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Special Issue "Molecular Mechanisms of Host Range and Pathogenicity of Influenza Viruses"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2017).

Special Issue Editors

Dr. Mikhail Matrosovich
Website
Guest Editor
Institute of Virology, Philipps University, Hans-Meerwein-Str. 2, 35043 Marburg, Germany
Interests: role of hemagglutinin and neuraminidase of influenza viruses in host range, cell tropism and pathogenicity
Prof. Dr. Hans-Dieter Klenk
Website
Guest Editor
Institute of Virology, Philipps University, Hans-Meerwein-Str. 2, 35043 Marburg, Germany
Interests: role of viral and host factors in pathogenicity and host range of emerging viruses

Special Issue Information

Dear Colleagues,

A large variety of influenza A viruses with 16 HA and 9 NA subtypes circulate in the major natural reservoir in aquatic birds. These viruses occasionally transmit and form stable lineages in other avian and mammalian species. Adaptation to domestic animals enhances chances of zoonotic transmission. On rare occasions, transmission and adaptation to humans of the virus with an antigenically novel HA initiates a pandemic. Following the pandemic, viruses continue to circulate in human population, causing annual seasonal influenza outbreaks. The pathogenesis of influenza varies widely depending on the virus and the animal or human host from unapparent infection to severe and fatal disease. The viral host range and pathogenesis are the result of complex interplay between virus and host at the systemic, the cellular and the molecular levels, and it involves the interaction of viral proteins with many host factors. Current understanding of these interactions is far from complete. This Special Issue will focus on mechanisms underlying cell and tissue tropism, spread of infection, virus load, escape of host defense, modification of inflammatory response, and synergism between viruses and bacteria. Original research and reviews on these and related topics in this area are invited.

Dr. Mikhail Matrosovich
Prof. Dr. Hans-Dieter Klenk
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • influenza
  • interspecies transmission
  • zoonoses, pandemics
  • pathogenesis
  • hemagglutinin
  • neuraminidase
  • receptors
  • polymerase
  • innate immunity

Published Papers (8 papers)

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Research

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Open AccessArticle
The RNA Helicase DDX6 Associates with RIG-I to Augment Induction of Antiviral Signaling
Int. J. Mol. Sci. 2018, 19(7), 1877; https://doi.org/10.3390/ijms19071877 - 26 Jun 2018
Cited by 8
Abstract
Virus infections induce sensitive antiviral responses within the host cell. The RNA helicase retinoic acid-inducible gene I (RIG-I) is a key sensor of influenza virus RNA that induces the expression of antiviral type I interferons. Recent evidence suggests a complex pattern of RIG-I [...] Read more.
Virus infections induce sensitive antiviral responses within the host cell. The RNA helicase retinoic acid-inducible gene I (RIG-I) is a key sensor of influenza virus RNA that induces the expression of antiviral type I interferons. Recent evidence suggests a complex pattern of RIG-I regulation involving multiple interactions and cellular sites. In an approach employing affinity purification and quantitative mass spectrometry, we identified proteins with increased binding to RIG-I in response to influenza B virus infection. Among them was the RIG-I related RNA helicase DEAD box helicase 6 (DDX6), a known component of cytoplasmic mRNA-ribonucleoprotein (mRNP) granules like P-bodies and stress granules (SGs). RIG-I and DDX6 both localized to the cytosol and were detected in virus-induced SGs. Coimmunoprecipitation assays detected a basal level of complexes harboring RIG-I and DDX6 that increased after infection. Functionally, DDX6 augmented RIG-I mediated induction of interferon (IFN)-β expression. Notably, DDX6 was found to bind viral RNA capable to stimulate RIG-I. These findings imply a novel function for DDX6 as an RNA co-sensor and signaling enhancer for RIG-I. Full article
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Open AccessArticle
Influenza A Virus M2 Protein: Roles from Ingress to Egress
Int. J. Mol. Sci. 2017, 18(12), 2649; https://doi.org/10.3390/ijms18122649 - 07 Dec 2017
Cited by 13
Abstract
Influenza A virus (IAV) matrix protein 2 (M2) is among the smallest bona fide, hence extensively studied, ion channel proteins. The M2 ion channel activity is not only essential for virus replication, but also involved in modulation of cellular homeostasis in a [...] Read more.
Influenza A virus (IAV) matrix protein 2 (M2) is among the smallest bona fide, hence extensively studied, ion channel proteins. The M2 ion channel activity is not only essential for virus replication, but also involved in modulation of cellular homeostasis in a variety of ways. It is also the target for ion channel inhibitors, i.e., anti-influenza drugs. Thus far, several studies have been conducted to elucidate its biophysical characteristics, structure-function relationships of the ion channel, and the M2-host interactome. In this review, we discuss M2 protein synthesis and assembly into an ion channel, its roles in IAV replication, and the pathophysiological impact on the host cell. Full article
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Open AccessArticle
Inter-Species Host Gene Expression Differences in Response to Human and Avian Influenza A Virus Strains
Int. J. Mol. Sci. 2017, 18(11), 2295; https://doi.org/10.3390/ijms18112295 - 01 Nov 2017
Cited by 2
Abstract
Low pathogenic avian influenza (LPAI) viruses are a source of sporadic human infections and could also contribute to future pandemic outbreaks but little is known about inter-species differences in the host responses to these viruses. Here, we studied host gene expression signatures of [...] Read more.
Low pathogenic avian influenza (LPAI) viruses are a source of sporadic human infections and could also contribute to future pandemic outbreaks but little is known about inter-species differences in the host responses to these viruses. Here, we studied host gene expression signatures of cell lines from three species (human, chicken, and canine) in response to six different viruses (H1N1/WSN, H5N2/F59, H5N2/F118, H5N2/F189, H5N3 and H9N2). Comprehensive microarray probe set re-annotation and ortholog mapping of the host genes was necessary to allow comparison over extended functionally annotated gene sets and orthologous pathways. The annotations are made available to the community for commonly used microarray chips. We observe a strong tendency of the response being cell type- rather than virus-specific. In chicken cells, we found up-regulation of host factors inducing virus infectivity (e.g., oxysterol binding protein like 1A (OSBPL1A) and Rho GTPase activating protein 21 (ARHGAP21)) while reducing apoptosis (e.g., mitochondrial ribosomal protein S27 (MRPS27)) and increasing cell proliferation (e.g., COP9 signalosome subunit 2 (COPS2)). On the other hand, increased antiviral, pro-apoptotic and inflammatory signatures have been identified in human cells while cell cycle and metabolic pathways were down-regulated. This signature describes how low pathogenic avian influenza (LPAI) viruses are being tolerated and shed from chicken but potentially causing cellular disruption in mammalian cells. Full article
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Open AccessArticle
Host Response Comparison of H1N1- and H5N1-Infected Mice Identifies Two Potential Death Mechanisms
Int. J. Mol. Sci. 2017, 18(8), 1631; https://doi.org/10.3390/ijms18081631 - 27 Jul 2017
Cited by 2
Abstract
Highly pathogenic influenza A viruses (IAV) infections represent a serious threat to humans due to their considerable morbidity and mortality capacities. A good understanding of the molecular mechanisms responsible for the acute lung injury observed during this kind of infection is essential to [...] Read more.
Highly pathogenic influenza A viruses (IAV) infections represent a serious threat to humans due to their considerable morbidity and mortality capacities. A good understanding of the molecular mechanisms responsible for the acute lung injury observed during this kind of infection is essential to design adapted therapies. In the current study, using an unbiased transcriptomic approach, we compared the host-responses of mice infected with two different subtypes of IAV: H1N1 vs. H5N1. The host-response comparison demonstrated a clear difference between the transcriptomic profiles of H1N1- and H5N1-infected mice despite identical survival kinetics and similar viral replications. The ontological analysis of the two transcriptomes showed two probable causes of death: induction of an immunopathological state of the lung for the H1N1 strain vs. development of respiratory dysfunction in the case of the H5N1 IAV. Finally, a clear signature responsible for lung edema was specifically associated with the H5N1 infection. We propose a potential mechanism of edema development based on predictive bioinformatics tools. Full article
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Review

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Open AccessReview
Evolution and Virulence of Influenza A Virus Protein PB1-F2
Int. J. Mol. Sci. 2018, 19(1), 96; https://doi.org/10.3390/ijms19010096 - 29 Dec 2017
Cited by 22
Abstract
PB1-F2 is an accessory protein of most human, avian, swine, equine, and canine influenza A viruses (IAVs). Although it is dispensable for virus replication and growth, it plays significant roles in pathogenesis by interfering with the host innate immune response, inducing death in [...] Read more.
PB1-F2 is an accessory protein of most human, avian, swine, equine, and canine influenza A viruses (IAVs). Although it is dispensable for virus replication and growth, it plays significant roles in pathogenesis by interfering with the host innate immune response, inducing death in immune and epithelial cells, altering inflammatory responses, and promoting secondary bacterial pneumonia. The effects of PB1-F2 differ between virus strains and host species. This can at least partially be explained by the presence of multiple PB1-F2 sequence variants, including premature stop codons that lead to the expression of truncated PB1-F2 proteins of different lengths and specific virulence-associated residues that enhance susceptibility to bacterial superinfection. Although there has been a tendency for human seasonal IAV to gradually reduce the number of virulence-associated residues, zoonotic IAVs contain a reservoir of PB1-F2 proteins with full length, virulence-associated sequences. Here, we review the molecular mechanisms by which PB1-F2 may affect influenza virulence, and factors associated with the evolution and selection of this protein. Full article
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Open AccessReview
Harnessing Invariant NKT Cells to Improve Influenza Vaccines: A Pig Perspective
Int. J. Mol. Sci. 2018, 19(1), 68; https://doi.org/10.3390/ijms19010068 - 27 Dec 2017
Cited by 5
Abstract
Invariant natural killer T (iNKT) cells are an “innate-like” T cell lineage that recognize glycolipid rather than peptide antigens by their semi-invariant T cell receptors. Because iNKT cells can stimulate an extensive array of immune responses, there is considerable interest in targeting these [...] Read more.
Invariant natural killer T (iNKT) cells are an “innate-like” T cell lineage that recognize glycolipid rather than peptide antigens by their semi-invariant T cell receptors. Because iNKT cells can stimulate an extensive array of immune responses, there is considerable interest in targeting these cells to enhance human vaccines against a wide range of microbial pathogens. However, long overlooked is the potential to harness iNKT cell antigens as vaccine adjuvants for domestic animal species that express the iNKT cell–CD1d system. In this review, we discuss the prospect of targeting porcine iNKT cells as a strategy to enhance the efficiency of swine influenza vaccines. In addition, we compare the phenotype and tissue distribution of porcine iNKT cells. Finally, we discuss the challenges that must be overcome before iNKT cell agonists can be contemplated for veterinary use in livestock. Full article
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Open AccessReview
Molecular Markers for Interspecies Transmission of Avian Influenza Viruses in Mammalian Hosts
Int. J. Mol. Sci. 2017, 18(12), 2706; https://doi.org/10.3390/ijms18122706 - 13 Dec 2017
Cited by 12
Abstract
In the last decade, a wide range of avian influenza viruses (AIVs) have infected various mammalian hosts and continuously threaten both human and animal health. It is a result of overcoming the inter-species barrier which is mostly associated with gene reassortment and accumulation [...] Read more.
In the last decade, a wide range of avian influenza viruses (AIVs) have infected various mammalian hosts and continuously threaten both human and animal health. It is a result of overcoming the inter-species barrier which is mostly associated with gene reassortment and accumulation of mutations in their gene segments. Several recent studies have shed insights into the phenotypic and genetic changes that are involved in the interspecies transmission of AIVs. These studies have a major focus on transmission from avian to mammalian species due to the high zoonotic potential of the viruses. As more mammalian species have been infected with these viruses, there is higher risk of genetic evolution of these viruses that may lead to the next human pandemic which represents and raises public health concern. Thus, understanding the mechanism of interspecies transmission and molecular determinants through which the emerging AIVs can acquire the ability to transmit to humans and other mammals is an important key in evaluating the potential risk caused by AIVs among humans. Here, we summarize previous and recent studies on molecular markers that are specifically involved in the transmission of avian-derived influenza viruses to various mammalian hosts including humans, pigs, horses, dogs, and marine mammals. Full article
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Open AccessReview
The Interplay between the Host Receptor and Influenza Virus Hemagglutinin and Neuraminidase
Int. J. Mol. Sci. 2017, 18(7), 1541; https://doi.org/10.3390/ijms18071541 - 17 Jul 2017
Cited by 55
Abstract
The hemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza A virus are responsible for the surface interactions of the virion with the host. Entry of the virus is mediated by functions of the HA: binding to cellular receptors and facilitating fusion of the [...] Read more.
The hemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza A virus are responsible for the surface interactions of the virion with the host. Entry of the virus is mediated by functions of the HA: binding to cellular receptors and facilitating fusion of the virion membrane with the endosomal membrane. The HA structure contains receptor binding sites in the globular membrane distal head domains of the trimer, and the fusion machinery resides in the stem region. These sites have specific characteristics associated with subtype and host, and the differences often define species barriers. For example, avian viruses preferentially recognize α2,3-Sialic acid terminating glycans as receptors and mammalian viruses recognize α2,6-Sialic acid. The neuraminidase, or the receptor-destroying protein, cleaves the sialic acid from cellular membrane constituents and viral glycoproteins allowing for egress of nascent virions. A functional balance of activity has been demonstrated between the two glycoproteins, resulting in an optimum level of HA affinity and NA enzymatic cleavage to allow for productive infection. As more is understood about both HA and NA, the relevance for functional balance between HA and NA continues to expand, with potential implications for interspecies transmission, host adaptation, and pathogenicity. Full article
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