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Viruses
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What’s New with Flu?
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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) | Viewed by 132360

Special Issue Editors

Dr. Christopher Byron Brooke

E-Mail Website
Guest Editor
1. Department of Microbiology, University of Illinois, Urbana, IL, USA
2. Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL, USA
Interests: host-pathogen interactions; viral evolution; viral immunology; regulation of gene ex-pression; virology
Dr. Seema Lakdawala

E-Mail Website
Guest Editor
Department of Microbiology and Molecular Genetics, Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA
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

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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 2600 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 (19 papers)

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Editorial

Jump to: Research, Review, Other

2 pages, 162 KiB  
Editorial
What’s New with Flu? An Overview
by Seema S. Lakdawala and Christopher B. Brooke
Viruses 2019, 11(5), 433; https://doi.org/10.3390/v11050433 - 10 May 2019
Cited by 2 | Viewed by 3362
Abstract
One hundred years have passed since the 1918 H1N1 pandemic, and influenza viruses continue to pose an enormous and unpredictable global public health threat [...] Full article
(This article belongs to the Special Issue What’s New with Flu?)

Research

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16 pages, 5120 KiB  
Article
Combination Therapy with Oseltamivir and Favipiravir Delays Mortality but Does Not Prevent Oseltamivir Resistance in Immunodeficient Mice Infected with Pandemic A(H1N1) Influenza Virus
by Mariana Baz, Julie Carbonneau, Chantal Rhéaume, Marie-Hélène Cavanagh and Guy Boivin
Viruses 2018, 10(11), 610; https://doi.org/10.3390/v10110610 - 03 Nov 2018
Cited by 25 | Viewed by 5219
Abstract
Immunosuppressed individuals can shed influenza virus for prolonged periods of time, leading to the frequent emergence of antiviral resistance. We evaluated the benefits of oseltamivir and favipiravir combination therapy compared to single antiviral agents and monitored the emergence of drug-resistant variants in a [...] Read more.
Immunosuppressed individuals can shed influenza virus for prolonged periods of time, leading to the frequent emergence of antiviral resistance. We evaluated the benefits of oseltamivir and favipiravir combination therapy compared to single antiviral agents and monitored the emergence of drug-resistant variants in a pharmacologically immunosuppressed mouse model infected with the A(H1N1) pandemic influenza virus. C57BL/6 mice were immunosuppressed with cyclophosphamide and infected with a lethal dose of pandemic influenza A(H1N1) virus. Forty-eight hours post-infection, mice were treated with oseltamivir (20 mg/kg), favipiravir (20 or 50 mg/kg) or both agents BID for 5 or 10 days. Body weight losses, survival rates, lung viral titers, cytokine levels and emergence of resistant viruses were evaluated. Treatment of immunosuppressed mice with high (50 mg/kg) but not low (20 mg/kg) doses of favipiravir in combination with oseltamivir (20 mg/kg) significantly delayed mortality and reduced lung viral titers compared to treatment with a single drug regimen with oseltamivir but did not prevent the emergence of oseltamivir-resistant H275Y neuraminidase variants. Combination therapy with oseltamivir and favipiravir should be considered for evaluation in clinical trials. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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11 pages, 1894 KiB  
Article
Non-Uniform and Non-Random Binding of Nucleoprotein to Influenza A and B Viral RNA
by Valerie Le Sage, Adalena V. Nanni, Amar R. Bhagwat, Dan J. Snyder, Vaughn S. Cooper, Seema S. Lakdawala and Nara Lee
Viruses 2018, 10(10), 522; https://doi.org/10.3390/v10100522 - 25 Sep 2018
Cited by 23 | Viewed by 4913
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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37 pages, 2304 KiB  
Article
Estimating Vaccine-Driven Selection in Seasonal Influenza
by Frank T. Wen, Sidney M. Bell, Trevor Bedford and Sarah Cobey
Viruses 2018, 10(9), 509; https://doi.org/10.3390/v10090509 - 18 Sep 2018
Cited by 6 | Viewed by 6228
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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13 pages, 2670 KiB  
Article
Neuraminidase Inhibitors in Influenza Treatment and Prevention–Is It Time to Call It a Day?
by César Parra-Rojas, Van Kinh Nguyen, Gustavo Hernandez-Mejia and Esteban A. Hernandez-Vargas
Viruses 2018, 10(9), 454; https://doi.org/10.3390/v10090454 - 25 Aug 2018
Cited by 19 | Viewed by 4888
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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21 pages, 4142 KiB  
Article
Influenza Virus Infection of Human Lymphocytes Occurs in the Immune Cell Cluster of the Developing Antiviral Response
by David J. Mock, Mark W. Frampton, Joan E. Nichols, Frank M. Domurat, Denise J. Signs and Norbert J. Roberts, Jr.
Viruses 2018, 10(8), 420; https://doi.org/10.3390/v10080420 - 10 Aug 2018
Cited by 7 | Viewed by 4212
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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16 pages, 3294 KiB  
Article
Host Long Noncoding RNA lncRNA-PAAN Regulates the Replication of Influenza A Virus
by Jing Wang, Yujia Wang, Rui Zhou, Jianyuan Zhao, Yongxin Zhang, Dongrong Yi, Quanjie Li, Jinming Zhou, Fei Guo, Chen Liang, Xiaoyu Li and Shan Cen
Viruses 2018, 10(6), 330; https://doi.org/10.3390/v10060330 - 16 Jun 2018
Cited by 44 | Viewed by 5437
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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17 pages, 2033 KiB  
Article
Adaptive Mutations in Influenza A/California/07/2009 Enhance Polymerase Activity and Infectious Virion Production
by Patrick D. Slaine, Cara MacRae, Mariel Kleer, Emily Lamoureux, Sarah McAlpine, Michelle Warhuus, André M. Comeau, Craig McCormick, Todd Hatchette and Denys A. Khaperskyy
Viruses 2018, 10(5), 272; https://doi.org/10.3390/v10050272 - 18 May 2018
Cited by 13 | Viewed by 5260
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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18 pages, 1675 KiB  
Article
Strain-Specific Antagonism of the Human H1N1 Influenza A Virus against Equine Tetherin
by Meiyue Wang, Zhenyu Zhang and Xiaojun Wang
Viruses 2018, 10(5), 264; https://doi.org/10.3390/v10050264 - 16 May 2018
Cited by 7 | Viewed by 3534
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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10 pages, 634 KiB  
Article
Immunization of Domestic Ducks with Live Nonpathogenic H5N3 Influenza Virus Prevents Shedding and Transmission of Highly Pathogenic H5N1 Virus to Chickens
by Alexandra Gambaryan, Ilya Gordeychuk, Elizaveta Boravleva, Natalia Lomakina, Ekaterina Kropotkina, Andrey Lunitsin, Hans-Dieter Klenk and Mikhail Matrosovich
Viruses 2018, 10(4), 164; https://doi.org/10.3390/v10040164 - 31 Mar 2018
Cited by 2 | Viewed by 4032
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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18 pages, 2998 KiB  
Review
Influenza Hemagglutinin and Neuraminidase: Yin–Yang Proteins Coevolving to Thwart Immunity
by Ivan Kosik and Jonathan W. Yewdell
Viruses 2019, 11(4), 346; https://doi.org/10.3390/v11040346 - 16 Apr 2019
Cited by 114 | Viewed by 13693
Abstract
Influenza A virions possess two surface glycoproteins—the hemagglutinin (HA) and neuraminidase (NA)—which exert opposite functions. HA attaches virions to cells by binding to terminal sialic acid residues on glycoproteins/glycolipids to initiate the infectious cycle, while NA cleaves terminal sialic acids, releasing virions to [...] Read more.
Influenza A virions possess two surface glycoproteins—the hemagglutinin (HA) and neuraminidase (NA)—which exert opposite functions. HA attaches virions to cells by binding to terminal sialic acid residues on glycoproteins/glycolipids to initiate the infectious cycle, while NA cleaves terminal sialic acids, releasing virions to complete the infectious cycle. Antibodies specific for HA or NA can protect experimental animals from IAV pathogenesis and drive antigenic variation in their target epitopes that impairs vaccine effectiveness in humans. Here, we review progress in understanding HA/NA co-evolution as each acquires epistatic mutations to restore viral fitness to mutants selected in the other protein by host innate or adaptive immune pressure. We also discuss recent exciting findings that antibodies to HA can function in vivo by blocking NA enzyme activity to prevent nascent virion release and enhance Fc receptor-based activation of innate immune cells. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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35 pages, 8902 KiB  
Review
Novel Approaches for The Development of Live Attenuated Influenza Vaccines
by Pilar Blanco-Lobo, Aitor Nogales, Laura Rodríguez and Luis Martínez-Sobrido
Viruses 2019, 11(2), 190; https://doi.org/10.3390/v11020190 - 22 Feb 2019
Cited by 45 | Viewed by 9003
Abstract
Influenza virus still represents a considerable threat to global public health, despite the advances in the development and wide use of influenza vaccines. Vaccination with traditional inactivate influenza vaccines (IIV) or live-attenuated influenza vaccines (LAIV) remains the main strategy in the control of [...] Read more.
Influenza virus still represents a considerable threat to global public health, despite the advances in the development and wide use of influenza vaccines. Vaccination with traditional inactivate influenza vaccines (IIV) or live-attenuated influenza vaccines (LAIV) remains the main strategy in the control of annual seasonal epidemics, but it does not offer protection against new influenza viruses with pandemic potential, those that have shifted. Moreover, the continual antigenic drift of seasonal circulating influenza viruses, causing an antigenic mismatch that requires yearly reformulation of seasonal influenza vaccines, seriously compromises vaccine efficacy. Therefore, the quick optimization of vaccine production for seasonal influenza and the development of new vaccine approaches for pandemic viruses is still a challenge for the prevention of influenza infections. Moreover, recent reports have questioned the effectiveness of the current LAIV because of limited protection, mainly against the influenza A virus (IAV) component of the vaccine. Although the reasons for the poor protection efficacy of the LAIV have not yet been elucidated, researchers are encouraged to develop new vaccination approaches that overcome the limitations that are associated with the current LAIV. The discovery and implementation of plasmid-based reverse genetics has been a key advance in the rapid generation of recombinant attenuated influenza viruses that can be used for the development of new and most effective LAIV. In this review, we provide an update regarding the progress that has been made during the last five years in the development of new LAIV and the innovative ways that are being explored as alternatives to the currently licensed LAIV. The safety, immunogenicity, and protection efficacy profile of these new LAIVs reveal their possible implementation in combating influenza infections. However, efforts by vaccine companies and government agencies will be needed for controlled testing and approving, respectively, these new vaccine methodologies for the control of influenza infections. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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23 pages, 790 KiB  
Review
Causes and Consequences of Spatial Within-Host Viral Spread
by Molly E. Gallagher, Christopher B. Brooke, Ruian Ke and Katia Koelle
Viruses 2018, 10(11), 627; https://doi.org/10.3390/v10110627 - 13 Nov 2018
Cited by 40 | Viewed by 6278
Abstract
The spread of viral pathogens both between and within hosts is inherently a spatial process. While the spatial aspects of viral spread at the epidemiological level have been increasingly well characterized, the spatial aspects of viral spread within infected hosts are still understudied. [...] Read more.
The spread of viral pathogens both between and within hosts is inherently a spatial process. While the spatial aspects of viral spread at the epidemiological level have been increasingly well characterized, the spatial aspects of viral spread within infected hosts are still understudied. Here, with a focus on influenza A viruses (IAVs), we first review experimental studies that have shed light on the mechanisms and spatial dynamics of viral spread within hosts. These studies provide strong empirical evidence for highly localized IAV spread within hosts. Since mathematical and computational within-host models have been increasingly used to gain a quantitative understanding of observed viral dynamic patterns, we then review the (relatively few) computational modeling studies that have shed light on possible factors that structure the dynamics of spatial within-host IAV spread. These factors include the dispersal distance of virions, the localization of the immune response, and heterogeneity in host cell phenotypes across the respiratory tract. While informative, we find in these studies a striking absence of theoretical expectations of how spatial dynamics may impact the dynamics of viral populations. To mitigate this, we turn to the extensive ecological and evolutionary literature on range expansions to provide informed theoretical expectations. We find that factors such as the type of density dependence, the frequency of long-distance dispersal, specific life history characteristics, and the extent of spatial heterogeneity are critical factors affecting the speed of population spread and the genetic composition of spatially expanding populations. For each factor that we identified in the theoretical literature, we draw parallels to its analog in viral populations. We end by discussing current knowledge gaps related to the spatial component of within-host IAV spread and the potential for within-host spatial considerations to inform the development of disease control strategies. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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20 pages, 1048 KiB  
Review
Host Shutoff in Influenza A Virus: Many Means to an End
by Rachel Emily Levene and Marta Maria Gaglia
Viruses 2018, 10(9), 475; https://doi.org/10.3390/v10090475 - 05 Sep 2018
Cited by 38 | Viewed by 5841
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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21 pages, 288 KiB  
Review
The Pandemic Threat of Emerging H5 and H7 Avian Influenza Viruses
by Troy C. Sutton
Viruses 2018, 10(9), 461; https://doi.org/10.3390/v10090461 - 28 Aug 2018
Cited by 109 | Viewed by 10548
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?)
13 pages, 857 KiB  
Review
Mutation and Epistasis in Influenza Virus Evolution
by Daniel M. Lyons and Adam S. Lauring
Viruses 2018, 10(8), 407; https://doi.org/10.3390/v10080407 - 03 Aug 2018
Cited by 73 | Viewed by 13045
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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27 pages, 1070 KiB  
Review
Redox Biology of Respiratory Viral Infections
by Olga A. Khomich, Sergey N. Kochetkov, Birke Bartosch and Alexander V. Ivanov
Viruses 2018, 10(8), 392; https://doi.org/10.3390/v10080392 - 26 Jul 2018
Cited by 263 | Viewed by 11203
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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9 pages, 3463 KiB  
Tutorial
Educational Material about Influenza Viruses
by Seema S. Lakdawala, Naina Nair and Edward Hutchinson
Viruses 2019, 11(3), 231; https://doi.org/10.3390/v11030231 - 07 Mar 2019
Cited by 6 | Viewed by 9285
Abstract
To supplement a special edition of the journal Viruses, entitled “What’s New with Flu?”, influenza virus researchers have worked together to generate simple educational material to communicate their science to school students. Educational materials suitable for a range of ages are included, [...] Read more.
To supplement a special edition of the journal Viruses, entitled “What’s New with Flu?”, influenza virus researchers have worked together to generate simple educational material to communicate their science to school students. Educational materials suitable for a range of ages are included, from coloring exercises for younger students through to explanations of cutting-edge science in straightforward language for older students. This article contains a handout with influenza facts, a coloring page, a glossary and word find and a connect-the-dots exercise explaining the ideas behind recently published scientific papers. Together, these materials are intended to make research on influenza viruses more accessible to students and teachers. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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6 pages, 180 KiB  
Opinion
Advances in Influenza Virus Research: A Personal Perspective
by Kanta Subbarao
Viruses 2018, 10(12), 724; https://doi.org/10.3390/v10120724 - 18 Dec 2018
Cited by 2 | Viewed by 4065
Abstract
Technical advances in the last decade have made it possible to investigate influenza virus infection from the cellular and subcellular level to intact animals and humans. As a result, we have gained a new understanding of the virus and disease. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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