scholarly journals Linking influenza virus evolution within and between human hosts

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Katherine S Xue ◽  
Jesse D Bloom
Keyword(s):  
Influenza Virus ◽  
Evolutionary Dynamics ◽  
Global Scale ◽  
Influenza Viruses ◽  
Global Evolution ◽  
Synonymous Sites ◽  
Selection For ◽  
H3n2 Influenza ◽  
Human Infections ◽  
Individual Human

Abstract Influenza viruses rapidly diversify within individual human infections. Several recent studies have deep-sequenced clinical influenza infections to identify viral variation within hosts, but it remains unclear how within-host mutations fare at the between-host scale. Here, we compare the genetic variation of H3N2 influenza within and between hosts to link viral evolutionary dynamics across scales. Synonymous sites evolve at similar rates at both scales, indicating that global evolution at these putatively neutral sites results from the accumulation of within-host variation. However, nonsynonymous mutations are depleted between hosts compared to within hosts, suggesting that selection purges many of the protein-altering changes that arise within hosts. The exception is at antigenic sites, where selection detectably favors nonsynonymous mutations at the global scale, but not within hosts. These results suggest that selection against deleterious mutations and selection for antigenic change are the main forces that act on within-host variants of influenza virus as they transmit and circulate between hosts.

scholarly journals Linking influenza virus evolution within and between human hosts

2019 ◽  
Author(s):  
Katherine S. Xue ◽  
Jesse D. Bloom
Keyword(s):  
Evolutionary Dynamics ◽  
Global Scale ◽  
Influenza Viruses ◽  
Viral Population ◽  
Global Evolution ◽  
Synonymous Sites ◽  
Host Genetic ◽  
Selection For ◽  
Human Infections ◽  
Individual Human

AbstractInfluenza viruses rapidly diversify within individual human infections. Several recent studies have deep-sequenced clinical influenza infections to identify viral variation within hosts, but it remains unclear how within-host mutations fare in the global viral population. Here, we compare viral variation within and between hosts to link influenza’s evolutionary dynamics across scales. Synonymous sites evolve at similar rates at both scales, indicating that global evolution at these putatively neutral sites results from the accumulation of within-host variation. However, nonsynonymous mutations are depleted in global viral populations compared to within hosts, suggesting that selection purges many of the protein-altering changes that arise within hosts. The exception is at antigenic sites, where selection detectably favors nonsynonymous mutations at the global scale, but not within hosts. These results suggest that selection against deleterious mutations and selection for antigenic change are the main forces that transform influenza’s within-host genetic variation into global 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.

scholarly journals A PB1-K577E Mutation in H9N2 Influenza Virus Increases Polymerase Activity and Pathogenicity in Mice

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 653 ◽  
Author(s):  
Haruhiko Kamiki ◽  
Hiromichi Matsugo ◽  
Tomoya Kobayashi ◽  
Hiroho Ishida ◽  
Akiko Takenaka-Uema ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Novel Mutation ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
H9n2 Virus ◽  
Wild Type Virus ◽  
H9n2 Influenza Virus ◽  
Pathogenicity Determinant ◽  
Lower Temperature ◽  
Human Infections

H9N2 avian influenza viruses are present in poultry worldwide. These viruses are considered to have pandemic potential, because recent isolates can recognize human-type receptor and several sporadic human infections have been reported. In this study, we aimed to identify mutations related to mammalian adaptation of H9N2 influenza virus. We found that mouse-adapted viruses had several mutations in hemagglutinin (HA), PB2, PA, and PB1. Among the detected mutations, PB1-K577E was a novel mutation that had not been previously reported to involve mammalian adaptation. A recombinant H9N2 virus bearing only the PB1-K577E mutation showed enhanced pathogenicity in mice, with increased virus titers in nasal turbinates compared to that in mice infected with the wild-type virus. In addition, the PB1-K577E mutation increased virus polymerase activity in human cell culture at a lower temperature. These data suggest that the PB1-K577E mutation is a novel pathogenicity determinant of H9N2 virus in mice and could be a signature for mammalian adaptation.

scholarly journals A Prevalent Focused Human Antibody Response to the Influenza Virus Hemagglutinin Head Interface

mBio ◽  
2021 ◽  
Author(s):  
Kevin R. McCarthy ◽  
Jiwon Lee ◽  
Akiko Watanabe ◽  
Masayuki Kuraoka ◽  
Lindsey R. Robinson-McCarthy ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Herd Immunity ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Human Antibody ◽  
Human Influenza ◽  
Human Antibodies ◽  
Influenza Virus Hemagglutinin ◽  
Selection For ◽  
Rapid Appearance

The rapid appearance of mutations in circulating human influenza viruses and selection for escape from herd immunity require prediction of likely variants for an annual updating of influenza vaccines. The identification of human antibodies that recognize conserved surfaces on the influenza virus hemagglutinin (HA) has prompted efforts to design immunogens that might selectively elicit such antibodies.

scholarly journals Parallel evolution of influenza across multiple spatiotemporal scales

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Katherine S Xue ◽  
Terry Stevens-Ayers ◽  
Angela P Campbell ◽  
Janet A Englund ◽  
Steven A Pergam ◽  
...  
Keyword(s):  
Evolutionary Dynamics ◽  
De Novo ◽  
Parallel Evolution ◽  
Global Scale ◽  
De Novo Mutations ◽  
Small Set ◽  
Spatiotemporal Scales ◽  
H3n2 Influenza ◽  
Multiple Patients

Viral variants that arise in the global influenza population begin as de novo mutations in single infected hosts, but the evolutionary dynamics that transform within-host variation to global genetic diversity are poorly understood. Here, we demonstrate that influenza evolution within infected humans recapitulates many evolutionary dynamics observed at the global scale. We deep-sequence longitudinal samples from four immunocompromised patients with long-term H3N2 influenza infections. We find parallel evolution across three scales: within individual patients, in different patients in our study, and in the global influenza population. In hemagglutinin, a small set of mutations arises independently in multiple patients. These same mutations emerge repeatedly within single patients and compete with one another, providing a vivid clinical example of clonal interference. Many of these recurrent within-host mutations also reach a high global frequency in the decade following the patient infections. Our results demonstrate surprising concordance in evolutionary dynamics across multiple spatiotemporal scales.

scholarly journals Moderate Vaccine Effectiveness against Severe Acute Respiratory Infection Caused by A(H1N1)pdm09 Influenza Virus and No Effectiveness against A(H3N2) Influenza Virus in the 2018/2019 Season in Italy

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 427 ◽  
Author(s):  
Caterina Rizzo ◽  
Francesco Gesualdo ◽  
Daniela Loconsole ◽  
Elisabetta Pandolfi ◽  
Antonino Bella ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Respiratory Infection ◽  
Acute Respiratory Infection ◽  
Vaccine Coverage ◽  
Type A ◽  
Vaccine Effectiveness ◽  
Influenza Viruses ◽  
Severe Acute Respiratory Infection ◽  
H3n2 Influenza ◽  
Subtype A

Every season, circulating influenza viruses change; therefore, vaccines must be reformulated each year. We aimed to estimate vaccine effectiveness (VE) against severe influenza infection for the 2018/19 season in Italy. We conducted a test-negative design case-control study at five Italian hospitals. We estimated influenza VE against severe acute respiratory infection (SARI) requiring hospitalisation overall, and by virus subtype, vaccine brand, and age. The 2018/19 season was characterised by A(H1N1)pmd09 and A(H3N2) influenza viruses. Vaccine coverage among <18 years recruited SARI cases was very low (3.2%). Seasonal vaccines were moderately effective against type A influenza overall (adjusted VE = 40.5%; 95% confidence interval (CI) = 18.7–56.4%) and subtype A(H1N1)pmd09 viruses (adjusted VE = 55%; 95% CI = 34.5–69.1%), but ineffective against subtype A(H3N2) viruses (adjusted VE = 2.5%; 95% CI = −50.0–36.7%). Both Fluad and Fluarix Tetra vaccines were effective against type A influenza overall and subtype A(H1N1)pdm09 viruses. VE appeared to be similar across age groups (0–64 years, ≥65 years). Seasonal influenza vaccines in the 2018/19 season were moderately effective in preventing SARI caused by A(H1N1)pdm09 influenza but ineffective against A(H3N2).

scholarly journals Alterations in Receptor Binding Properties of Recent Human Influenza H3N2 Viruses Are Associated with Reduced Natural Killer Cell Lysis of Infected Cells

2007 ◽  
Vol 81 (20) ◽  
pp. 11170-11178 ◽  
Author(s):  
Rachel E. Owen ◽  
Eriko Yamada ◽  
Catherine I. Thompson ◽  
Louisa J. Phillipson ◽  
Clare Thompson ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Natural Killer ◽  
Nk Cell ◽  
Glycosylation Site ◽  
Influenza Viruses ◽  
Host Cells ◽  
Cell Recognition ◽  
Binding Properties ◽  
Infected Cells ◽  
H3n2 Influenza

ABSTRACT Natural killer (NK) cell recognition of influenza virus-infected cells involves hemagglutinin (HA) binding to sialic acid (SA) on activating NK receptors. SA also acts as a receptor for the binding of influenza virus to its target host cells. The SA binding properties of H3N2 influenza viruses have been observed to change during circulation in humans: recent isolates are unable to agglutinate chicken red blood cells and show reduced affinity for synthetic glycopolymers representing SA-α-2,3-lactose (3′SL-PAA) and SA-α-2,6-N-acetyl lactosamine (6′SLN-PAA) carbohydrates. Here, NK lysis of cells infected with human H3N2 influenza viruses isolated between 1969 and 2003 was analyzed. Cells infected with recent isolates (1999 to 2003) were found to be lysed less effectively than cells infected with older isolates (1969 to 1996). This change occurred concurrently with the acquisition of two new potential glycosylation site motifs in HA. Deletion of the potential glycosylation site motif at 133 to 135 in HA1 from a recent isolate partially restored the agglutination phenotype to a recombinant virus, indicating that the HA-SA interaction is inhibited by the glycosylation modification. Deletion of either of the recently acquired potential glycosylation sites from HA led to increased NK lysis of cells infected with recombinant viruses carrying modified HA. These results indicate that alterations in HA glycosylation may affect NK cell recognition of influenza virus-infected cells in addition to virus binding to host cells.

scholarly journals Stochastic processes constrain the within and between host evolution of influenza virus

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
John T McCrone ◽  
Robert J Woods ◽  
Emily T Martin ◽  
Ryan E Malosh ◽  
Arnold S Monto ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Stochastic Processes ◽  
Positive Selection ◽  
Evolutionary Dynamics ◽  
Sequence Data ◽  
Influenza Viruses ◽  
Single Nucleotide Variants ◽  
Individual Host ◽  
The Individual ◽  
Host Evolution

The evolutionary dynamics of influenza virus ultimately derive from processes that take place within and between infected individuals. Here we define influenza virus dynamics in human hosts through sequencing of 249 specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected from individuals in a prospective community-based cohort, they are broadly representative of natural infections with seasonal viruses. Consistent with a neutral model of evolution, sequence data from 49 serially sampled individuals illustrated the dynamic turnover of synonymous and nonsynonymous single nucleotide variants and provided little evidence for positive selection of antigenic variants. We also identified 43 genetically-validated transmission pairs in this cohort. Maximum likelihood optimization of multiple transmission models estimated an effective transmission bottleneck of 1–2 genomes. Our data suggest that positive selection is inefficient at the level of the individual host and that stochastic processes dominate the host-level evolution of influenza viruses.

scholarly journals Clinically Relevant Influenza Virus Evolution Reconstituted in a Human Lung Airway-on-a-Chip

2021 ◽  
Author(s):  
Longlong Si ◽  
Haiqing Bai ◽  
Crystal Yuri Oh ◽  
Lei Jin ◽  
Rachelle Prantil-Baun ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Severe Acute Respiratory Syndrome ◽  
Human Lung ◽  
Viral Evolution ◽  
Rapid Evolution ◽  
Virus Evolution ◽  
Influenza Viruses ◽  
Epidemiological Factors ◽  
Global Evolution ◽  
Evolution Of Viruses

The rapid evolution of viruses, such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is challenging the use and development of antivirals and vaccines. Studies of within-host viral evolution can contribute to our understanding of the evolutionary and epidemiological factors that shape viral global evolution as well as development of better antivirals and vaccines.

scholarly journals Immunodominance of Antigenic Site B in the Hemagglutinin of the Current H3N2 Influenza Virus in Humans and Mice

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Felix Broecker ◽  
Sean T. H. Liu ◽  
Weina Sun ◽  
Florian Krammer ◽  
Viviana Simon ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Hemagglutination Inhibition ◽  
Neutralizing Antibodies ◽  
Antigenic Site ◽  
Influenza Viruses ◽  
Antigenic Sites ◽  
Head Domain ◽  
Hemagglutinin Protein ◽  
H3n2 Influenza ◽  
H3n2 Influenza Virus

ABSTRACTThe hemagglutinin protein of H3N2 influenza viruses is the major target of neutralizing antibodies induced by infection and vaccination. However, the virus frequently escapes antibody-mediated neutralization due to mutations in the globular head domain. Five topologically distinct antigenic sites in the head domain of H3 hemagglutinin, A to E, have been previously described by mapping the binding sites of monoclonal antibodies, yet little is known about the contribution of each site to the immunogenicity of modern H3 hemagglutinins, as measured by hemagglutination inhibition activity, which is known to correlate with protection. To investigate the hierarchy of antibody immunodominance, five Δ1 recombinant influenza viruses expressing hemagglutinin of the A/Hong Kong/4801/2014 (H3N2) strain with mutations in single antigenic sites were generated. Next, the Δ1 viruses were used to determine the hierarchy of immunodominance by measuring the hemagglutination inhibition reactivity of mouse antisera and plasma from 18 human subjects before and after seasonal influenza vaccination in 2017-2018. In both mice and humans, mutations in antigenic site B caused the most significant decrease in hemagglutination inhibition titers compared to wild-type hemagglutinin. This study revealed that antigenic site B is immunodominant in the H3N2 influenza virus strain included in the current vaccine preparations.IMPORTANCEInfluenza viruses rapidly evade humoral immunity through antigenic drift, making current vaccines poorly effective and antibody-mediated protection short-lived. The majority of neutralizing antibodies target five antigenic sites in the head domain of the hemagglutinin protein that are also the most sequence-variable regions. A better understanding of the contribution of each antigenic site to the overall antibody response to hemagglutinin may help in the design of improved influenza virus vaccines.

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