scholarly journals Selection on non-antigenic gene segments of seasonal influenza A virus and its impact on adaptive evolution

2017 ◽  
Author(s):  
Jayna Raghwani ◽  
Robin Thompson ◽  
Katia Koelle
Keyword(s):  
Adaptive Evolution ◽  
Genetic Background ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Evolutionary Dynamics ◽  
Gene Segment ◽  
Influenza Viruses ◽  
Neutral Evolution ◽  
H3n2 Virus ◽  
Genome Wide

ABSTRACTMost studies on seasonal influenza A/H3N2 virus adaptation have focused on the main antigenic gene, haemagglutinin. However, there is increasing evidence that the genome-wide genetic background of novel antigenic variants can influence these variants’ emergence probabilities and impact their patterns of dominance in the population. This suggests that non-antigenic genes may be important in shaping the viral evolutionary dynamics. To better understand the role of selection on non-antigenic genes in the adaptive evolution of seasonal influenza viruses, we here develop a simple population genetic model that considers a virus with one antigenic and one non-antigenic gene segment. By simulating this model under different regimes of selection and reassortment, we find that the empirical patterns of lineage turnover for the antigenic and non-antigenic gene segments are best captured when there is both limited viral coinfection and selection operating on both gene segments. In contrast, under a scenario of only neutral evolution in the non-antigenic gene segment, we see persistence of multiple lineages for long periods of time in that segment, which is not compatible with the observed molecular evolutionary patterns. Further, we find that reassortment, occurring in coinfected individuals, can increase the speed of viral adaptive evolution by primarily reducing selective interference and genetic linkage effects mediated by the non-antigenic gene segment. Together, these findings suggest that, for influenza, with 6 internal or non-antigenic gene segments, the evolutionary dynamics of novel antigenic variants are likely to be influenced by the genome-wide genetic background as a result of linked selection among both beneficial and deleterious mutations.

scholarly journals The Dynamics of Influenza A H3N2 Defective Viral Genomes from a Human Challenge Study

2019 ◽  
Author(s):  
Michael A. Martin ◽  
Drishti Kaul ◽  
Gene S. Tan ◽  
Christopher W. Woods ◽  
Katia Koelle
Keyword(s):  
Genetic Drift ◽  
Influenza A ◽  
Evolutionary Dynamics ◽  
De Novo ◽  
Gene Segment ◽  
Influenza Viruses ◽  
Genomic Variation ◽  
Wild Type Virus ◽  
Single Nucleotide Variants ◽  
Viral Genomes

AbstractThe rapid evolution of influenza is an important contributing factor to its high worldwide incidence. The emergence and spread of genetic point mutations has been thoroughly studied both within populations and within individual hosts. In addition, influenza viruses are also known to generate genomic variation during their replication in the form of defective viral genomes (DVGs). These DVGs are formed by internal deletions in at least one gene segment that render them incapable of replication without the presence of wild-type virus. DVGs have previously been identified in natural human infections and may be associated with less severe clinical outcomes. These studies have not been able to address how DVG populations evolve in vivo in individual infections due to their cross-sectional design. Here we present an analysis of DVGs present in samples from two longitudinal influenza A H3N2 human challenge studies. We observe the generation of DVGs in almost all subjects. Although the genetic composition of DVG populations was highly variable, identical DVGs were observed both between multiple samples within single hosts as well as between hosts. Most likely due to stochastic effects, we did not observe clear instances of selection for specific DVGs or for shorter DVGs over the course of infection. Furthermore, DVG presence was not found to be associated with peak viral titer or peak symptom scores. Our analyses highlight the diversity of DVG populations within a host over the course of infection and the apparent role that genetic drift plays in their population dynamics.ImportanceThe evolution of influenza virus, in terms of single nucleotide variants and the reassortment of gene segments, has been studied in detail. However, influenza is known to generate defective viral genomes (DVGs) during replication, and little is known about how these genomes evolve both within hosts and at the population level. Studies in animal models have indicated that prophylactically or therapeutically administered DVGs can impact patterns of disease progression. However, the formation of naturally-occurring DVGs, their evolutionary dynamics, and their contribution to disease severity in human hosts is not well understood. Here, we identify the formation of de novo DVGs in samples from human challenge studies throughout the course of infection. We analyze their evolutionary trajectories, revealing the important role of genetic drift in shaping DVG populations during acute infections with well-adapted viral strains.

scholarly journals The evolutionary dynamics of influenza A virus adaptation to mammalian hosts

2013 ◽  
Vol 368 (1614) ◽  
pp. 20120382 ◽  
Author(s):  
S. Bhatt ◽  
T. T. Lam ◽  
S. J. Lycett ◽  
A. J. Leigh Brown ◽  
T. A. Bowden ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Adaptive Evolution ◽  
Influenza A ◽  
Evolutionary Dynamics ◽  
Adaptive Dynamics ◽  
Swine Influenza ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Influenza A Viruses ◽  
Entire Genome

Few questions on infectious disease are more important than understanding how and why avian influenza A viruses successfully emerge in mammalian populations, yet little is known about the rate and nature of the virus’ genetic adaptation in new hosts. Here, we measure, for the first time, the genomic rate of adaptive evolution of swine influenza viruses (SwIV) that originated in birds. By using a curated dataset of more than 24 000 human and swine influenza gene sequences, including 41 newly characterized genomes, we reconstructed the adaptive dynamics of three major SwIV lineages (Eurasian, EA; classical swine, CS; triple reassortant, TR). We found that, following the transfer of the EA lineage from birds to swine in the late 1970s, EA virus genes have undergone substantially faster adaptive evolution than those of the CS lineage, which had circulated among swine for decades. Further, the adaptation rates of the EA lineage antigenic haemagglutinin and neuraminidase genes were unexpectedly high and similar to those observed in human influenza A. We show that the successful establishment of avian influenza viruses in swine is associated with raised adaptive evolution across the entire genome for many years after zoonosis, reflecting the contribution of multiple mutations to the coordinated optimization of viral fitness in a new environment. This dynamics is replicated independently in the polymerase genes of the TR lineage, which established in swine following separate transmission from non-swine hosts.

scholarly journals H3N2 Virus as Causative Agent of ARDS Requiring Extracorporeal Membrane Oxygenation Support

2014 ◽  
Vol 2014 ◽  
pp. 1-3
Author(s):  
Adriano Peris ◽  
Giovanni Zagli ◽  
Pasquale Bernardo ◽  
Massimo Bonacchi ◽  
Morena Cozzolino ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Extracorporeal Membrane Oxygenation ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Season ◽  
Influenza Viruses ◽  
H3n2 Virus ◽  
Membrane Oxygenation ◽  
Viral Aetiology ◽  
Increased Risk

Pandemic influenza virus A(H1N1) 2009 was associated with a higher risk of viral pneumonia in comparison with seasonal influenza viruses. The influenza season 2011-2012 was characterized by the prevalent circulation of influenza A(H3N2) viruses. Whereas most H3N2 patients experienced mild, self-limited influenza-like illness, some patients were at increased risk for influenza complications because of age or underlying medical conditions. Cases presented were patients admitted to the Intensive Care Unit (ICU) of ECMO referral center (Careggi Teaching Hospital, Florence, Italy). Despite extracorporeal membrane oxygenation treatment (ECMO), one patient with H3N2-induced ARDS did not survive. Our experience suggests that viral aetiology is becoming more important and hospitals should be able to perform a fast differential diagnosis between bacterial and viral aetiology.

scholarly journals Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

2017 ◽  
Vol 91 (16) ◽  
Author(s):  
Mélia Magnen ◽  
Fabien Gueugnon ◽  
Antoine Guillon ◽  
Thomas Baranek ◽  
Virginie C. Thibault ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Respiratory Tract ◽  
Serine Proteases ◽  
Lower Respiratory Tract ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
H3n2 Virus ◽  
Influenza A Viruses

ABSTRACT Hemagglutinin (HA) of influenza virus must be activated by proteolysis before the virus can become infectious. Previous studies indicated that HA cleavage is driven by membrane-bound or extracellular serine proteases in the respiratory tract. However, there is still uncertainty as to which proteases are critical for activating HAs of seasonal influenza A viruses (IAVs) in humans. This study focuses on human KLK1 and KLK5, 2 of the 15 serine proteases known as the kallikrein-related peptidases (KLKs). We find that their mRNA expression in primary human bronchial cells is stimulated by IAV infection. Both enzymes cleaved recombinant HA from several strains of the H1 and/or H3 virus subtype in vitro, but only KLK5 promoted the infectivity of A/Puerto Rico/8/34 (H1N1) and A/Scotland/20/74 (H3N2) virions in MDCK cells. We assessed the ability of treated viruses to initiate influenza in mice. The nasal instillation of only the KLK5-treated virus resulted in weight loss and lethal outcomes. The secretion of this protease in the human lower respiratory tract is enhanced during influenza. Moreover, we show that pretreatment of airway secretions with a KLK5-selective inhibitor significantly reduced the activation of influenza A/Scotland/20/74 virions, providing further evidence of its importance. Differently, increased KLK1 secretion appeared to be associated with the recruitment of inflammatory cells in human airways regardless of the origin of inflammation. Thus, our findings point to the involvement of KLK5 in the proteolytic activation and spread of seasonal influenza viruses in humans. IMPORTANCE Influenza A viruses (IAVs) cause acute infection of the respiratory tract that affects millions of people during seasonal outbreaks every year. Cleavage of the hemagglutinin precursor by host proteases is a critical step in the life cycle of these viruses. Consequently, host proteases that activate HA can be considered promising targets for the development of new antivirals. However, the specific proteases that activate seasonal influenza viruses, especially H3N2 viruses, in the human respiratory tract have remain undefined despite many years of work. Here we demonstrate that the secreted, extracellular protease KLK5 (kallikrein-related peptidase 5) is efficient in promoting the infectivity of H3N2 IAV in vitro and in vivo. Furthermore, we found that its secretion was selectively enhanced in the human lower respiratory tract during a seasonal outbreak dominated by an H3N2 virus. Collectively, our data support the clinical relevance of this protease in human influenza pathogenesis.

scholarly journals An influenza reassortant with polymerase of pH1N1 and NS gene of H3N2 influenza A virus is attenuated in vivo

2012 ◽  
Vol 93 (5) ◽  
pp. 998-1006 ◽  
Author(s):  
Holly Shelton ◽  
Matt Smith ◽  
Lorian Hartgroves ◽  
Peter Stilwell ◽  
Kim Roberts ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Mdck Cells ◽  
Gene Segment ◽  
Influenza Viruses ◽  
Interferon Response ◽  
H3n2 Virus ◽  
M Gene ◽  
Ns Gene

Influenza viruses readily mutate by accumulating point mutations and also by reassortment in which they acquire whole gene segments from another virus in a co-infected host. The NS1 gene is a major virulence factor of influenza A virus. The effects of changes in NS1 sequence depend on the influenza polymerase constellation. Here, we investigated the consequences of a virus with the polymerase of pandemic H1N1 2009 acquiring an NS gene segment derived from a seasonal influenza A H3N2 virus, a combination that might arise during natural reassortment of viruses that currently circulate in humans. We generated recombinant influenza viruses with surface HA and NA genes and matrix M gene segment from A/PR/8/34 virus, but different combinations of polymerase and NS genes. Thus, any changes in phenotype were not due to differences in receptor use, entry, uncoating or virus release. In Madin–Darby canine kidney (MDCK) cells, the virus with the NS gene from the H3N2 parent showed enhanced replication, probably a result of increased control of the interferon response. However, in mice the same virus was attenuated in comparison with the virus containing homologous pH1N1 polymerase and NS genes. Levels of viral RNA during single-cycles of replication were lower for the virus with H3N2 NS, and this virus reached lower titres in the lungs of infected mice. Thus, virus with pH1N1 polymerase genes did not increase its virulence by acquiring the H3N2 NS gene segment, and MDCK cells were a poor predictor of the outcome of infection in vivo.

EVOLUTION OF INFLUENZA A NUCLEOTIDE SEGMENTS THROUGH THE LENS OF DIFFERENT COMPLEXITY MEASURES

2018 ◽  
Vol 21 (05) ◽  
pp. 1850009
Author(s):  
IGOR BALAZ ◽  
TAICHI HARUNA
Keyword(s):  
Shannon Entropy ◽  
Influenza A ◽  
Evolutionary Dynamics ◽  
Large Body ◽  
Epidemiological Data ◽  
Influenza Viruses ◽  
Complexity Measures ◽  
Genome Wide ◽  
Complex Process ◽  
Entropy Measures

Evolution of influenza viruses is a highly complex process that is still poorly understood. Multiyear persistence of similar variants and accumulating evidences of existence of multigenic traits indicates that influenza viruses operate as integrated units and not only as sets of distinct genes. However, there is still no consensus on whether it is the case, and to what extent. One of the main problems is the lack of framework for analyzing and interpreting large body of available high dimensional genomic, clinical and epidemiological data. By reducing dimensionality of data we intend to show whether in addition to gene-centric selective pressure, the evolution of influenza RNA segments is also shaped by their mutual interactions. Therefore, we will analyze how different complexity/entropy measures (Shannon entropy, topological entropy and Lempel–Ziv complexity) can be used to study evolution of nucleotide segments of different influenza subtypes, while reducing data dimensionality. We show that, at the nucleotide level, multiyear clusters of genome-wide entropy/complexity correlations emerged during the H1N1 pandemic in 2009. Our data are the first empirical results that indirectly support the suggestion that a component of influenza evolutionary dynamics involves correlation between RNA segments. Of all used complexity/entropy measures, Shannon entropy shows the best correlation with epidemiological data.

scholarly journals Virologic Differences Do Not Fully Explain the Diversification of Swine Influenza Viruses in the United States

2016 ◽  
Vol 90 (22) ◽  
pp. 10074-10082 ◽  
Author(s):  
Thomas P. Fabrizio ◽  
Yilun Sun ◽  
Sun-Woo Yoon ◽  
Trushar Jeevan ◽  
Daniel Dlugolenski ◽  
...  
Keyword(s):  
Influenza A ◽  
Gene Segment ◽  
The United States ◽  
Influenza Viruses ◽  
H3n2 Virus ◽  
Polymerase Gene ◽  
Double Positive ◽  
Human Virus ◽  
Swine Virus ◽  
Influenza A H1n1

ABSTRACTInfluenza A(H1N1) viruses entered the U.S. swine population following the 1918 pandemic and remained genetically stable for roughly 80 years. In 1998, there was an outbreak of influenza-like illness among swine that was caused by A(H3N2) viruses containing the triple reassortant internal gene (TRIG) cassette. Following the TRIG cassette emergence, numerous reassortant viruses were isolated in nature, suggesting that the TRIG virus had an enhanced ability to reassort compared to the classical swine virus. The present study was designed to quantify the relative reassortment capacities of classical and TRIG swine viruses. Reverse genetic viruses were generated from the classical H1N1 virus A/swine/MN/37866/1999 (MN/99), the TRIG virus A/swine/NC/18161/2002 (NC/02), and a seasonal human H3N2 virus, A/TX/6/1996 (TX/96), to measurein vitroreassortment and growth potentials. After coinfection with NC/02 or MN/99 plus TX/96, H1/H3 double-positive cells were identified. Delayed TX/96 infection was fully excluded by both swine viruses. We then analyzed reassortant H3 viruses. Seventy-seven of 81 (95.1%) TX/96-NC/02 reassortants contained at least one polymerase gene segment from NC/02, whereas only 34 of 61 (55.7%) MN/99-TX/96 reassortants contained at least one polymerase gene segment from MN/99. Additionally, 38 of 81 (46.9%) NC/02-TX/96 reassortants contained all NC/02 polymerase gene segments, while none of the MN/99-TX/96 reassortants contained all MN/99 polymerase genes. There were 21 H3 reassortants between MN/99 and TX/96, compared to only 17 H3 reassortants between NC/02 and TX/96. Overall, the results indicate that there are no distinct differences in the ability of the TRIG to reassort with a human virus compared to the classical swine virus.IMPORTANCEThere appear to be no differences in the abilities of classical swine and TRIG swine viruses to exclude a second virus, suggesting that under the right circumstances both viruses have similar opportunities to reassort. The increased percentage of TRIG polymerase gene segments in reassortant H3 viruses indicates that these viruses may be more compatible with gene segments from other viruses; however, this needs to be investigated further. Nevertheless, the classical swine virus also showed the ability to reassort, suggesting that factors other than reassortment capacity alone are responsible for the different epidemiologies of TRIG and classical swine viruses. The post-TRIG diversity was likely driven by increased intensive farming practices rather than virologic properties. Our results indicate that host ecology can be a significant factor in viral evolution.

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.

A 75-year-old woman with seasonal influenza A (H3N2) virus infection and diarrhea

2010 ◽  
Vol 48 (4) ◽  
pp. 231-233 ◽  
Author(s):  
Martin C.W. Chan ◽  
Nelson Lee ◽  
Rity Y.K. Wong ◽  
Wing-Shan Ho ◽  
Joseph J.Y. Sung
Keyword(s):  
Virus Infection ◽  
Influenza A ◽  
Seasonal Influenza ◽  
H3n2 Virus

scholarly journals Molecular Characterization of Seasonal Influenza A and B from Hospitalized Patients in Thailand in 2018–2019

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 977
Author(s):  
Kobporn Boonnak ◽  
Chayasin Mansanguan ◽  
Dennis Schuerch ◽  
Usa Boonyuen ◽  
Hatairat Lerdsamran ◽  
...  
Keyword(s):  
Amino Acid ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Surface Proteins ◽  
Antigenic Drift ◽  
Influenza B ◽  
Receptor Binding Site ◽  
Antigenic Sites ◽  
Ha Protein

Influenza viruses continue to be a major public health threat due to the possible emergence of more virulent influenza virus strains resulting from dynamic changes in virus adaptability, consequent of functional mutations and antigenic drift in surface proteins, especially hemagglutinin (HA) and neuraminidase (NA). In this study, we describe the genetic and evolutionary characteristics of H1N1, H3N2, and influenza B strains detected in severe cases of seasonal influenza in Thailand from 2018 to 2019. We genetically characterized seven A/H1N1 isolates, seven A/H3N2 isolates, and six influenza B isolates. Five of the seven A/H1N1 viruses were found to belong to clade 6B.1 and were antigenically similar to A/Switzerland/3330/2017 (H1N1), whereas two isolates belonged to clade 6B.1A1 and clustered with A/Brisbane/02/2018 (H1N1). Interestingly, we observed additional mutations at antigenic sites (S91R, S181T, T202I) as well as a unique mutation at a receptor binding site (S200P). Three-dimensional (3D) protein structure analysis of hemagglutinin protein reveals that this unique mutation may lead to the altered binding of the HA protein to a sialic acid receptor. A/H3N2 isolates were found to belong to clade 3C.2a2 and 3C.2a1b, clustering with A/Switzerland/8060/2017 (H3N2) and A/South Australia/34/2019 (H3N2), respectively. Amino acid sequence analysis revealed 10 mutations at antigenic sites including T144A/I, T151K, Q213R, S214P, T176K, D69N, Q277R, N137K, N187K, and E78K/G. All influenza B isolates in this study belong to the Victoria lineage. Five out of six isolates belong to clade 1A3-DEL, which relate closely to B/Washington/02/2009, with one isolate lacking the three amino acid deletion on the HA segment at position K162, N163, and D164. In comparison to the B/Colorado/06/2017, which is the representative of influenza B Victoria lineage vaccine strain, these substitutions include G129D, G133R, K136E, and V180R for HA protein. Importantly, the susceptibility to oseltamivir of influenza B isolates, but not A/H1N1 and A/H3N2 isolates, were reduced as assessed by the phenotypic assay. This study demonstrates the importance of monitoring genetic variation in influenza viruses regarding how acquired mutations could be associated with an improved adaptability for efficient transmission.

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