody staining in double-stranded DNA and positive-strand RNA virus infections but not in negative-strand RNA virus infections. Other reports in the literature seemed to support these observations. This suggested that negative-strand RNA viruses produce little, if any, dsRNA or that more efficient viral countermeasures to mask dsRNA are mounted. Because of our interest in the use of dsRNA antibodies for virus discovery, particularly in pathological specimens, we wanted to determine how universal immunostaining for dsRNA might be in animal virus infections. We have detected thein situformation of dsRNA in cells infected with vesicular stomatitis virus, measles virus, influenza A virus, and Nyamanini virus, which represent viruses from different negative-strand RNA virus families. dsRNA was also detected in cells infected with lymphocytic choriomeningitis virus, an ambisense RNA virus, and minute virus of mice (MVM), a single-stranded DNA (ssDNA) parvovirus, but not hepatitis B virus. Although dsRNA staining was primarily observed in the cytoplasm, it was also seen in the nucleus of cells infected with influenza A virus, Nyamanini virus, and MVM. Thus, it is likely that most animal virus infections produce dsRNA species that can be detected by immunofluorescence staining. The apoptosis induced in several uninfected cell lines failed to upregulate dsRNA formation.IMPORTANCEAn effective antiviral host immune response depends on recognition of viral invasion and an intact innate immune system as a first line of defense. Double-stranded RNA (dsRNA) is a viral product essential for the induction of innate immunity, leading to the production of type I interferons (IFNs) and the activation of hundreds of IFN-stimulated genes. The present study demonstrates that infections, including those by ssDNA viruses and positive- and negative-strand RNA viruses, produce dsRNAs detectable by standard immunofluorescence staining. While dsRNA staining was primarily observed in the cytoplasm, nuclear staining was also present in some RNA and DNA virus infections. The nucleus is unlikely to have pathogen-associated molecular pattern (PAMP) receptors for dsRNA because of the presence of host dsRNA molecules. Thus, it is likely that most animal virus infections produce dsRNA species detectable by immunofluorescence staining, which may prove useful in viral discovery as well.

TMPRSS2 is essential for pathogenicity of H7N9 and H1N1 influenza A viruses in mice

Pneumologie ◽  
2014 ◽  
Vol 68 (02) ◽  
Author(s):  
C Tarnow ◽  
G Engels ◽  
A Arendt ◽  
F Schwalm ◽  
H Sediri ◽  
...  
Keyword(s):  
Influenza A ◽  
H1n1 Influenza ◽  
Influenza A Viruses

Killing two birds with one stone – Prenylated flavonoids disrupt the lethal synergism of influenza A viruses and pneumococci

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
U Grienke ◽  
M Richter ◽  
E Walther ◽  
A Hoffmann ◽  
J Kirchmair ◽  
...  
Keyword(s):  
Influenza A ◽  
Influenza A Viruses ◽  
Prenylated Flavonoids
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