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Open AccessArticle

Bax Inhibitor-1 Acts as an Anti-Influenza Factor by Inhibiting ROS Mediated Cell Death and Augmenting Heme-Oxygenase 1 Expression in Influenza Virus Infected Cells

by Mohammed Kawser Hossain, Subbroto Kumar Saha, Ahmed Abdal Dayem, Jung-Hyun Kim, Kyeongseok Kim, Gwang-Mo Yang, Hye Yeon Choi and Ssang-Goo Cho

Int. J. Mol. Sci. 2018, 19(3), 712; https://doi.org/10.3390/ijms19030712 - 2 Mar 2018

Cited by 16 | Viewed by 5808

Abstract

Influenza virus remains a major health concern worldwide, and there have been continuous efforts to develop effective antivirals despite the use of annual vaccination programs. The purpose of this study was to determine the anti-influenza activity of Bax inhibitor-1 (BI-1). Madin-Darby [...] Read more.

Influenza virus remains a major health concern worldwide, and there have been continuous efforts to develop effective antivirals despite the use of annual vaccination programs. The purpose of this study was to determine the anti-influenza activity of Bax inhibitor-1 (BI-1). Madin-Darby Canine Kidney (MDCK) cells expressing wild type BI-1 and a non-functional BI-1 mutant, BI-1 ∆C (with the C-terminal 14 amino acids deleted) were prepared and infected with A/PR/8/34 influenza virus. BI-1 overexpression led to the suppression of virus-induced cell death and virus production compared to control Mock or BI-1 ∆C overexpression. In contrast to BI-1 ∆C-overexpressing cells, BI-1-overexpressing cells exhibited markedly reduced virus-induced expression of several viral genes, accompanied by a substantial decrease in ROS production. We found that treatment with a ROS scavenging agent, N-acetyl cysteine (NAC), led to a dramatic decrease in virus production and viral gene expression in control MDCK and BI-1 ∆C-overexpressing cells. In contrast, NAC treatment resulted in the slight additional suppression of virus production and viral gene expression in BI-1-overexpressing cells but was statistically significant. Moreover, the expression of heme oxygenase-1 (HO-1) was also significantly increased following virus infection in BI-1-overexpressing cells compared to control cells. Taken together, our data suggest that BI-1 may act as an anti-influenza protein through the suppression of ROS mediated cell death and upregulation of HO-1 expression in influenza virus infected MDCK cells. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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5929 KiB

Open AccessArticle

Molecular Evolution of MERS Coronavirus: Dromedaries as a Recent Intermediate Host or Long-Time Animal Reservoir?

by Susanna K. P. Lau, Antonio C. P. Wong, Terrence C. K. Lau and Patrick C. Y. Woo

Int. J. Mol. Sci. 2017, 18(10), 2138; https://doi.org/10.3390/ijms18102138 - 16 Oct 2017

Cited by 31 | Viewed by 7324

Abstract

While dromedary camels are the immediate animal source of MERS coronavirus (MERS-CoV) infection, the evolutionary origin of MERS-CoV remains obscure. We analyzed 219 camel and human MERS-CoV genome sequences available in GenBank. Phylogenetic analysis showed that 5 and 214 strains belong to clade [...] Read more.

While dromedary camels are the immediate animal source of MERS coronavirus (MERS-CoV) infection, the evolutionary origin of MERS-CoV remains obscure. We analyzed 219 camel and human MERS-CoV genome sequences available in GenBank. Phylogenetic analysis showed that 5 and 214 strains belong to clade A and B, respectively, with clade A further divided into lineage A1 (3 human strains) and lineage A2 (2 camel strains), and clade B divided into B1 to B6 (each containing both human and camel strains). Recombination analysis showed potential recombination events in five strains from dromedaries in Saudi Arabia, with recombination between lineage B5 and B3 in four strains, and between lineage B3 and B4 in one strain. The spike protein showed the highest number of amino acid substitutions, especially between A2 and other lineages, and contained positively selected codons. Notably, codon 1020 was positively selected among B and B5 strains, and can distinguish between clade A (Q1020) and B (R1020/H1020) strains, suggesting that this residue may play a role in the evolution of S protein during divergence of different lineages. The time of the most recent common ancestor of all MERS-CoV was dated to approximately 2010. The implications on the role of camels in the evolution of MERS-CoV are discussed. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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3568 KiB

Open AccessArticle

Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral

by Yanmei Hu, Jiantao Zhang, Rami Musharrafieh, Raymond Hau, Chunlong Ma and Jun Wang

Int. J. Mol. Sci. 2017, 18(9), 1929; https://doi.org/10.3390/ijms18091929 - 8 Sep 2017

Cited by 19 | Viewed by 5919

Abstract

Influenza viruses are respiratory pathogens that are responsible for annual influenza epidemics and sporadic influenza pandemics. Oseltamivir (Tamiflu^®) is currently the only FDA-approved oral drug that is available for the prevention and treatment of influenza virus infection. However, its narrow therapeutic [...] Read more.

Influenza viruses are respiratory pathogens that are responsible for annual influenza epidemics and sporadic influenza pandemics. Oseltamivir (Tamiflu^®) is currently the only FDA-approved oral drug that is available for the prevention and treatment of influenza virus infection. However, its narrow therapeutic window, coupled with the increasing incidence of drug resistance, calls for the next generation of influenza antivirals. In this study, we discovered hesperadin, an aurora B kinase inhibitor, as a broad-spectrum influenza antiviral through forward chemical genomics screening. Hesperadin inhibits multiple human clinical isolates of influenza A and B viruses with single to submicromolar efficacy, including oseltamivir-resistant strains. Mechanistic studies revealed that hesperadin inhibits the early stage of viral replication by delaying the nuclear entry of viral ribonucleoprotein complex, thereby inhibiting viral RNA transcription and translation as well as viral protein synthesis. Moreover, a combination of hesperadin with oseltamivir shows synergistic antiviral activity, therefore hesperadin can be used either alone to treat infections by oseltamivir-resistant influenza viruses or used in combination with oseltamivir to delay resistance evolution among oseltamivir-sensitive strains. In summary, the discovery of hesperadin as a broad-spectrum influenza antiviral offers an alternative to combat future influenza epidemics and pandemics. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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1263 KiB

Open AccessArticle

Modulation of Immunogenicity and Conformation of HA1 Subunit of Influenza A Virus H1/N1 Hemagglutinin in Tubular Immunostimulating Complexes

by Nina Sanina, Ludmila Davydova, Natalia Chopenko, Eduard Kostetsky and Valery Shnyrov

Int. J. Mol. Sci. 2017, 18(9), 1895; https://doi.org/10.3390/ijms18091895 - 3 Sep 2017

Cited by 6 | Viewed by 4098

Abstract

The HA1 subunit of the influenza virus hemagglutinin (HA) is a valuable antigen for the development of vaccines against flu due to the availability of most antigenic sites which are conformational. Therefore, a novel adjuvanted antigen delivery system, tubular immunostimulating complexes (TI-complexes) comprising [...] Read more.

The HA1 subunit of the influenza virus hemagglutinin (HA) is a valuable antigen for the development of vaccines against flu due to the availability of most antigenic sites which are conformational. Therefore, a novel adjuvanted antigen delivery system, tubular immunostimulating complexes (TI-complexes) comprising monogalactosyldiacylglycerol (MGDG) from different marine macrophytes as a lipid matrix for an antigen, was applied to enhance the immunogenicity of recombinant HA1 of influenza A H1N1 and to study the relation between its immunogenicity and conformation. The content of anti-HA1 antibodies and cytokines was estimated by ELISA after the immunization of mice with HA1 alone, and HA1 was incorporated in TI-complexes based on different MGDGs isolated from green algae Ulva lactuca, brown algae Sargassum pallidum, and seagrass Zostera marina. Conformational changes of HA1 were estimated by differential scanning calorimetry and intrinsic fluorescence. It was shown that the adjuvant activity of TI-complexes depends on the microviscosity of MGDGs, which differently influence the conformation of HA1. The highest production of anti-HA1 antibodies (compared with the control) was induced by HA1 incorporated in a TI-complex based on MGDG from S. pallidum, which provided the relaxation of the spatial structure and, likely, the proper presentation of the antigen to immunocompetent cells. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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1743 KiB

Open AccessArticle

Biological Evaluation of Uridine Derivatives of 2-Deoxy Sugars as Potential Antiviral Compounds against Influenza A Virus

by Ewelina Krol, Ilona Wandzik, Martyna Krejmer-Rabalska and Boguslaw Szewczyk

Int. J. Mol. Sci. 2017, 18(8), 1700; https://doi.org/10.3390/ijms18081700 - 4 Aug 2017

Cited by 7 | Viewed by 5441

Abstract

Influenza virus infection is a major cause of morbidity and mortality worldwide. Due to the limited ability of currently available treatments, there is an urgent need for new anti-influenza drugs with broad spectrum protection. We have previously shown that two 2-deoxy sugar derivatives [...] Read more.

Influenza virus infection is a major cause of morbidity and mortality worldwide. Due to the limited ability of currently available treatments, there is an urgent need for new anti-influenza drugs with broad spectrum protection. We have previously shown that two 2-deoxy sugar derivatives of uridine (designated IW3 and IW7) targeting the glycan processing steps during maturation of viral glycoproteins show good anti-influenza virus activity and may be a promising alternative approach for the development of new anti-influenza therapy. In this study, a number of IW3 and IW7 analogues with different structural modifications in 2-deoxy sugar or uridine parts were synthesized and evaluated for their ability to inhibit influenza A virus infection in vitro. Using the cytopathic effect (CPE) inhibition assay and viral plaque reduction assay in vitro, we showed that compounds 2, 3, and 4 exerted the most inhibitory effect on influenza virus A/ostrich/Denmark/725/96 (H5N2) infection in Madin-Darby canine kidney (MDCK) cells, with 50% inhibitory concentrations (IC₅₀) for virus growth ranging from 82 to 100 (μM) without significant toxicity for the cells. The most active compound (2) showed activity of 82 μM with a selectivity index value of 5.27 against type A (H5N2) virus. Additionally, compound 2 reduced the formation of HA glycoprotein in a dose-dependent manner. Moreover, an analysis of physicochemical properties of studied compounds demonstrated a significant linear correlation between lipophilicity and antiviral activity. Therefore, inhibition of influenza A virus infection by conjugates of uridine and 2-deoxy sugars is a new promising approach for the development of new derivatives with anti-influenza activities. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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4889 KiB

Open AccessArticle

Visualization of Alternative Functional Configurations of Influenza Virus Hemagglutinin Facilitates Rapid Selection of Complementing Vaccines in Emergency Situations

by Ashraf Metwally and Ausama Yousif

Int. J. Mol. Sci. 2017, 18(4), 766; https://doi.org/10.3390/ijms18040766 - 4 Apr 2017

Cited by 1 | Viewed by 5327

Abstract

Successful immunization against avian influenza virus (AIV) requires eliciting an adequate polyclonal response to AIV hemagglutinin (HA) subunit 1 (HA1) epitopes. Outbreaks of highly-pathogenic (HP) AIV subtype H5N1 can occur in vaccinated flocks in many endemic areas. Protection against emerging AIV is partly [...] Read more.

Successful immunization against avian influenza virus (AIV) requires eliciting an adequate polyclonal response to AIV hemagglutinin (HA) subunit 1 (HA1) epitopes. Outbreaks of highly-pathogenic (HP) AIV subtype H5N1 can occur in vaccinated flocks in many endemic areas. Protection against emerging AIV is partly hindered by the limitations of vaccine production and transport, the use of leaky vaccines, and the use of multiple, and often antigenically-diverse, vaccines. It was hypothesized that the majority of alternative functional configurations (AFC) within the AIV HA1 can be represented by the pool of vaccine seed viruses currently in production because only a finite number of AFC are possible within each substructure of the molecule. Therefore, combinations of commercial vaccines containing complementing structural units (CSU) to each HA1 substructure can elicit responses to the totality of a given emerging AIV HA1 substructure isoforms. Analysis of homology-based 3D models of vaccine seed and emerging viruses facilitated the definition of HA1 AFC isoforms. CSU-based plots were used to predict which commercial vaccine combinations could have been used to cover nine selected AFC isoforms on recent Egyptian HP AIV H5N1 outbreak viruses. It is projected that expansion of the vaccine HA1 3D model database will improve international emergency responses to AIV. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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Review

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Open AccessReview

New Insights Contributing to the Development of Effective Vaccines and Therapies to Reduce the Pathology Caused by hRSV

by Nicolás M. S. Gálvez, Jorge A. Soto and Alexis M. Kalergis

Int. J. Mol. Sci. 2017, 18(8), 1753; https://doi.org/10.3390/ijms18081753 - 11 Aug 2017

Cited by 15 | Viewed by 7034

Abstract

Human Respiratory Syncytial Virus (hRSV) is one of the major causes of acute lower respiratory tract infections (ALRTI) worldwide, leading to significant levels of immunocompromisation as well as morbidity and mortality in infants. Its main target of infection is the ciliated epithelium of [...] Read more.

Human Respiratory Syncytial Virus (hRSV) is one of the major causes of acute lower respiratory tract infections (ALRTI) worldwide, leading to significant levels of immunocompromisation as well as morbidity and mortality in infants. Its main target of infection is the ciliated epithelium of the lungs and the host immune responses elicited is ineffective at achieving viral clearance. It is thought that the lack of effective immunity against hRSV is due in part to the activity of several viral proteins that modulate the host immune response, enhancing a Th2-like pro-inflammatory state, with the secretion of cytokines that promote the infiltration of immune cells to the lungs, with consequent damage. Furthermore, the adaptive immunity triggered by hRSV infection is characterized by weak cytotoxic T cell responses and secretion of low affinity antibodies by B cells. These features of hRSV infection have meant that, to date, no effective and safe vaccines have been licensed. In this article, we will review in detail the information regarding hRSV characteristics, pathology, and host immune response, along with several prophylactic treatments and vaccine prototypes. We will also expose significant data regarding the newly developed BCG-based vaccine that promotes protective cellular and humoral response against hRSV infection, which is currently undergoing clinical evaluation. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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232 KiB

Open AccessReview

Evolution of Influenza A Virus by Mutation and Re-Assortment

by Wenhan Shao, Xinxin Li, Mohsan Ullah Goraya, Song Wang and Ji-Long Chen

Int. J. Mol. Sci. 2017, 18(8), 1650; https://doi.org/10.3390/ijms18081650 - 7 Aug 2017

Cited by 230 | Viewed by 20016

Abstract

Influenza A virus (IAV), a highly infectious respiratory pathogen, has continued to be a significant threat to global public health. To complete their life cycle, influenza viruses have evolved multiple strategies to interact with a host. A large number of studies have revealed [...] Read more.

Influenza A virus (IAV), a highly infectious respiratory pathogen, has continued to be a significant threat to global public health. To complete their life cycle, influenza viruses have evolved multiple strategies to interact with a host. A large number of studies have revealed that the evolution of influenza A virus is mainly mediated through the mutation of the virus itself and the re-assortment of viral genomes derived from various strains. The evolution of influenza A virus through these mechanisms causes worldwide annual epidemics and occasional pandemics. Importantly, influenza A virus can evolve from an animal infected pathogen to a human infected pathogen. The highly pathogenic influenza virus has resulted in stupendous economic losses due to its morbidity and mortality both in human and animals. Influenza viruses fall into a category of viruses that can cause zoonotic infection with stable adaptation to human, leading to sustained horizontal transmission. The rapid mutations of influenza A virus result in the loss of vaccine optimal efficacy, and challenge the complete eradication of the virus. In this review, we highlight the current understanding of influenza A virus evolution caused by the mutation and re-assortment of viral genomes. In addition, we discuss the specific mechanisms by which the virus evolves. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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Open AccessReview

Respiratory Syncytial Virus: The Influence of Serotype and Genotype Variability on Clinical Course of Infection

by Silvia Vandini, Carlotta Biagi and Marcello Lanari

Int. J. Mol. Sci. 2017, 18(8), 1717; https://doi.org/10.3390/ijms18081717 - 6 Aug 2017

Cited by 102 | Viewed by 8337

Abstract

Respiratory syncytial virus (RSV) belongs to the recently defined Pneumoviridae family, Orthopneumovirus genus. It is the leading cause of acute bronchiolitis and one of the most common causes of infant viral death worldwide, with infection typically occurring as recurrent seasonal epidemics. There are [...] Read more.

Respiratory syncytial virus (RSV) belongs to the recently defined Pneumoviridae family, Orthopneumovirus genus. It is the leading cause of acute bronchiolitis and one of the most common causes of infant viral death worldwide, with infection typically occurring as recurrent seasonal epidemics. There are two major RSV subtypes, A and B, and multiple genotypes, which can coexist during RSV epidemic season every year and result in different disease severity. Recently, new RSV genomic sequences and analysis of RSV genotypes have provided important data for understanding RSV pathogenesis. Novel RSV strains do spread rapidly and widely, and a knowledge of viral strain-specific phenotypes may be important in order to include the more virulent strains in future therapeutical options and vaccine development. Here we summarize recent literature exploring genetic and molecular aspects related to RSV infection, their impact on the clinical course of the disease and their potential utility in the development of safe and effective preventive and therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

509 KiB

Open AccessReview

Influenza A Virus–Host Protein Interactions Control Viral Pathogenesis

by Mengmeng Zhao, Lingyan Wang and Shitao Li

Int. J. Mol. Sci. 2017, 18(8), 1673; https://doi.org/10.3390/ijms18081673 - 1 Aug 2017

Cited by 46 | Viewed by 10757

Abstract

The influenza A virus (IAV), a member of the Orthomyxoviridae family, is a highly transmissible respiratory pathogen and represents a continued threat to global health with considerable economic and social impact. IAV is a zoonotic virus that comprises a plethora of strains with [...] Read more.

The influenza A virus (IAV), a member of the Orthomyxoviridae family, is a highly transmissible respiratory pathogen and represents a continued threat to global health with considerable economic and social impact. IAV is a zoonotic virus that comprises a plethora of strains with different pathogenic profiles. The different outcomes of viral pathogenesis are dependent on the engagement between the virus and the host cellular protein interaction network. The interactions may facilitate virus hijacking of host molecular machinery to fulfill the viral life cycle or trigger host immune defense to eliminate the virus. In recent years, much effort has been made to discover the virus–host protein interactions and understand the underlying mechanisms. In this paper, we review the recent advances in our understanding of IAV–host interactions and how these interactions contribute to host defense and viral pathogenesis. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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711 KiB

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From Variation of Influenza Viral Proteins to Vaccine Development

by Wandi Zhu, Chao Wang and Bao-Zhong Wang

Int. J. Mol. Sci. 2017, 18(7), 1554; https://doi.org/10.3390/ijms18071554 - 18 Jul 2017

Cited by 24 | Viewed by 9258

Abstract

Recurrent influenza epidemics and occasional pandemics are one of the most important global public health concerns and are major causes of human morbidity and mortality. Influenza viruses can evolve through antigen drift and shift to overcome the barriers of human immunity, leading to [...] Read more.

Recurrent influenza epidemics and occasional pandemics are one of the most important global public health concerns and are major causes of human morbidity and mortality. Influenza viruses can evolve through antigen drift and shift to overcome the barriers of human immunity, leading to host adaption and transmission. Mechanisms underlying this viral evolution are gradually being elucidated. Vaccination is an effective method for the prevention of influenza virus infection. However, the emergence of novel viruses, including the 2009 pandemic influenza A (H1N1), the avian influenza A virus (H7N9), and the highly pathogenic avian influenza A virus (HPAI H5N1), that have infected human populations frequently in recent years reveals the tremendous challenges to the current influenza vaccine strategy. A better vaccine that provides protection against a wide spectrum of various influenza viruses and long-lasting immunity is urgently required. Here, we review the evolutionary changes of several important influenza proteins and the influence of these changes on viral antigenicity, host adaption, and viral pathogenicity. Furthermore, we discuss the development of a potent universal influenza vaccine based on this knowledge. Full article

(This article belongs to the Special Issue Molecular Epidemiology of Respiratory Viruses: Surveillance, Phylogenetics and Evolution)

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