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3 pages, 175 KiB

Open AccessEditorial

Influenza A Virus: Host–Virus Relationships

by Sunil K. Lal

Viruses 2020, 12(8), 870; https://doi.org/10.3390/v12080870 - 9 Aug 2020

Cited by 2 | Viewed by 2784

Abstract

We are in the midst of a pandemic where the infective agent has been identified, but how it causes mild disease in some and fatally severe disease in other infected individuals remains a mystery [...] Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

Research

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13 pages, 2304 KiB

Open AccessArticle

Live Visualization of Hemagglutinin Dynamics during Infection by Using a Novel Reporter Influenza A Virus

by Luiz Gustavo dos Anjos Borges, Giuseppe Pisanelli, Oyahida Khatun, Adolfo García-Sastre and Shashank Tripathi

Viruses 2020, 12(6), 687; https://doi.org/10.3390/v12060687 - 26 Jun 2020

Cited by 2 | Viewed by 5658

Abstract

Live visualization of influenza A virus (IAV) structural proteins during viral infection in cells is highly sought objective to study different aspects of the viral replication cycle. To achieve this, we engineered an IAV to express a Tetra Cysteine tag (TC tag) from [...] Read more.

Live visualization of influenza A virus (IAV) structural proteins during viral infection in cells is highly sought objective to study different aspects of the viral replication cycle. To achieve this, we engineered an IAV to express a Tetra Cysteine tag (TC tag) from hemagglutinin (HA), which allows intracellular labeling of the engineered HA protein with biarsenic dyes and subsequent fluorescence detection. Using such constructs, we rescued a recombinant IAV with TC tag inserted in HA, in A/Puerto Rico/8/1934(H1N1) background (HA-TC). This recombinant HA-TC tag reporter IAV was replication-competent; however, as compared to wild type PR8 IAV, it was attenuated in multicycle replication. We confirmed expression of TC tag and biarsenical labeling of HA by immunofluorescence assay in cells infected with an HA-TC tag reporter IAV. Further, we used this reporter virus to visualize HA expression and translocation in IAV infected cells by live confocal imaging. We also tested the utility of the HA-TC IAV in testing chemical inhibitors of the HA translocation. Overall, HA-TC IAV is a versatile tool that will be useful for studying viral life cycle events, virus-host interactions, and anti-viral testing. Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

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18 pages, 3869 KiB

Open AccessArticle

Upregulation of miR-101 during Influenza A Virus Infection Abrogates Viral Life Cycle by Targeting mTOR Pathway

by Shipra Sharma, Anirvan Chatterjee, Purnima Kumar, Sunil Lal and Kiran Kondabagil

Viruses 2020, 12(4), 444; https://doi.org/10.3390/v12040444 - 15 Apr 2020

Cited by 17 | Viewed by 3879

Abstract

Micro RNAs (miRNAs) are a class of small non-coding single-stranded RNA, which play an important role in modulating host-Influenza A virus (IAV) crosstalk. The interplay between influenza and miRNA interaction is defined by a plethora of complex mechanisms, which are not fully understood [...] Read more.

Micro RNAs (miRNAs) are a class of small non-coding single-stranded RNA, which play an important role in modulating host-Influenza A virus (IAV) crosstalk. The interplay between influenza and miRNA interaction is defined by a plethora of complex mechanisms, which are not fully understood yet. Here, we demonstrate that in IAV infected A549 cells, a synchronous increase was observed in the expression of mTOR up to 24 hpi and significant downregulation at 48 hpi. Additionally, NP of IAV interacts with mTOR and modulates the levels of mTOR mRNA and protein, thus regulating the translation of host cell. RNA sequencing and qPCR analysis of IAV-infected A549 cells and NP transfected cells revealed that miR-101 downregulates mTOR transcripts at later stages of infection. Ectopic expression of miR-101 mimic led to a decrease in expression of NP, a reduction in IAV titer and replication. Moreover, treatment of the cells with Everolimus, a potent inhibitor of mTOR, resulted in an increase of miR-101 transcript levels, which further suppressed the viral protein synthesis. Collectively, the data suggest a novel mechanism that IAV stimulates mTOR pathway at early stages of infection; however, at a later time-point, positive regulation of miR-101 restrains the mTOR expression, and hence, the viral propagation. Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

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13 pages, 2886 KiB

Open AccessArticle

A Well-Defined H9N2 Avian Influenza Virus Genotype with High Adaption in Mammals was Prevalent in Chinese Poultry Between 2016 to 2019

by Zhaokun Chen, Qinghua Huang, Shaohua Yang, Shuai Su, Baoquan Li, Ning Cui and Chuantian Xu

Viruses 2020, 12(4), 432; https://doi.org/10.3390/v12040432 - 11 Apr 2020

Cited by 5 | Viewed by 2972

Abstract

H9N2 subtype avian influenza virus (AIV) is widely prevalent in poultry, and the virus is becoming adaptive to mammals, which poses pandemic importance. Here, BALB/c mice were employed as a model to evaluate the adaption in mammals of 21 field H9N2 viruses isolated [...] Read more.

H9N2 subtype avian influenza virus (AIV) is widely prevalent in poultry, and the virus is becoming adaptive to mammals, which poses pandemic importance. Here, BALB/c mice were employed as a model to evaluate the adaption in mammals of 21 field H9N2 viruses isolated from avian species between 2016 to 2019 in China. The replication capacity of the viruses was evaluated in the lungs of mice. The pathogenicity of the viruses were compared by weight loss and lung lesions from infected mice. The whole genomic sequences of the viruses were further characterized to define the associated phenotypes of the H9N2 viruses in vitro and in vivo. The results showed that most viruses could replicate well and cause lesions in the mouse lungs. The propagation capacity in MDCK cells and damage to respiratory tissues of the infected mice corresponded to relative viral titers in the mouse lungs. Further genome analysis showed that all of the H9N2 viruses belonged to the same genotype, G57, and contained a couple of amino acid substitutions or deletions that have been demonstrated as avian-human markers. Additionally, nine amino acids residues in seven viral proteins were found to be correlated with the replication phenotypes of the H9N2 viruses in mammals. The study demonstrated that a well-defined H9N2 AIV genotype with high adaption in mammals was prevalent in China in recent years. Further investigations on the role of the identified residues and continuous surveillance of newly identified mutations associated with host adaption should be strengthened to prevent any devastating human influenza pandemics. Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

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15 pages, 3472 KiB

Open AccessArticle

Role of CARD Region of MDA5 Gene in Canine Influenza Virus Infection

by Cheng Fu, Shaotang Ye, Yongbo Liu and Shoujun Li

Viruses 2020, 12(3), 307; https://doi.org/10.3390/v12030307 - 12 Mar 2020

Cited by 11 | Viewed by 2679

Abstract

MDA5 belongs to the RIG-I-like receptor family, which is involved in innate immunity. During viral infection, MDA5 generates an antiviral response by recognizing the ligand to activate interferon. However, the role and mechanism of MDA5 in canine influenza virus (CIV) infection are unclear. [...] Read more.

MDA5 belongs to the RIG-I-like receptor family, which is involved in innate immunity. During viral infection, MDA5 generates an antiviral response by recognizing the ligand to activate interferon. However, the role and mechanism of MDA5 in canine influenza virus (CIV) infection are unclear. To understand the mechanism of canine MDA5-mediated innate immunity during CIV infection, we detected the distribution of MDA5 in beagles, and the structural prediction showed that MDA5 was mainly composed of a CARD domain, RD domain, and DExD/H helix structure. Moreover, we found that MDA5 inhibits CIV replication. Furthermore, in the dual luciferase assay, we revealed that the CARD region of MDA5 strongly activated the IFN-β promoter and mainly transmitted signals through the CARD region. Overexpression of the CARD region of MDA5 revealed that the MDA5-mediated signaling pathway could transmit signals by activating the IRF3/NF-κB and IRF3 promoters, promoting the expression of antiviral proteins and cytokine release, thereby inhibiting CIV replication. Upon silencing of MDA5, cytokine production decreased, while the replication ability of CIV was increased. Thus, this study revealed a novel mechanism by which MDA5 mediated CIV infection and provided new avenues for the development of antiviral strategies. Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

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Review

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21 pages, 2556 KiB

Open AccessReview

Host Protective Immune Responses against Influenza A Virus Infection

by Hi Eun Jung and Heung Kyu Lee

Viruses 2020, 12(5), 504; https://doi.org/10.3390/v12050504 - 3 May 2020

Cited by 28 | Viewed by 10294

Abstract

Influenza viruses cause infectious respiratory disease characterized by fever, myalgia, and congestion, ranging in severity from mild to life-threating. Although enormous efforts have aimed to prevent and treat influenza infections, seasonal and pandemic influenza outbreaks remain a major public health concern. This is [...] Read more.

Influenza viruses cause infectious respiratory disease characterized by fever, myalgia, and congestion, ranging in severity from mild to life-threating. Although enormous efforts have aimed to prevent and treat influenza infections, seasonal and pandemic influenza outbreaks remain a major public health concern. This is largely because influenza viruses rapidly undergo genetic mutations that restrict the long-lasting efficacy of vaccine-induced immune responses and therapeutic regimens. In this review, we discuss the virological features of influenza A viruses and provide an overview of current knowledge of the innate sensing of invading influenza viruses and the protective immune responses in the host. Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

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12 pages, 1666 KiB

Open AccessReview

The Multifarious Role of 14-3-3 Family of Proteins in Viral Replication

by Kavitha Ganesan Nathan and Sunil K. Lal

Viruses 2020, 12(4), 436; https://doi.org/10.3390/v12040436 - 13 Apr 2020

Cited by 24 | Viewed by 4592

Abstract

The 14-3-3 proteins are a family of ubiquitous and exclusively eukaryotic proteins with an astoundingly significant number of binding partners. Their binding alters the activity, stability, localization, and phosphorylation state of a target protein. The association of 14-3-3 proteins with the regulation of [...] Read more.

The 14-3-3 proteins are a family of ubiquitous and exclusively eukaryotic proteins with an astoundingly significant number of binding partners. Their binding alters the activity, stability, localization, and phosphorylation state of a target protein. The association of 14-3-3 proteins with the regulation of a wide range of general and specific signaling pathways suggests their crucial role in health and disease. Recent studies have linked 14-3-3 to several RNA and DNA viruses that may contribute to the pathogenesis and progression of infections. Therefore, comprehensive knowledge of host–virus interactions is vital for understanding the viral life cycle and developing effective therapeutic strategies. Moreover, pharmaceutical research is already moving towards targeting host proteins in the control of virus pathogenesis. As such, targeting the right host protein to interrupt host–virus interactions could be an effective therapeutic strategy. In this review, we generated a 14-3-3 protein interactions roadmap in viruses, using the freely available Virusmentha network, an online virus–virus or virus–host interaction tool. Furthermore, we summarize the role of the 14-3-3 family in RNA and DNA viruses. The participation of 14-3-3 in viral infections underlines its significance as a key regulator for the expression of host and viral proteins. Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

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23 pages, 2193 KiB

Open AccessReview

Die Another Way: Interplay between Influenza A Virus, Inflammation and Cell Death

by Gabriel Laghlali, Kate E. Lawlor and Michelle D. Tate

Viruses 2020, 12(4), 401; https://doi.org/10.3390/v12040401 - 4 Apr 2020

Cited by 43 | Viewed by 7138

Abstract

Influenza A virus (IAV) is a major concern to human health due to the ongoing global threat of a pandemic. Inflammatory and cell death signalling pathways play important roles in host defence against IAV infection. However, severe IAV infections in humans are characterised [...] Read more.

Influenza A virus (IAV) is a major concern to human health due to the ongoing global threat of a pandemic. Inflammatory and cell death signalling pathways play important roles in host defence against IAV infection. However, severe IAV infections in humans are characterised by excessive inflammation and tissue damage, often leading to fatal disease. While the molecular mechanisms involved in the induction of inflammation during IAV infection have been well studied, the pathways involved in IAV-induced cell death and their impact on immunopathology have not been fully elucidated. There is increasing evidence of significant crosstalk between cell death and inflammatory pathways and a greater understanding of their role in host defence and disease may facilitate the design of new treatments for IAV infection. Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

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23 pages, 899 KiB

Open AccessReview

Host–Virus Interaction: How Host Cells Defend against Influenza A Virus Infection

by Yun Zhang, Zhichao Xu and Yongchang Cao

Viruses 2020, 12(4), 376; https://doi.org/10.3390/v12040376 - 29 Mar 2020

Cited by 22 | Viewed by 5574

Abstract

Influenza A viruses (IAVs) are highly contagious pathogens infecting human and numerous animals. The viruses cause millions of infection cases and thousands of deaths every year, thus making IAVs a continual threat to global health. Upon IAV infection, host innate immune system is [...] Read more.

Influenza A viruses (IAVs) are highly contagious pathogens infecting human and numerous animals. The viruses cause millions of infection cases and thousands of deaths every year, thus making IAVs a continual threat to global health. Upon IAV infection, host innate immune system is triggered and activated to restrict virus replication and clear pathogens. Subsequently, host adaptive immunity is involved in specific virus clearance. On the other hand, to achieve a successful infection, IAVs also apply multiple strategies to avoid be detected and eliminated by the host immunity. In the current review, we present a general description on recent work regarding different host cells and molecules facilitating antiviral defenses against IAV infection and how IAVs antagonize host immune responses. Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

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19 pages, 1200 KiB

Open AccessReview

Key Role of the Influenza A Virus PA Gene Segment in the Emergence of Pandemic Viruses

by Michael M. Lutz IV, Megan M. Dunagan, Yuki Kurebayashi and Toru Takimoto

Viruses 2020, 12(4), 365; https://doi.org/10.3390/v12040365 - 26 Mar 2020

Cited by 19 | Viewed by 4846

Abstract

Influenza A viruses (IAVs) are a significant human pathogen that cause seasonal epidemics and occasional pandemics. Avian waterfowl are the natural reservoir of IAVs, but a wide range of species can serve as hosts. Most IAV strains are adapted to one host species [...] Read more.

Influenza A viruses (IAVs) are a significant human pathogen that cause seasonal epidemics and occasional pandemics. Avian waterfowl are the natural reservoir of IAVs, but a wide range of species can serve as hosts. Most IAV strains are adapted to one host species and avian strains of IAV replicate poorly in most mammalian hosts. Importantly, IAV polymerases from avian strains function poorly in mammalian cells but host adaptive mutations can restore activity. The 2009 pandemic H1N1 (H1N1pdm09) virus acquired multiple mutations in the PA gene that activated polymerase activity in mammalian cells, even in the absence of previously identified host adaptive mutations in other polymerase genes. These mutations in PA localize within different regions of the protein suggesting multiple mechanisms exist to activate polymerase activity. Additionally, an immunomodulatory protein, PA-X, is expressed from the PA gene segment. PA-X expression is conserved amongst many IAV strains but activity varies between viruses specific for different hosts, suggesting that PA-X also plays a role in host adaptation. Here, we review the role of PA in the emergence of currently circulating H1N1pdm09 viruses and the most recent studies of host adaptive mutations in the PA gene that modulate polymerase activity and PA-X function. Full article

(This article belongs to the Special Issue Influenza A Virus: Host-Virus Relationship)

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