scholarly journals Identification of combinatorial and singular genomic signatures of host adaptation in influenza A H1N1 and H3N2 subtypes

2016 ◽  
Author(s):  
Zeeshan Khaliq ◽  
Mikael Leijon ◽  
Sándor Belák ◽  
Jan Komorowski
Keyword(s):  
Influenza A ◽  
Molecular Mechanisms ◽  
Host Adaptation ◽  
H1n1 Subtype ◽  
Species Barrier ◽  
New Host ◽  
Rule Based ◽  
H3n2 Subtype ◽  
Genomic Signatures ◽  
Influenza A H1n1

AbstractBackgroundThe underlying strategies used by influenza A viruses (IAVs) to adapt to new hosts while crossing the species barrier are complex and yet to be understood completely. Several studies have been published identifying singular genomic signatures that indicate such a host switch. The complexity of the problem suggested that in addition to the singular signatures, there might be a combinatorial use of such genomic features, in nature, defining adaptation to hosts..ResultsWe used computational rule-based modeling to identify combinatorial sets of interacting amino acid (aa) residues in 12 proteins of IAVs of H1N1 and H3N2 subtypes. We built highly accurate rule-based models for each protein that could differentiate between viral aa sequences coming from avian and human hosts,. We found 68 combinations of aa residues associated to host adaptation (HAd) on HA, M1, M2, NP, NS1, NEP, PA, PA-X, PB1 and PB2 proteins of the H1N1 subtype and 24 on M1, M2, NEP, PB1 and PB2 proteins of the H3N2 subtypes. In addition to these combinations, we found 132 novel singular aa signatures distributed among all proteins, including the newly discovered PA-X protein, of both subtypes. We showed that HA, NA, NP, NS1, NEP, PA-X and PA proteins of the H1N1 subtype carry H1N1-specific and HA, NA, PA-X, PA, PB1-F2 and PB1 of the H3N2 subtype carry H3N2-specific HAd signatures. M1, M2, PB1-F2, PB1 and PB2 of H1N1 subtype, in addition to H1N1 signatures, also carry H3N2 signatures. Similarly M1, M2, NP, NS1, NEP and PB2 of H3N2 subtype were shown to carry both H3N2 and H1N1 HAd signatures.ConclusionsTo sum it up, we computationally constructed simple IF-THEN rule-based models that could distinguish between aa sequences of virus particles originating from avian and human hosts. From the rules we identified combinations of aa residues as signatures facilitating the adaptation to specific hosts. The identification of combinatorial aa signatures suggests that the process of adaptation of IAVs to a new host is more complex than previously suggested. The present study provides a basis for further detailed studies with the aim to elucidate the molecular mechanisms providing the foundation for the adaptation process.

scholarly journals The PA Subunit of the Influenza Virus Polymerase Complex Affects Replication and Airborne Transmission of the H9N2 Subtype Avian Influenza Virus

Viruses ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 40 ◽  
Author(s):  
Mengchan Hao ◽  
Shaojie Han ◽  
Dan Meng ◽  
Rong Li ◽  
Jing Lin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Guinea Pigs ◽  
Influenza A ◽  
Reverse Genetics ◽  
Species Barrier ◽  
Airborne Transmission ◽  
H9n2 Subtype ◽  
Influenza A H1n1

The polymerase acidic (PA) protein is the third subunit of the influenza A virus polymerase. In recent years, studies have shown that PA plays an important role in overcoming the host species barrier and host adaptation of the avian influenza virus (AIV). The objective of this study was to elucidate the role of the PA subunit on the replication and airborne transmission of the H9N2 subtype AIV. By reverse genetics, a reassortant rSD01-PA was derived from the H9N2 subtype AIV A/Chicken/Shandong/01/2008 (SD01) by introducing the PA gene from the pandemic influenza A H1N1 virus A/swine/Shandong/07/2011 (SD07). Specific pathogen-free (SPF) chickens and guinea pigs were selected as the animal models for replication and aerosol transmission studies. Results show that rSD01-PA lost the ability of airborne transmission among SPF chickens because of the single substitution of the PA gene. However, rSD01-PA could infect guinea pigs through direct contact, while the parental strain SD01 could not, even though the infection of rSD01-PA could not be achieved through aerosol. In summary, our results indicate that the protein encoded by the PA gene plays a key role in replication and airborne transmission of the H9N2 subtype AIV.

scholarly journals Interaction of the Influenza A Virus Polymerase PB2 C-terminal Region with Importin α Isoforms Provides Insights into Host Adaptation and Polymerase Assembly

2011 ◽  
Vol 286 (12) ◽  
pp. 10439-10448 ◽  
Author(s):  
Stephane Boivin ◽  
Darren J. Hart
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Influenza A ◽  
Host Adaptation ◽  
New Host ◽  
Adaptive Mutations ◽  
C Terminus ◽  
Importin Α ◽  
Localization Signal ◽  
Import Receptors

In the adaptation of avian viruses to mammalian hosts, mutations in the viral polymerase, notably in the PB2 subunit, play an important role. A PB2 C-terminal domain rich in putative host adaptation residues has been shown to bind importin α nuclear import receptors. Adaptation has been proposed to involve binding of PB2 to importins of the new host. To date PB2-importin complexes have been characterized semiquantitatively with no precise measurement of binding parameters. To investigate the effects of adaptive mutations on importin interaction and selectivity, surface plasmon resonance was used to compare the binding rate constants and affinities of avian H5N1 and human H3N2 PB2 C-terminal variants with importin isoforms human α 1, 3, 5 and 7, and avian α 1. Using purified proteins eliminates host environment effects and permits measurement of intrinsic affinities and rates of complex formation and dissociation. Two effects were observed: first, adaptive mutations D701N, R702K, and S714R in the nuclear localization signal domain increased 2–4-fold the association rates with avian and human importins; second, measurement of different structural forms of the PB2 C terminus demonstrated that the upstream 627 domain reduced binding affinity, consistent with a steric clash predicted from crystal structures. From these kinetic data, structural analyses, and the data of others, a model is proposed in which an increase in charged surface residues during host adaptation increases the association rate of PB2 to cytoplasmic importins and where the C-terminal 627-nuclear localization signal domain may reorganize upon importin binding, consistent with a role in active polymerase assembly.

In vitro Inhibitory Effects of Combinations of anti-Influenza Agents

1995 ◽  
Vol 6 (2) ◽  
pp. 109-113 ◽  
Author(s):  
L. K. Madren ◽  
C. Shipman ◽  
F. G. Hayden
Keyword(s):  
Viral Replication ◽  
Influenza A ◽  
H1n1 Virus ◽  
Mdck Cells ◽  
Clinical Isolates ◽  
H1n1 Subtype ◽  
Additive Effects ◽  
Inhibitory Effects ◽  
Influenza A H1n1

To assess the possible interactions among candidate anti-influenza agents, dual combinations of rimantadine, ribavirin, 2′-deoxy-2′-fluoroguanosine (2-FDG) and 4-guanidino-Neu5Ac2en (GG167) were tested against clinical isolates of influenza A H3N2 and H1N1 subtype viruses in MDCK cells by ELISA. Each of the dual combinations showed additive effects, except for the combination of 2-FDG and ribavirin which was synergistic against the influenza A (H1N1) virus. However, this combination also showed enhanced cytotoxicity. In this assay system, influenza agents with differing mechanisms of antiviral interaction interacted in an additive fashion with respect to inhibition of viral replication.

scholarly journals Construction and Immunogenicity Evaluation of Recombinant Influenza A Viruses Containing Chimeric Hemagglutinin Genes Derived from Genetically Divergent Influenza A H1N1 Subtype Viruses

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0127649 ◽  
Author(s):  
Kara McCormick ◽  
Zhiyong Jiang ◽  
Longchao Zhu ◽  
Steven R. Lawson ◽  
Robert Langenhorst ◽  
...  
Keyword(s):  
Influenza A ◽  
H1n1 Subtype ◽  
Influenza A Viruses ◽  
Influenza A H1n1

scholarly journals The Critical Interspecies Transmission Barrier at the Animal–Human Interface

2019 ◽  
Vol 4 (2) ◽  
pp. 72 ◽  
Author(s):  
Subbarao
Keyword(s):  
Influenza A ◽  
Influenza Pandemic ◽  
Interspecies Transmission ◽  
Small Subset ◽  
Influenza A Viruses ◽  
Species Barrier ◽  
New Host ◽  
Human Interface ◽  
Wide Range ◽  
Reservoir Hosts

Influenza A viruses (IAVs) infect humans and a wide range of animal species in nature, and waterfowl and shorebirds are their reservoir hosts. Of the 18 haemagglutinin (HA) and 11 neuraminidase (NA) subtypes of IAV, 16 HA and 9 NA subtypes infect aquatic birds. However, among the diverse pool of IAVs in nature, only a limited number of animal IAVs cross the species barrier to infect humans and a small subset of those have spread efficiently from person to person to cause an influenza pandemic. The ability to infect a different species, replicate in the new host and transmit are three distinct steps in this process. Viral and host factors that are critical determinants of the ability of an avian IAV to infect and spread in humans are discussed.

scholarly journals Influenza A virus hemagglutinin prevents extensive membrane damage upon dehydration

2021 ◽  
Author(s):  
Maiara A. Iriarte-Alonso ◽  
Salvatore Chiantia ◽  
Alexander M. Bittner
Keyword(s):  
Relative Humidity ◽  
Influenza A ◽  
Molecular Mechanisms ◽  
Membrane Damage ◽  
Correlation Spectroscopy ◽  
Viral Envelope ◽  
Image Correlation ◽  
Membrane Properties ◽  
Virus Infectivity ◽  
Influenza A H1n1

While the molecular mechanisms of virus infectivity are rather well known, the detailed consequences of environmental factors on virus biophysical properties are poorly understood. 20 Seasonal influenza outbreaks are usually connected to the low winter temperature, but also to the low relative air humidity. Indeed, transmission rates increase in cold regions during winter. While low temperature must slow degradation processes, the role of low humidity is not clear. We studied the effect of relative humidity on a model of influenza A H1N1 virus envelope, a supported lipid bilayer containing the surface glycoprotein hemagglutinin (HA), which is 25 present in the viral envelope in very high density. For complete cycles of hydration, dehydration and rehydration, we evaluate the membrane properties in terms of structure and dynamics, which we assess by combining confocal fluorescence microscopy, raster image correlation spectroscopy, line-scan fluorescence correlation spectroscopy and atomic force microscopy. Our findings indicate that the presence of HA prevents macroscopic membrane 30 damage after dehydration. Without HA, fast membrane disruption is followed by irreversible loss of lipid and protein mobility. Although our model is principally limited by the membrane composition, the macroscopic effects of HA under dehydration stress reveal new insights on the stability of the virus at low relative humidity.

scholarly journals Infection with influenza A H1N1: 2. The effect of past experience on natural challenge

1986 ◽  
Vol 96 (2) ◽  
pp. 345-352 ◽  
Author(s):  
J. R. Davies ◽  
E. A. Grilli ◽  
A. J. Smith
Keyword(s):  
Protective Effect ◽  
Attack Rate ◽  
Influenza A ◽  
Boarding School ◽  
Antigenic Drift ◽  
H1n1 Subtype ◽  
Outbreak Strain ◽  
Past Infection ◽  
Influenza A H1n1 ◽  
Large Outbreak

SUMMARYFollowing its reintroduction in 1978 influenza A H1N1 spread widely in the child population. By the autumn of 1979, 75% of 11-year olds entering a boys' boarding school had detectable antibody. The protective effect of previous experience could be assessed during two outbreaks in the school. In the first outbreak in 1979, 90% of those known to have been infected in the previous year were protected against reinfection. In 1983 after strains of the H1N1 subtype had undergone antigenic drift a large outbreak occurred. It was estimated that past infection conferred protection against clinical influenza in 55%. Where past infection resulted in the presence of antibody which reacted with the outbreak strain the attack rate was further reduced. A large number of sub-clinical infections was detected in all groups.

scholarly journals Human Properdin Released By Infiltrating Neutrophils Can Modulate Influenza A Virus Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Praveen M. Varghese ◽  
Shuvechha Mukherjee ◽  
Futwan A. Al-Mohanna ◽  
Souad M. Saleh ◽  
Fahad N. Almajhdi ◽  
...  
Keyword(s):  
Virus Infection ◽  
Inflammatory Response ◽  
Viral Replication ◽  
Influenza A Virus ◽  
Influenza A ◽  
Alternative Pathway ◽  
A549 Cells ◽  
H1n1 Subtype ◽  
H3n2 Subtype ◽  
Influenza A Virus Infection

The complement system is designed to recognise and eliminate invading pathogens via activation of classical, alternative and lectin pathways. Human properdin stabilises the alternative pathway C3 convertase, resulting in an amplification loop that leads to the formation of C5 convertase, thereby acting as a positive regulator of the alternative pathway. It has been noted that human properdin on its own can operate as a pattern recognition receptor and exert immune functions outside its involvement in complement activation. Properdin can bind directly to microbial targets via DNA, sulfatides and glycosaminoglycans, apoptotic cells, nanoparticles, and well-known viral virulence factors. This study was aimed at investigating the complement-independent role of properdin against Influenza A virus infection. As one of the first immune cells to arrive at the site of IAV infection, we show here that IAV challenged neutrophils released properdin in a time-dependent manner. Properdin was found to directly interact with haemagglutinin, neuraminidase and matrix 1 protein Influenza A virus proteins in ELISA and western blot. Furthermore, modelling studies revealed that properdin could bind HA and NA of the H1N1 subtype with higher affinity compared to that of H3N2 due to the presence of an HA cleavage site in H1N1. In an infection assay using A549 cells, properdin suppressed viral replication in pH1N1 subtype while promoting replication of H3N2 subtype, as revealed by qPCR analysis of M1 transcripts. Properdin treatment triggered an anti-inflammatory response in H1N1-challenged A549 cells and a pro-inflammatory response in H3N2-infected cells, as evident from differential mRNA expression of TNF-α, NF-κB, IFN-α, IFN-β, IL-6, IL-12 and RANTES. Properdin treatment also reduced luciferase reporter activity in MDCK cells transduced with H1N1 pseudotyped lentiviral particles; however, it was increased in the case of pseudotyped H3N2 particles. Collectively, we conclude that infiltrating neutrophils at the site of IAV infection can release properdin, which then acts as an entry inhibitor for pandemic H1N1 subtype while suppressing viral replication and inducing an anti-inflammatory response. H3N2 subtype can escape this immune restriction due to altered haemagglutinin and neuraminindase, leading to enhanced viral entry, replication and pro-inflammatory response. Thus, depending on the subtype, properdin can either limit or aggravate IAV infection in the host.

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