scholarly journals S-Acylation of Proteins of Coronavirus and Influenza Virus: Conservation of Acylation Sites in Animal Viruses and DHHC Acyltransferases in Their Animal Reservoirs

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 669
Author(s):  
Dina A. Abdulrahman ◽  
Xiaorong Meng ◽  
Michael Veit
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Ion Channels ◽  
Substrate Specificity ◽  
Influenza A ◽  
3D Structure ◽  
Viral Fitness ◽  
Amino Acid Substitutions ◽  
Essential Function ◽  
Animal Reservoirs

Recent pandemics of zoonotic origin were caused by members of coronavirus (CoV) and influenza A (Flu A) viruses. Their glycoproteins (S in CoV, HA in Flu A) and ion channels (E in CoV, M2 in Flu A) are S-acylated. We show that viruses of all genera and from all hosts contain clusters of acylated cysteines in HA, S and E, consistent with the essential function of the modification. In contrast, some Flu viruses lost the acylated cysteine in M2 during evolution, suggesting that it does not affect viral fitness. Members of the DHHC family catalyze palmitoylation. Twenty-three DHHCs exist in humans, but the number varies between vertebrates. SARS-CoV-2 and Flu A proteins are acylated by an overlapping set of DHHCs in human cells. We show that these DHHC genes also exist in other virus hosts. Localization of amino acid substitutions in the 3D structure of DHHCs provided no evidence that their activity or substrate specificity is disturbed. We speculate that newly emerged CoVs or Flu viruses also depend on S-acylation for replication and will use the human DHHCs for that purpose. This feature makes these DHHCs attractive targets for pan-antiviral drugs.

scholarly journals Characterization of H9N2 influenza A viruses isolated from chicken products imported into Japan from China

2006 ◽  
Vol 135 (3) ◽  
pp. 386-391 ◽  
Author(s):  
M. MASE ◽  
M. ETO ◽  
K. IMAI ◽  
K. TSUKAMOTO ◽  
S. YAMAGUCHI
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Influenza A ◽  
H9n2 Virus ◽  
Amino Acid Substitutions ◽  
Influenza A Viruses ◽  
Potential Sources

We characterized eleven H9N2 influenza A viruses isolated from chicken products imported from China. Genetically they were classified into six distinct genotypes, including five already known genotypes and one novel genotype. This suggested that such multiple genotypes of the H9N2 virus have possibly already become widespread and endemic in China. Two isolates have amino-acid substitutions that confer resistance to amantadine in the M2 region, and this supported the evidence that this mutation might be a result of the wide application of amantadine for avian influenza treatment in China. These findings emphasize the importance of surveillance for avian influenza virus in this region, and of quarantining imported chicken products as potential sources for the introduction of influenza virus.

scholarly journals Functional Constraints of Influenza A Virus Epitopes Limit Escape from Cytotoxic T Lymphocytes

2005 ◽  
Vol 79 (17) ◽  
pp. 11239-11246 ◽  
Author(s):  
E. G. M. Berkhoff ◽  
E. de Wit ◽  
M. M. Geelhoed-Mieras ◽  
A. C. M. Boon ◽  
J. Symons ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Lymphocytes ◽  
Influenza A Virus ◽  
Cytotoxic T Lymphocytes ◽  
Influenza A ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Amino Acid Substitutions ◽  
Functional Constraints ◽  
Ctl Epitopes

ABSTRACT Viruses can exploit a variety of strategies to evade immune surveillance by cytotoxic T lymphocytes (CTL), including the acquisition of mutations in CTL epitopes. Also for influenza A viruses a number of amino acid substitutions in the nucleoprotein (NP) have been associated with escape from CTL. However, other previously identified influenza A virus CTL epitopes are highly conserved, including the immunodominant HLA-A*0201-restricted epitope from the matrix protein, M158-66. We hypothesized that functional constraints were responsible for the conserved nature of influenza A virus CTL epitopes, limiting escape from CTL. To assess the impact of amino acid substitutions in conserved epitopes on viral fitness and recognition by specific CTL, we performed a mutational analysis of CTL epitopes. Both alanine replacements and more conservative substitutions were introduced at various positions of different influenza A virus CTL epitopes. Alanine replacements for each of the nine amino acids of the M158-66 epitope were tolerated to various extents, except for the anchor residue at the second position. Substitution of anchor residues in other influenza A virus CTL epitopes also affected viral fitness. Viable mutant viruses were used in CTL recognition experiments. The results are discussed in the light of the possibility of influenza viruses to escape from specific CTL. It was speculated that functional constraints limit variation in certain epitopes, especially at anchor residues, explaining the conserved nature of these epitopes.

scholarly journals Multiple Natural Substitutions in Avian Influenza A Virus PB2 Facilitate Efficient Replication in Human Cells

2016 ◽  
Vol 90 (13) ◽  
pp. 5928-5938 ◽  
Author(s):  
Benjamin Mänz ◽  
Miranda de Graaf ◽  
Ramona Mögling ◽  
Mathilde Richard ◽  
Theo M. Bestebroer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Avian Influenza ◽  
Mammalian Cells ◽  
Influenza A ◽  
Polymerase Activity ◽  
Host Adaptation ◽  
Influenza Viruses ◽  
Amino Acid Substitutions ◽  
Avian Influenza A Virus

ABSTRACTA strong restriction of the avian influenza A virus polymerase in mammalian cells generally limits viral host-range switching. Although substitutions like E627K in the PB2 polymerase subunit can facilitate polymerase activity to allow replication in mammals, many human H5N1 and H7N9 viruses lack this adaptive substitution. Here, several previously unknown, naturally occurring, adaptive substitutions in PB2 were identified by bioinformatics, and their enhancing activity was verified usingin vitroassays. Adaptive substitutions enhanced polymerase activity and virus replication in mammalian cells for avian H5N1 and H7N9 viruses but not for a partially human-adapted H5N1 virus. Adaptive substitutions toward basic amino acids were frequent and were mostly clustered in a putative RNA exit channel in a polymerase crystal structure. Phylogenetic analysis demonstrated divergent dependency of influenza viruses on adaptive substitutions. The novel adaptive substitutions found in this study increase basic understanding of influenza virus host adaptation and will help in surveillance efforts.IMPORTANCEInfluenza viruses from birds jump the species barrier into humans relatively frequently. Such influenza virus zoonoses may pose public health risks if the virus adapts to humans and becomes a pandemic threat. Relatively few amino acid substitutions—most notably in the receptor binding site of hemagglutinin and at positions 591 and 627 in the polymerase protein PB2—have been identified in pandemic influenza virus strains as determinants of host adaptation, to facilitate efficient virus replication and transmission in humans. Here, we show that substantial numbers of amino acid substitutions are functionally compensating for the lack of the above-mentioned mutations in PB2 and could facilitate influenza virus emergence in humans.

scholarly journals In Vitro Assessment of Attachment Pattern and Replication Efficiency of H5N1 Influenza A Viruses with Altered Receptor Specificity

2010 ◽  
Vol 84 (13) ◽  
pp. 6825-6833 ◽  
Author(s):  
Salin Chutinimitkul ◽  
Debby van Riel ◽  
Vincent J. Munster ◽  
Judith M. A. van den Brand ◽  
Guus F. Rimmelzwaan ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Respiratory Tract ◽  
Influenza A Virus ◽  
Influenza A ◽  
Amino Acid Substitutions ◽  
Human Influenza ◽  
Receptor Specificity ◽  
Hpai H5n1 ◽  
Attachment Pattern

ABSTRACT The continuous circulation of the highly pathogenic avian influenza (HPAI) H5N1 virus has been a cause of great concern. The possibility of this virus acquiring specificity for the human influenza A virus receptor, α2,6-linked sialic acids (SA), and being able to transmit efficiently among humans is a constant threat to human health. Different studies have described amino acid substitutions in hemagglutinin (HA) of clinical HPAI H5N1 isolates or that were introduced experimentally that resulted in an increased, but not exclusive, binding of these virus strains to α2,6-linked SA. We introduced all previously described amino acid substitutions and combinations thereof into a single genetic background, influenza virus A/Indonesia/5/05 HA, and tested the receptor specificity of these 27 mutant viruses. The attachment pattern to ferret and human tissues of the upper and lower respiratory tract of viruses with α2,6-linked SA receptor preference was then determined and compared to the attachment pattern of a human influenza A virus (H3N2). At least three mutant viruses showed an attachment pattern to the human respiratory tract similar to that of the human H3N2 virus. Next, the replication efficiencies of these mutant viruses and the effects of three different neuraminidases on virus replication were determined. These data show that influenza virus A/Indonesia/5/05 potentially requires only a single amino acid substitution to acquire human receptor specificity, while at the same time remaining replication competent, thus suggesting that the pandemic threat posed by HPAI H5N1 is far from diminished.

scholarly journals Antigenic drift in influenza A viruses. I. Selection and characterization of antigenic variants of A/PR/8/34 [HON1] influenza virus with monoclonal antibodies

1978 ◽  
Vol 148 (2) ◽  
pp. 383-392 ◽  
Author(s):  
W Gerhard ◽  
RG Webster
Keyword(s):  
Influenza Virus ◽  
Monoclonal Antibodies ◽  
Amino Acid ◽  
Influenza A ◽  
Antigenic Drift ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Parent Virus ◽  
Influenza A Viruses

Antigenic variants of A/PR/8/34 [HON1] influenza virus were selected after a single passage of the parent virus in embryonated chicken eggs in the presence of monoclonal antibodies to this virus. The monoclonal antibodies were produced by a hybridoma and were specific for an antigenic determinant on the HA molecule of the parent virus. Seven antigenic variants were analyzed with 95 monoclonal anti-HA antibodies prepared in vitro in the splenic fragment culture system. Three subgroups of antigenic variants were distinguished. The antigenic changes were primarily recognized by monoclonal antibodies to the strain- specific determinants of the parental hemagglutinin (HA) molecule. Monoclonal antibodies to HA determinants shared (in an identical or cross-reactive form) by parental virus and more than three heterologous viruses of the HON1 and H1N1 subtypes were unable to recognize the antigenic change on the variants. Similarly, heterogeneous antibody preparations could not differentiate between parental and variant viruses. The results are compatible with the idea that the HA of PR8 has available a large repertoire of antigenic modifications that may result from single amino acid substitutions, and that antigenic changes can occur in the strain- specific determinants on the HA molecule in the absence of concomitant changes in the cross-reactive HA determinants. The findings suggest that antigenic drift, in order to be epidemiologically significant, probably requires a series of amino acid substitutions in, or close to, the antigenic area on the HA molecule.

scholarly journals Predominance of a Drifted Influenza A (H3N2) Clade and Its Association with Age-Specific Influenza Vaccine Effectiveness Variations, Influenza Season 2018–2019

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 78 ◽  
Author(s):  
Aharona Glatman-Freedman ◽  
Rakefet Pando ◽  
Hanna Sefty ◽  
Itay Omer ◽  
Alina Rosenberg ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Influenza A ◽  
Gene Mutations ◽  
Vaccine Virus ◽  
Vaccine Effectiveness ◽  
Influenza Viruses ◽  
Amino Acid Substitutions ◽  
Ha Gene ◽  
H3n2 Vaccine

Background: Influenza A (H3N2) clade 3C.3a was the predominant influenza virus in Israel throughout the 2018-2019 season, constituting a drift from the influenza A (H3N2) vaccine. We estimated the end-of season vaccine effectiveness (VE) by age, among community patients with influenza-like illness (ILI), considering the hemagglutinin (HA) gene mutations and amino acid substitutions of influenza A (H3N2) viruses detected. Methods: Nose-throat samples were analyzed for the presence of influenza virus, type/subtype, and HA gene sequence. HA gene sequences and amino acid substitutions were compared to the influenza A/Singapore/INFIMH-16-0019/2016 (H3N2)-like 2018-2019 vaccine virus, and a phylogenetic tree was generated. Influenza VE against influenza A (H3N2) was estimated using the test-negative design. VE was estimated by age group and by 15 year moving age intervals. Results: In total, 90% of the influenza A (H3N2) viruses belonged to the 3C.3a clade, constituting a unique situation in the northern hemisphere. Adjusted all-age influenza A (H3N2) VE was −3.5% (95% CI: −51.2 to 29.1). Although adjusted VEs were very low among infants, children, and young adults, a VE of 45% (95% CI: −19.2 to 74.6) was estimated among adults aged ≥45 years old. Conclusions: The higher VE point estimates among older adults may be related to previous exposure to similar influenza viruses.

scholarly journals Mutations in the alpha 2 helix of HLA-A2 affect presentation but do not inhibit binding of influenza virus matrix peptide.

1988 ◽  
Vol 168 (2) ◽  
pp. 725-736 ◽  
Author(s):  
K T Hogan ◽  
N Shimojo ◽  
S F Walk ◽  
V H Engelhard ◽  
W L Maloy ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Binding Site ◽  
Influenza A ◽  
Matrix Protein ◽  
Peptide Binding ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Apparent Difference ◽  
Peptide Binding Site

Previous studies have suggested that MHC class I molecules bind and present peptides to CTL in a manner that is analogous to the presentation of peptides by class II molecules to Th. Crystallographic studies of HLA-A2 have led to the assignment of a putative peptide binding site that is bordered by two alpha helices consisting of residues 50-84 and 138-180. In this study, we have investigated whether residues in the alpha 2 helix are involved in the binding and/or presentation of a peptide to CTL. We have generated CTL to type A influenza virus by stimulation of human PBL with a synthetic peptide from the influenza A virus matrix protein (M1 residues 57-68) in the presence of rIL-2. Such HLA-A2.1-restricted influenza virus-immune CTL do not recognize infected HLA-A2.3+ targets. A2.1 and A2.3 differ by three amino acids in the alpha 2 domain: Ala vs. Thr at position 149, Val vs. Glu at position 152, and Leu vs. Trp at position 156. Site-directed mutants of the A2.1 gene that encode A2 molecules that resemble A2.3 at positions 149, 152, and 156 have been constructed, transfected into human cells, and assayed for their ability to present the M1 peptide. The results demonstrate that most, but not all, A2.1-restricted M1-peptide-specific CTL fail to recognize M1 peptide-exposed transfectants with certain single amino acid substitutions at positions 152 and 156. In contrast, M1 peptide-exposed transfectants that express A2 molecules with an Ala----Thr substitution at position 149 were recognized by all CTL tested, but they exhibited an apparent difference in the kinetics of peptide binding. These results indicate that amino acid substitutions at positions 152 and 156 of the putative peptide binding site of the A2 molecule can affect presentation without eliminating binding, and indicate that the failure to recognize complexes between the peptide and the mutant A2 molecules is due to different TCR specificities and not to the failure to bind the peptide.

Detection of Variants With Reduced Baloxavir Marboxil Susceptibility After Treatment of Children With Influenza A During the 2018–2019 Influenza Season

2020 ◽  
Vol 222 (1) ◽  
pp. 121-125 ◽  
Author(s):  
Masatoki Sato ◽  
Emi Takashita ◽  
Masahiko Katayose ◽  
Kenji Nemoto ◽  
Nobuko Sakai ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Ribonucleic Acid ◽  
Influenza A ◽  
Clinical Symptoms ◽  
Influenza Season ◽  
Virus Titer ◽  
Amino Acid Substitutions

Abstract During the 2018–2019 influenza seasons, we detected reduced baloxavir marboxil (baloxavir) susceptible variants with I38S or I38T amino acid substitutions on the PA subunit of influenza virus ribonucleic acid polymerase in 7 of 18 baloxavi-treated children and found that virus titer rebounded in some of these children with variants. We also found fever durations to be similar between patients with or without the variants, but the patients with variants shed the virus 3 days longer and took longer to improve clinical symptoms than those without variants. The emergence of these variants should be monitored during future influenza seasons.

scholarly journals Identification of mammalian-adapting mutations involved into antigenic change of H1N1 influenza virus

2020 ◽  
Author(s):  
Zhijun Yu ◽  
Kaihui Cheng ◽  
Weiyang Sun ◽  
Xinghai Zhang ◽  
Tiecheng Wang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Influenza A ◽  
H1n1 Virus ◽  
Serial Passage ◽  
Antigenic Drift ◽  
Amino Acid Substitutions ◽  
Pandemic H1n1 ◽  
Potential Threat ◽  
Ha Protein

Abstract Though the 2009 pandemic H1N1 virus has become a seasonal influenza A virus, continued host adaptation and antigenic drift may limit the effectiveness of current vaccines. Here, we assess viral antigenic change of a 2009 pandemic H1N1 virus (A/Changchun/01/2009) in the absence and presence of immune-mediated selective pressures and further identify the key amino acid substitutions involved into the antigenic change of the 2009 pandemic H1N1 virus. We found that serial passage of the 2009 pandemic H1N1 virus in both naïve and previously immunized mice generated antigenically distinct variants and that serial passage in previously immunized mice generated viruses with lower overall antigenic relatedness to the parental virus when compared to variants generated by serial passage in naïve mice, suggesting that antibody pressure may accelerate the antigenic variation rate of the 2009 pandemic H1N1 virus. Furthermore, we found that three amino acid substitutions in the viral HA protein (N159D, S186P, and D225G), both alone and in combination, affected viral antigenicity. It is noted that all three mutations (N159D, S186P, and D225G) in the viral HA protein have been found in the natural 2009 pandemic H1N1 virus isolates and can also enhance the pathogenicity of the 2009 pandemic H1N1 virus to mammals, suggesting that these mutations in the viral HA protein may pose a potential threat to public health and should be paid more attention. Taken together, our work defines some novel molecular determinants of the pandemic H1N1 virus antigenicity and has important implications for ongoing human influenza virus surveillance efforts.

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