scholarly journals Insertions of codons encoding basic amino acids in H7 hemagglutinins of influenza A viruses occur by recombination with RNA at hotspots near snoRNA binding sites

2020 ◽  
Author(s):  
Alexander P. Gultyaev ◽  
Monique I. Spronken ◽  
Mathis Funk ◽  
Ron A.M. Fouchier ◽  
Mathilde Richard
Keyword(s):  
Amino Acids ◽  
Cleavage Site ◽  
Influenza A ◽  
Rna Recombination ◽  
Influenza A Viruses ◽  
Rna Sequences ◽  
Rna Molecules ◽  
Basic Amino Acids ◽  
Molecular Determinant ◽  
Ha Protein

ABSTRACTThe presence of multiple basic amino acids in the protease cleavage site of the hemagglutinin (HA) protein is the main molecular determinant of virulence of highly pathogenic avian influenza (HPAI) viruses. Recombination of HA RNA with other RNA molecules of host or virus origin is a dominant mechanism of multi basic cleavage site (MBCS) acquisition for H7 subtype HA. Using alignments of HA RNA sequences from documented cases of MBCS insertion due to recombination, we show that such recombination with host RNAs is most likely to occur at particular hotspots in ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and viral RNAs. The locations of these hotspots in highly abundant RNAs indicate that RNA recombination is facilitated by the binding of small nucleolar RNA (snoRNA) near the recombination points.

scholarly journals Insertions of codons encoding basic amino acids in H7 hemagglutinins of influenza A viruses occur by recombination with RNA at hotspots near snoRNA binding sites

RNA ◽  
2020 ◽  
pp. rna.077495.120
Author(s):  
Alexander P Gultyaev ◽  
Monique I Spronken ◽  
Mathis Funk ◽  
Ron A.M. Fouchier ◽  
Mathilde Richard
Keyword(s):  
Amino Acids ◽  
Binding Sites ◽  
Influenza A ◽  
Influenza A Viruses ◽  
Basic Amino Acids

scholarly journals Effects of Basic Amino Acids and Their Derivatives on SARS-CoV-2 and Influenza-A Virus Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1301
Author(s):  
Ivonne Melano ◽  
Li-Lan Kuo ◽  
Yan-Chung Lo ◽  
Po-Wei Sung ◽  
Ni Tien ◽  
...  
Keyword(s):  
Amino Acids ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Enveloped Viruses ◽  
Virus Attachment ◽  
Basic Amino Acids ◽  
Ester Derivative ◽  
Endosomal Acidification

Amino acids have been implicated with virus infection and replication. Here, we demonstrate the effects of two basic amino acids, arginine and lysine, and their ester derivatives on infection of two enveloped viruses, SARS-CoV-2, and influenza A virus. We found that lysine and its ester derivative can efficiently block infection of both viruses in vitro. Furthermore, the arginine ester derivative caused a significant boost in virus infection. Studies on their mechanism of action revealed that the compounds potentially disturb virus uncoating rather than virus attachment and endosomal acidification. Our findings suggest that lysine supplementation and the reduction of arginine-rich food intake can be considered as prophylactic and therapeutic regimens against these viruses while also providing a paradigm for the development of broad-spectrum antivirals.

scholarly journals The RNA origin of transfer RNA aminoacylation and beyond

2011 ◽  
Vol 366 (1580) ◽  
pp. 2959-2964 ◽  
Author(s):  
Hiroaki Suga ◽  
Gosuke Hayashi ◽  
Naohiro Terasaka
Keyword(s):  
Amino Acids ◽  
Evolutionary History ◽  
Transfer Rna ◽  
Translation System ◽  
Rna Sequences ◽  
Rna Molecules ◽  
Rna Catalysts ◽  
Modern System ◽  
History Of

Aminoacylation of tRNA is an essential event in the translation system. Although in the modern system protein enzymes play the sole role in tRNA aminoacylation, in the primitive translation system RNA molecules could have catalysed aminoacylation onto tRNA or tRNA-like molecules. Even though such RNA enzymes so far are not identified from known organisms, in vitro selection has generated such RNA catalysts from a pool of random RNA sequences. Among them, a set of RNA sequences, referred to as flexizymes (Fxs), discovered in our laboratory are able to charge amino acids onto tRNAs. Significantly, Fxs allow us to charge a wide variety of amino acids, including those that are non-proteinogenic, onto tRNAs bearing any desired anticodons, and thus enable us to reprogramme the genetic code at our will. This article summarizes the evolutionary history of Fxs and also the most recent advances in manipulating a translation system by integration with Fxs.

scholarly journals Plasticity of the Influenza Virus H5 HA Protein

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huihui Kong ◽  
David F. Burke ◽  
Tiago Jose da Silva Lopes ◽  
Kosuke Takada ◽  
Masaki Imai ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Mammalian Cells ◽  
Influenza A ◽  
Viral Antigen ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Highly Pathogenic ◽  
Antigenic Properties ◽  
Ha Protein

ABSTRACT Since the emergence of highly pathogenic avian influenza viruses of the H5 subtype, the major viral antigen, hemagglutinin (HA), has undergone constant evolution, resulting in numerous genetic and antigenic (sub)clades. To explore the consequences of amino acid changes at sites that may affect the antigenicity of H5 viruses, we simultaneously mutated 17 amino acid positions of an H5 HA by using a synthetic gene library that, theoretically, encodes all combinations of the 20 amino acids at the 17 positions. All 251 mutant viruses sequenced possessed ≥13 amino acid substitutions in HA, demonstrating that the targeted sites can accommodate a substantial number of mutations. Selection with ferret sera raised against H5 viruses of different clades resulted in the isolation of 39 genotypes. Further analysis of seven variants demonstrated that they were antigenically different from the parental virus and replicated efficiently in mammalian cells. Our data demonstrate the substantial plasticity of the influenza virus H5 HA protein, which may lead to novel antigenic variants. IMPORTANCE The HA protein of influenza A viruses is the major viral antigen. In this study, we simultaneously introduced mutations at 17 amino acid positions of an H5 HA expected to affect antigenicity. Viruses with ≥13 amino acid changes in HA were viable, and some had altered antigenic properties. H5 HA can therefore accommodate many mutations in regions that affect antigenicity. The substantial plasticity of H5 HA may facilitate the emergence of novel antigenic variants.

scholarly journals Targeting Hemagglutinin: Approaches for Broad Protection against the Influenza A Virus

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 405 ◽  
Author(s):  
Zhang ◽  
Xu ◽  
Zhang ◽  
Liu ◽  
Xue ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Protective Efficacy ◽  
Structure And Function ◽  
Antigenic Drift ◽  
Influenza A Viruses ◽  
Universal Vaccine ◽  
Vaccine Candidates ◽  
And Function ◽  
Ha Protein

Influenza A viruses are dynamically epidemic and genetically diverse. Due to the antigenic drift and shift of the virus, seasonal vaccines are required to be reformulated annually to match with current circulating strains. However, the mismatch between vaccinal strains and circulating strains occurs frequently, resulting in the low efficacy of seasonal vaccines. Therefore, several “universal” vaccine candidates based on the structure and function of the hemagglutinin (HA) protein have been developed to meet the requirement of a broad protection against homo-/heterosubtypic challenges. Here, we review recent novel constructs and discuss several important findings regarding the broad protective efficacy of HA-based universal vaccines.

scholarly journals Insertion of Basic Amino Acids in the Hemagglutinin Cleavage Site of H4N2 Avian Influenza Virus (AIV)—Reduced Virus Fitness in Chickens is Restored by Reassortment with Highly Pathogenic H5N1 AIV

2020 ◽  
Vol 21 (7) ◽  
pp. 2353
Author(s):  
Marcel Gischke ◽  
Reiner Ulrich ◽  
Olanrewaju I. Fatola ◽  
David Scheibner ◽  
Ahmed H. Salaheldin ◽  
...  
Keyword(s):  
Amino Acids ◽  
Avian Influenza ◽  
Cleavage Site ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Highly Pathogenic ◽  
Basic Amino Acids ◽  
The Impact ◽  
Virus Fitness

Highly pathogenic (HP) avian influenza viruses (AIVs) are naturally restricted to H5 and H7 subtypes with a polybasic cleavage site (CS) in hemagglutinin (HA) and any AIV with an intravenous pathogenicity index (IVPI) ≥ 1.2. Although only a few non-H5/H7 viruses fulfill the criteria of HPAIV; it remains unclear why these viruses did not spread in domestic birds. In 2012, a unique H4N2 virus with a polybasic CS 322PEKRRTR/G329 was isolated from quails in California which, however, was avirulent in chickens. This is the only known non-H5/H7 virus with four basic amino acids in the HACS. Here, we investigated the virulence of this virus in chickens after expansion of the polybasic CS by substitution of T327R (322PEKRRRR/G329) or T327K (322PEKRRKR/G329) with or without reassortment with HPAIV H5N1 and H7N7. The impact of single mutations or reassortment on virus fitness in vitro and in vivo was studied. Efficient cell culture replication of T327R/K carrying H4N2 viruses increased by treatment with trypsin, particularly in MDCK cells, and reassortment with HPAIV H5N1. Replication, virus excretion and bird-to-bird transmission of H4N2 was remarkably compromised by the CS mutations, but restored after reassortment with HPAIV H5N1, although not with HPAIV H7N7. Viruses carrying the H4-HA with or without R327 or K327 mutations and the other seven gene segments from HPAIV H5N1 exhibited high virulence and efficient transmission in chickens. Together, increasing the number of basic amino acids in the H4N2 HACS was detrimental for viral fitness particularly in vivo but compensated by reassortment with HPAIV H5N1. This may explain the absence of non-H5/H7 HPAIV in poultry.

scholarly journals Matriptase, HAT, and TMPRSS2 Activate the Hemagglutinin of H9N2 Influenza A Viruses

2012 ◽  
Vol 87 (3) ◽  
pp. 1811-1820 ◽  
Author(s):  
Joanna Baron ◽  
Carolin Tarnow ◽  
Deborah Mayoli-Nüssle ◽  
Eva Schilling ◽  
Daniela Meyer ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Influenza A ◽  
Surface Glycoprotein ◽  
Virus Infectivity ◽  
Kidney Cells ◽  
Cleavage Sites ◽  
Influenza A Viruses ◽  
Proteolytic Activation ◽  
Wide Range ◽  
Canine Kidney

ABSTRACTInfluenza A viruses of the subtype H9N2 circulate worldwide and have become highly prevalent in poultry in many countries. Moreover, they are occasionally transmitted to humans, raising concern about their pandemic potential. Influenza virus infectivity requires cleavage of the surface glycoprotein hemagglutinin (HA) at a distinct cleavage site by host cell proteases. H9N2 viruses vary remarkably in the amino acid sequence at the cleavage site, and many isolates from Asia and the Middle East possess the multibasic motifs R-S-S-R and R-S-R-R, but are not activated by furin. Here, we investigated proteolytic activation of the early H9N2 isolate A/turkey/Wisconsin/1/66 (H9-Wisc) and two recent Asian isolates, A/quail/Shantou/782/00 (H9-782) and A/quail/Shantou/2061/00 (H9-2061), containing mono-, di-, and tribasic HA cleavage sites, respectively. All H9N2 isolates were activated by human proteases TMPRSS2 (transmembrane protease, serine S1 member 2) and HAT (human airway trypsin-like protease). Interestingly, H9-782 and H9-2061 were also activated by matriptase, a protease widely expressed in most epithelia with high expression levels in the kidney. Nephrotropism of H9N2 viruses has been observed in chickens, and here we found that H9-782 and H9-2061 were proteolytically activated in canine kidney (MDCK-II) and chicken embryo kidney (CEK) cells, whereas H9-Wisc was not. Virus activation was inhibited by peptide-mimetic inhibitors of matriptase, strongly suggesting that matriptase is responsible for HA cleavage in these kidney cells. Our data demonstrate that H9N2 viruses with R-S-S-R or R-S-R-R cleavage sites are activated by matriptase in addition to HAT and TMPRSS2 and, therefore, can be activated in a wide range of tissues what may affect virus spread, tissue tropism and pathogenicity.

scholarly journals Minor variants of swine H1N1 influenza viruses with enhanced polymerase activity and HA stability promote airborne transmission in ferrets

2021 ◽  
Author(s):  
Meng Hu ◽  
Jeremy Jones ◽  
Balaji Banoth ◽  
Chet R Ojha ◽  
Jeri Carol Crumpton ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Deep Sequencing ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Polymerase Activity ◽  
Protein Stabilization ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Airborne Transmission ◽  
Ha Protein

Understanding how animal influenza A viruses (IAVs) acquire airborne transmissibility in humans and ferrets is needed to prepare for and respond to pandemics. Previously, we showed that hemagglutinin (HA) protein stabilization promotes replication and airborne transmission in ferrets using swine H1N1 gamma strains P4 and G15 (Hu et al. 2020). Here, we show that a combination of enhanced polymerase activity and HA stability is necessary for efficient airborne transmission in ferrets and that minor variants containing both properties are quickly selected. P4 and G15 were found to have decreased polymerase activity and relatively poor HA stability, respectively. Polymerase-enhancing variant PA-S321 was selected in half of P4 isolates that airborne-transmitted in ferrets. HA-stabilizing variant HA1-S210 was selected in all G15-inoculated ferrets and was transmitted. With an efficient polymerase and a stable HA, purified G15-HA1-S210 had earlier and higher peak titers in inoculated ferrets and was recovered at a higher frequency after airborne transmission than P4 and G15. Pandemic risk-assessment studies may benefit from deep sequencing capable of identifying minor variants with human-adapted traits.

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