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Special Issue "What’s New with Flu?"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 September 2018)

Special Issue Editors

Guest Editor
Dr. Christopher Byron Brooke

Department of Microbiology, University of Illinois, Urbana, IL, USAAffiliation 2: Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL, USA
Website | E-Mail
Interests: Host-Pathogen Interactions, Viral Evolution, Viral Immunology, Regulation of Gene Expression, Virology
Guest Editor
Dr. Seema Lakdawala

Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA
Website | E-Mail
Interests: Virology, Emerging influenza viruses, Virus Assembly, Virus Transmission, Microscopy, Live Cell Imaging

Special Issue Information

Dear Colleagues,

One hundred years have passed since the 1918 H1N1 pandemic, and influenza viruses continue to pose an enormous and unpredictable global public health threat. Recent technological and methodological advances have greatly expanded our understanding of the basic biology of influenza infection, shedding new light on old problems in the influenza field. This special issue will focus on recent discoveries that have emerged from the use of novel approaches to study long-standing questions in influenza biology. Articles in this issue will span molecular and quantitative virology, immunology, evolutionary biology and ecology, transmission and environmental control, mathematical modeling, and novel therapeutics.

Dr. Christopher Byron Brooke
Dr. Seema Lakdawala
Guest Editors

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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular and quantitative virology
  • immunology
  • evolutionary biology and ecology
  • transmission and environmental control
  • mathematical modeling

Published Papers (12 papers)

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Research

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Open AccessArticle Non-Uniform and Non-Random Binding of Nucleoprotein to Influenza A and B Viral RNA
Viruses 2018, 10(10), 522; https://doi.org/10.3390/v10100522
Received: 15 August 2018 / Revised: 17 September 2018 / Accepted: 22 September 2018 / Published: 25 September 2018
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Abstract
The genomes of influenza A and B viruses have eight, single-stranded RNA segments that exist in the form of a viral ribonucleoprotein complex in association with nucleoprotein (NP) and an RNA-dependent RNA polymerase complex. We previously used high-throughput RNA sequencing coupled with crosslinking
[...] Read more.
The genomes of influenza A and B viruses have eight, single-stranded RNA segments that exist in the form of a viral ribonucleoprotein complex in association with nucleoprotein (NP) and an RNA-dependent RNA polymerase complex. We previously used high-throughput RNA sequencing coupled with crosslinking immunoprecipitation (HITS-CLIP) to examine where NP binds to the viral RNA (vRNA) and demonstrated for two H1N1 strains that NP binds vRNA in a non-uniform, non-random manner. In this study, we expand on those initial observations and describe the NP-vRNA binding profile for a seasonal H3N2 and influenza B virus. We show that, similar to H1N1 strains, NP binds vRNA in a non-uniform and non-random manner. Each viral gene segment has a unique NP binding profile with areas that are enriched for NP association as well as free of NP-binding. Interestingly, NP-vRNA binding profiles have some conservation between influenza A viruses, H1N1 and H3N2, but no correlation was observed between influenza A and B viruses. Our study demonstrates the conserved nature of non-uniform NP binding within influenza viruses. Mapping of the NP-bound vRNA segments provides information on the flexible NP regions that may be involved in facilitating assembly. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Open AccessArticle Estimating Vaccine-Driven Selection in Seasonal Influenza
Viruses 2018, 10(9), 509; https://doi.org/10.3390/v10090509
Received: 22 August 2018 / Revised: 13 September 2018 / Accepted: 14 September 2018 / Published: 18 September 2018
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Abstract
Vaccination could be an evolutionary pressure on seasonal influenza if vaccines reduce the transmission rates of some (“targeted”) strains more than others. In theory, more vaccinated populations should have a lower prevalence of targeted strains compared to less vaccinated populations. We tested for
[...] Read more.
Vaccination could be an evolutionary pressure on seasonal influenza if vaccines reduce the transmission rates of some (“targeted”) strains more than others. In theory, more vaccinated populations should have a lower prevalence of targeted strains compared to less vaccinated populations. We tested for vaccine-induced selection in influenza by comparing strain frequencies between more and less vaccinated human populations. We defined strains in three ways: first as influenza types and subtypes, next as lineages of type B, and finally as clades of influenza A/H3N2. We detected spatial differences partially consistent with vaccine use in the frequencies of subtypes and types and between the lineages of influenza B, suggesting that vaccines do not select strongly among all these phylogenetic groups at regional scales. We did detect a significantly greater frequency of an H3N2 clade with known vaccine escape mutations in more vaccinated countries during the 2014–2015 season, which is consistent with vaccine-driven selection within the H3N2 subtype. Overall, we find more support for vaccine-driven selection when large differences in vaccine effectiveness suggest a strong effect size. Variation in surveillance practices across countries could obscure signals of selection, especially when strain-specific differences in vaccine effectiveness are small. Further examination of the influenza vaccine’s evolutionary effects would benefit from improvements in epidemiological surveillance and reporting. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Open AccessArticle Neuraminidase Inhibitors in Influenza Treatment and Prevention–Is It Time to Call It a Day?
Viruses 2018, 10(9), 454; https://doi.org/10.3390/v10090454
Received: 16 July 2018 / Revised: 15 August 2018 / Accepted: 22 August 2018 / Published: 25 August 2018
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Abstract
Stockpiling neuraminidase inhibitors (NAIs) such as oseltamivir and zanamivir is part of a global effort to be prepared for an influenza pandemic. However, the contribution of NAIs for the treatment and prevention of influenza and its complications is largely debatable due to constraints
[...] Read more.
Stockpiling neuraminidase inhibitors (NAIs) such as oseltamivir and zanamivir is part of a global effort to be prepared for an influenza pandemic. However, the contribution of NAIs for the treatment and prevention of influenza and its complications is largely debatable due to constraints in the ability to control for confounders and to explore unobserved areas of the drug effects. For this study, we used a mathematical model of influenza infection which allowed transparent analyses. The model recreated the oseltamivir effects and indicated that: (i) the efficacy was limited by design, (ii) a 99% efficacy could be achieved by using high drug doses (however, taking high doses of drug 48 h post-infection could only yield a maximum of 1.6-day reduction in the time to symptom alleviation), and (iii) contributions of oseltamivir to epidemic control could be high, but were observed only in fragile settings. In a typical influenza infection, NAIs’ efficacy is inherently not high, and even if their efficacy is improved, the effect can be negligible in practice. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Open AccessArticle Influenza Virus Infection of Human Lymphocytes Occurs in the Immune Cell Cluster of the Developing Antiviral Response
Viruses 2018, 10(8), 420; https://doi.org/10.3390/v10080420
Received: 16 July 2018 / Revised: 7 August 2018 / Accepted: 8 August 2018 / Published: 10 August 2018
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Abstract
Monocytes-macrophages and lymphocytes are recruited to the respiratory tract in response to influenza virus challenge and are exposed to the virus during the establishment of immune defenses. The susceptibility of human lymphocytes to infection was assessed. The presence of monocytes-macrophages was required to
[...] Read more.
Monocytes-macrophages and lymphocytes are recruited to the respiratory tract in response to influenza virus challenge and are exposed to the virus during the establishment of immune defenses. The susceptibility of human lymphocytes to infection was assessed. The presence of monocytes-macrophages was required to attain infection of both resting and proliferating lymphocytes. Lymphocyte infection occurred in the context of immune cell clusters and was blocked by the addition of anti-intercellular adhesion molecule-1 (ICAM-1) antibody to prevent cell clustering. Both peripheral blood-derived and bronchoalveolar lymphocytes were susceptible to infection. Both CD4+ and CD8+ T lymphocytes were susceptible to influenza virus infection, and the infected CD4+ and CD8+ lymphocytes served as infectious foci for other nonpermissive or even virus-permissive cells. These data show that monocytes-macrophages and both CD4+ and CD8+ lymphocytes can become infected during the course of an immune response to influenza virus challenge. The described leukocyte interactions during infection may play an important role in the development of effective anti-influenza responses. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Open AccessArticle Host Long Noncoding RNA lncRNA-PAAN Regulates the Replication of Influenza A Virus
Viruses 2018, 10(6), 330; https://doi.org/10.3390/v10060330
Received: 13 April 2018 / Revised: 13 June 2018 / Accepted: 14 June 2018 / Published: 16 June 2018
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Abstract
The productive infection of influenza A virus (IAV) depends on host factors. However, the involvement of long non-coding RNAs (lncRNAs) in IAV infection remains largely uninvestigated. In this work, we have discovered a human lncRNA, named lncRNA-PAAN (PA-associated noncoding RNA) that enhances IAV
[...] Read more.
The productive infection of influenza A virus (IAV) depends on host factors. However, the involvement of long non-coding RNAs (lncRNAs) in IAV infection remains largely uninvestigated. In this work, we have discovered a human lncRNA, named lncRNA-PAAN (PA-associated noncoding RNA) that enhances IAV replication. The level of lncRNA-PAAN increases upon infection of IAV, but not other viruses, nor interferon treatment, suggesting specific up-regulation of lncRNA-PAAN expression by IAV. Silencing lncRNA-PAAN significantly decreases IAV replication through impairing the activity of viral RNA-dependent RNA polymerase (RdRp). This function of lncRNA-PAAN is a result of its association with viral PA protein, a key component of IAV RNA polymerase complex. Consequently, depletion of lncRNA-PAAN prevents the formation of functional RdRp. Together, these results suggest that lncRNA-PAAN promotes the assembly of viral RNA polymerase, thus warranting efficient viral RNA synthesis. Elucidating the functions of lncRNAs in IAV infection is expected to advance our understanding of IAV pathogenesis and open new avenues to the development of novel anti-IAV therapeutics. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Open AccessArticle Adaptive Mutations in Influenza A/California/07/2009 Enhance Polymerase Activity and Infectious Virion Production
Viruses 2018, 10(5), 272; https://doi.org/10.3390/v10050272
Received: 16 March 2018 / Revised: 15 May 2018 / Accepted: 15 May 2018 / Published: 18 May 2018
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Abstract
Mice are not natural hosts for influenza A viruses (IAVs), but they are useful models for studying antiviral immune responses and pathogenesis. Serial passage of IAV in mice invariably causes the emergence of adaptive mutations and increased virulence. Here, we report the adaptation
[...] Read more.
Mice are not natural hosts for influenza A viruses (IAVs), but they are useful models for studying antiviral immune responses and pathogenesis. Serial passage of IAV in mice invariably causes the emergence of adaptive mutations and increased virulence. Here, we report the adaptation of IAV reference strain A/California/07/2009(H1N1) (also known as CA/07) in outbred Swiss Webster mice. Serial passage led to increased virulence and lung titers, and dissemination of the virus to brains. We adapted a deep-sequencing protocol to identify and enumerate adaptive mutations across all genome segments. Among mutations that emerged during mouse-adaptation, we focused on amino acid substitutions in polymerase subunits: polymerase basic-1 (PB1) T156A and F740L and polymerase acidic (PA) E349G. These mutations were evaluated singly and in combination in minigenome replicon assays, which revealed that PA E349G increased polymerase activity. By selectively engineering three PB1 and PA mutations into the parental CA/07 strain, we demonstrated that these mutations in polymerase subunits decreased the production of defective viral genome segments with internal deletions and dramatically increased the release of infectious virions from mouse cells. Together, these findings increase our understanding of the contribution of polymerase subunits to successful host adaptation. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Open AccessArticle Strain-Specific Antagonism of the Human H1N1 Influenza A Virus against Equine Tetherin
Viruses 2018, 10(5), 264; https://doi.org/10.3390/v10050264
Received: 21 March 2018 / Revised: 11 May 2018 / Accepted: 14 May 2018 / Published: 16 May 2018
Cited by 1 | PDF Full-text (1675 KB) | HTML Full-text | XML Full-text
Abstract
Tetherin/BST-2/CD317 is an interferon-induced host restriction factor that can block the budding of enveloped viruses by tethering them to the cell surface. Many viruses use certain proteins to counteract restriction by tetherin from their natural hosts, but not from other species. The influenza
[...] Read more.
Tetherin/BST-2/CD317 is an interferon-induced host restriction factor that can block the budding of enveloped viruses by tethering them to the cell surface. Many viruses use certain proteins to counteract restriction by tetherin from their natural hosts, but not from other species. The influenza A virus (FLUAV) has a wide range of subtypes with different host tropisms. Human tetherin (huTHN) has been reported to restrict only specific FLUAV strains and the viral hemagglutinin (HA) and neuraminidase (NA) genes determine the sensitivity to huTHN. Whether tetherins from other hosts can block human FLUAV is still unknown. Here, we evaluate the impact of equine tetherin (eqTHN) and huTHN on the replication of A/Sichuan/1/2009 (H1N1) and A/equine/Xinjiang/1/2007 (H3N8) strains. Our results show that eqTHN had higher restriction activity towards both viruses, and its shorter cytoplasmic tail contributed to that activity. We further demonstrated that HA and NA of A/Hamburg/4/2009 (H1N1) could counteract eqTHN. Notably, our results indicate that four amino acids, 13T and 49L of HA and 32T and 80V of NA, were involved in blocking the restriction activity of eqTHN. These findings reveal interspecies restriction by eqTHN towards FLUAV, and the role of the HA and NA proteins in overcoming this restriction. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Open AccessArticle Immunization of Domestic Ducks with Live Nonpathogenic H5N3 Influenza Virus Prevents Shedding and Transmission of Highly Pathogenic H5N1 Virus to Chickens
Viruses 2018, 10(4), 164; https://doi.org/10.3390/v10040164
Received: 5 March 2018 / Revised: 27 March 2018 / Accepted: 30 March 2018 / Published: 31 March 2018
Cited by 1 | PDF Full-text (634 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Wild ducks are known to be able to carry avian influenza viruses over long distances and infect domestic ducks, which in their turn infect domestic chickens. Therefore, prevention of virus transmission between ducks and chickens is important to control the spread of avian
[...] Read more.
Wild ducks are known to be able to carry avian influenza viruses over long distances and infect domestic ducks, which in their turn infect domestic chickens. Therefore, prevention of virus transmission between ducks and chickens is important to control the spread of avian influenza. Here we used a low pathogenic wild aquatic bird virus A/duck/Moscow/4182/2010 (H5N3) for prevention of highly pathogenic avian influenza virus (HPAIV) transmission between ducks and chickens. We first confirmed that the ducks orally infected with H5N1 HPAIV A/chicken/Kurgan/3/2005 excreted the virus in feces. All chickens that were in contact with the infected ducks became sick, excreted the virus, and died. However, the ducks orally inoculated with 104 50% tissue culture infective doses of A/duck/Moscow/4182/2010 and challenged 14 to 90 days later with H5N1 HPAIV did not excrete the challenge virus. All contact chickens survived and did not excrete the virus. Our results suggest that low pathogenic virus of wild aquatic birds can be used for prevention of transmission of H5N1 viruses between ducks and chickens. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Review

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Open AccessReview Host Shutoff in Influenza A Virus: Many Means to an End
Viruses 2018, 10(9), 475; https://doi.org/10.3390/v10090475
Received: 14 August 2018 / Revised: 31 August 2018 / Accepted: 1 September 2018 / Published: 5 September 2018
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Abstract
Influenza A virus carries few of its own proteins, but uses them effectively to take control of the infected cells and avoid immune responses. Over the years, host shutoff, the widespread down-regulation of host gene expression, has emerged as a key process that
[...] Read more.
Influenza A virus carries few of its own proteins, but uses them effectively to take control of the infected cells and avoid immune responses. Over the years, host shutoff, the widespread down-regulation of host gene expression, has emerged as a key process that contributes to cellular takeover in infected cells. Interestingly, multiple mechanisms of host shutoff have been described in influenza A virus, involving changes in translation, RNA synthesis and stability. Several viral proteins, notably the non-structural protein NS1, the RNA-dependent RNA polymerase and the endoribonuclease PA-X have been implicated in host shutoff. This multitude of host shutoff mechanisms indicates that host shutoff is an important component of the influenza A virus replication cycle. Here we review the various mechanisms of host shutoff in influenza A virus and the evidence that they contribute to immune evasion and/or viral replication. We also discuss what the purpose of having multiple mechanisms may be. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Open AccessReview The Pandemic Threat of Emerging H5 and H7 Avian Influenza Viruses
Viruses 2018, 10(9), 461; https://doi.org/10.3390/v10090461
Received: 6 August 2018 / Revised: 23 August 2018 / Accepted: 27 August 2018 / Published: 28 August 2018
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Abstract
The 1918 H1N1 Spanish Influenza pandemic was the most severe pandemic in modern history. Unlike more recent pandemics, most of the 1918 H1N1 virus’ genome was derived directly from an avian influenza virus. Recent avian-origin H5 A/goose/Guangdong/1/1996 (GsGd) and Asian H7N9 viruses have
[...] Read more.
The 1918 H1N1 Spanish Influenza pandemic was the most severe pandemic in modern history. Unlike more recent pandemics, most of the 1918 H1N1 virus’ genome was derived directly from an avian influenza virus. Recent avian-origin H5 A/goose/Guangdong/1/1996 (GsGd) and Asian H7N9 viruses have caused several hundred human infections with high mortality rates. While these viruses have not spread beyond infected individuals, if they evolve the ability to transmit efficiently from person-to-person, specifically via the airborne route, they will initiate a pandemic. Therefore, this review examines H5 GsGd and Asian H7N9 viruses that have caused recent zoonotic infections with a focus on viral properties that support airborne transmission. Several GsGd H5 and Asian H7N9 viruses display molecular changes that potentiate transmission and/or exhibit ability for limited transmission between ferrets. However, the hemagglutinin of these viruses is unstable; this likely represents the most significant obstacle to the emergence of a virus capable of efficient airborne transmission. Given the global disease burden of an influenza pandemic, continued surveillance and pandemic preparedness efforts against H5 GsGd and Asian lineage H7N9 viruses are warranted. Full article
(This article belongs to the Special Issue What’s New with Flu?)
Open AccessReview Mutation and Epistasis in Influenza Virus Evolution
Viruses 2018, 10(8), 407; https://doi.org/10.3390/v10080407
Received: 17 July 2018 / Revised: 30 July 2018 / Accepted: 30 July 2018 / Published: 3 August 2018
PDF Full-text (857 KB) | HTML Full-text | XML Full-text
Abstract
Influenza remains a persistent public health challenge, because the rapid evolution of influenza viruses has led to marginal vaccine efficacy, antiviral resistance, and the annual emergence of novel strains. This evolvability is driven, in part, by the virus’s capacity to generate diversity through
[...] Read more.
Influenza remains a persistent public health challenge, because the rapid evolution of influenza viruses has led to marginal vaccine efficacy, antiviral resistance, and the annual emergence of novel strains. This evolvability is driven, in part, by the virus’s capacity to generate diversity through mutation and reassortment. Because many new traits require multiple mutations and mutations are frequently combined by reassortment, epistatic interactions between mutations play an important role in influenza virus evolution. While mutation and epistasis are fundamental to the adaptability of influenza viruses, they also constrain the evolutionary process in important ways. Here, we review recent work on mutational effects and epistasis in influenza viruses. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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Open AccessReview Redox Biology of Respiratory Viral Infections
Viruses 2018, 10(8), 392; https://doi.org/10.3390/v10080392
Received: 13 June 2018 / Revised: 17 July 2018 / Accepted: 24 July 2018 / Published: 26 July 2018
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Abstract
Respiratory viruses cause infections of the upper or lower respiratory tract and they are responsible for the common cold—the most prevalent disease in the world. In many cases the common cold results in severe illness due to complications, such as fever or pneumonia.
[...] Read more.
Respiratory viruses cause infections of the upper or lower respiratory tract and they are responsible for the common cold—the most prevalent disease in the world. In many cases the common cold results in severe illness due to complications, such as fever or pneumonia. Children, old people, and immunosuppressed patients are at the highest risk and require fast diagnosis and therapeutic intervention. However, the availability and efficiencies of existing therapeutic approaches vary depending on the virus. Investigation of the pathologies that are associated with infection by respiratory viruses will be paramount for diagnosis, treatment modalities, and the development of new therapies. Changes in redox homeostasis in infected cells are one of the key events that is linked to infection with respiratory viruses and linked to inflammation and subsequent tissue damage. Our review summarizes current knowledge on changes to redox homeostasis, as induced by the different respiratory viruses. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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