International Journal of Molecular Sciences

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17 pages, 5402 KiB

Open AccessArticle

Lipidomic Profiling Reveals Significant Perturbations of Intracellular Lipid Homeostasis in Enterovirus-Infected Cells

by Bingpeng Yan, Zijiao Zou, Hin Chu, Gabriella Chan, Jessica Oi-Ling Tsang, Pok-Man Lai, Shuofeng Yuan, Cyril Chik-Yan Yip, Feifei Yin, Richard Yi-Tsun Kao, Kong-Hung Sze, Susanna Kar-Pui Lau, Jasper Fuk-Woo Chan and Kwok-Yung Yuen

Int. J. Mol. Sci. 2019, 20(23), 5952; https://doi.org/10.3390/ijms20235952 - 26 Nov 2019

Cited by 28 | Viewed by 4755

Abstract

Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are the most common causes of hand, foot, and mouth disease. Severe EV-A71 and CV-A16 infections may be associated with life-threatening complications. However, the pathogenic mechanisms underlying these severe clinical and pathological features remain incompletely understood. [...] Read more.

Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are the most common causes of hand, foot, and mouth disease. Severe EV-A71 and CV-A16 infections may be associated with life-threatening complications. However, the pathogenic mechanisms underlying these severe clinical and pathological features remain incompletely understood. Lipids are known to play critical roles in multiple stages of the virus replication cycle. The specific lipid profile induced upon virus infection is required for optimal virus replication. The perturbations in the host cell lipidomic profiles upon enterovirus infection have not been fully characterized. To this end, we performed ultra-high performance liquid chromatography–electrospray ionization–quadrupole–time of flight-mass spectrometry (UPLC-ESI-Q-TOF-MS)-based lipidomics to characterize the change in host lipidome upon EV-A71 and CV-A16 infections. Our results revealed that 47 lipids within 11 lipid classes were significantly perturbed after EV-A71 and CV-A16 infection. Four polyunsaturated fatty acids (PUFAs), namely, arachidonic acid (AA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA), were consistently upregulated upon EV-A71 and CV-A16 infection. Importantly, exogenously supplying three of these four PUFAs, including AA, DHA, and EPA, in cell cultures significantly reduced EV-A71 and CV-A16 replication. Taken together, our results suggested that enteroviruses might specifically modulate the host lipid pathways for optimal virus replication. Excessive exogenous addition of lipids that disrupted this delicate homeostatic state could prevent efficient viral replication. Precise manipulation of the host lipid profile might be a potential host-targeting antiviral strategy for enterovirus infection. Full article

(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)

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10 pages, 3159 KiB

Open AccessArticle

A Novel Immunochromatographic Strip for Antigen Detection of Avian Infectious Bronchitis Virus

by I-Li Liu, Yi-Chun Lin, Yong-Chong Lin, Cai-Zhen Jian, Ivan-Chen Cheng and Hui-Wen Chen

Int. J. Mol. Sci. 2019, 20(9), 2216; https://doi.org/10.3390/ijms20092216 - 6 May 2019

Cited by 21 | Viewed by 4618

Abstract

Avian infectious bronchitis virus (IBV) causes considerable economic losses in the poultry industry worldwide, including Taiwan. IBV is among the most important pathogens in chickens, and it spreads rapidly among flocks. In addition to dozens of known serotypes, new viral variants have emerged [...] Read more.

Avian infectious bronchitis virus (IBV) causes considerable economic losses in the poultry industry worldwide, including Taiwan. IBV is among the most important pathogens in chickens, and it spreads rapidly among flocks. In addition to dozens of known serotypes, new viral variants have emerged due to the viral evolution and antigenic variation in IBVs. Therefore, the development of a sensitive, specific, and easily performed assay is crucial for the rapid detection and surveillance of IBV infections. A rapid and simple immunochromatographic strip (ICS) was developed in this study by employing monoclonal antibodies against spike and nucleocapsid proteins of IBV as the tracer and the capture antibody. The ICS showed high specificity in detecting IBV antigens, including several IBV genotypes and novel variants, as opposed to three other common avian respiratory viruses. The detection limit of the strip reached 10^4.4 50% embryo-infective dose. Moreover, in the experimental chicken model, the strip test demonstrated consistency in detecting IBV with RT-PCR gene detection. Taken together, this antigen detection strip has the potential to serve as an on-farm rapid test for IBV; therefore, it may facilitate surveillance and control of the disease. Full article

(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)

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16 pages, 9810 KiB

Open AccessArticle

Targeting SUMO Modification of the Non-Structural Protein 5 of Zika Virus as a Host-Targeting Antiviral Strategy

by Zheng Zhu, Hin Chu, Lei Wen, Shuofeng Yuan, Kenn Ka-Heng Chik, Terrence Tsz-Tai Yuen, Cyril Chik-Yan Yip, Dong Wang, Jie Zhou, Feifei Yin, Dong-Yan Jin, Kin-Hang Kok, Kwok-Yung Yuen and Jasper Fuk-Woo Chan

Int. J. Mol. Sci. 2019, 20(2), 392; https://doi.org/10.3390/ijms20020392 - 17 Jan 2019

Cited by 20 | Viewed by 5313

Abstract

Post-translational modifications of host or viral proteins are key strategies exploited by viruses to support virus replication and counteract host immune response. SUMOylation is a post-translational modification process mediated by a family of ubiquitin-like proteins called small ubiquitin-like modifier (SUMO) proteins. Multiple sequence [...] Read more.

Post-translational modifications of host or viral proteins are key strategies exploited by viruses to support virus replication and counteract host immune response. SUMOylation is a post-translational modification process mediated by a family of ubiquitin-like proteins called small ubiquitin-like modifier (SUMO) proteins. Multiple sequence alignment of 78 representative flaviviruses showed that most (72/78, 92.3%) have a putative SUMO-interacting motif (SIM) at their non-structural 5 (NS5) protein’s N-terminal domain. The putative SIM was highly conserved among 414 pre-epidemic and epidemic Zika virus (ZIKV) strains, with all of them having a putative SIM core amino acid sequence of VIDL (327/414, 79.0%) or VVDL (87/414, 21.0%). Molecular docking predicted that the hydrophobic SIM core residues bind to the β2 strand of the SUMO-1 protein, and the acidic residues flanking the core strengthen the binding through interactions with the basic surface of the SUMO protein. The SUMO inhibitor 2-D08 significantly reduced replication of flaviviruses and protected cells against ZIKV-induced cytopathic effects in vitro. A SIM-mutated ZIKV NS5 failed to efficiently suppress type I interferon signaling. Overall, these findings may suggest SUMO modification of the viral NS5 protein to be an evolutionarily conserved post-translational modification process among flaviviruses to enhance virus replication and suppress host antiviral response. Full article

(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)

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Review

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14 pages, 585 KiB

Open AccessReview

Emerging Highly Virulent Porcine Epidemic Diarrhea Virus: Molecular Mechanisms of Attenuation and Rational Design of Live Attenuated Vaccines

by Yixuan Hou and Qiuhong Wang

Int. J. Mol. Sci. 2019, 20(21), 5478; https://doi.org/10.3390/ijms20215478 - 4 Nov 2019

Cited by 37 | Viewed by 5815

Abstract

The highly virulent porcine epidemic diarrhea virus (PEDV) emerged in China in 2010. It infects pigs of all ages, and causes severe diarrhea and high mortality rates in newborn pigs, leading to devastating economic losses in the pork industry worldwide. Effective and safe [...] Read more.

The highly virulent porcine epidemic diarrhea virus (PEDV) emerged in China in 2010. It infects pigs of all ages, and causes severe diarrhea and high mortality rates in newborn pigs, leading to devastating economic losses in the pork industry worldwide. Effective and safe vaccines against highly virulent PEDV strains are still unavailable, hampering the further prevention, control and eradication of the disease in herds. Vaccination of pregnant sows with live attenuated vaccines (LAVs) is the most effective strategy to induce lactogenic immunity in the sows, which provides A passive protection of suckling piglets against PEDV via the colostrum (beestings, or first milk) and milk. Several LAV candidates have been developed via serially passaging the highly virulent PEDV isolates in non-porcine Vero cells. However, their efficacies in the induction of sufficient protection against virulent PEDV challenge vary in vivo. In this review, we summarize the current knowledge of the virulence-related mutations of PEDV and their potential roles in PEDV attenuation in vivo. With the successful development of reverse genetics systems for PEDV, we also discuss how to use them to generate promising LAV candidates that are safe, effective and genetically stable. This article provides timely insight into the rational design of effective and safe PEDV LAV candidates. Full article

(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)

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16 pages, 2412 KiB

Open AccessReview

Enterovirus-Associated Hand-Foot and Mouth Disease and Neurological Complications in Japan and the Rest of the World

by Gabriel Gonzalez, Michael J. Carr, Masaaki Kobayashi, Nozomu Hanaoka and Tsuguto Fujimoto

Int. J. Mol. Sci. 2019, 20(20), 5201; https://doi.org/10.3390/ijms20205201 - 20 Oct 2019

Cited by 84 | Viewed by 48397

Abstract

Enteroviruses (EVs) are responsible for extremely large-scale, periodic epidemics in pediatric cohorts, particularly in East and Southeast Asia. Clinical presentation includes a diverse disease spectrum, including hand-foot and mouth disease (HFMD), aseptic meningitis, encephalitis, acute flaccid paralysis, and acute flaccid myelitis. HFMD is [...] Read more.

Enteroviruses (EVs) are responsible for extremely large-scale, periodic epidemics in pediatric cohorts, particularly in East and Southeast Asia. Clinical presentation includes a diverse disease spectrum, including hand-foot and mouth disease (HFMD), aseptic meningitis, encephalitis, acute flaccid paralysis, and acute flaccid myelitis. HFMD is predominantly attributable to EV-A types, including the major pathogen EV-A71, and coxsackieviruses, particularly CV-A6, CV-A16, and CV-A10. There have been multiple EV-A71 outbreaks associated with a profound burden of neurological disease and fatal outcomes in Asia since the early 1980s. Efficacious vaccines against EV-A71 have been developed in China but widespread pediatric vaccination programs have not been introduced in other countries. Encephalitis, as a consequence of complications arising from HFMD infection, leads to damage to the thalamus and medulla oblongata. Studies in Vietnam suggest that myoclonus is a significant indicator of central nervous system (CNS) complications in EV-A71-associated HFMD cases. Rapid response in HFMD cases in children is imperative to prevent the progression to a CNS infection; however, prophylactic and therapeutic agents have not been well established internationally, therefore surveillance and functional studies including development of antivirals and multivalent vaccines is critically important to reduce disease burden in pediatric populations. Full article

(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)

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33 pages, 3453 KiB

Open AccessReview

Impact of RNA Virus Evolution on Quasispecies Formation and Virulence

by Madiiha Bibi Mandary, Malihe Masomian and Chit Laa Poh

Int. J. Mol. Sci. 2019, 20(18), 4657; https://doi.org/10.3390/ijms20184657 - 19 Sep 2019

Cited by 33 | Viewed by 10765

Abstract

RNA viruses are known to replicate by low fidelity polymerases and have high mutation rates whereby the resulting virus population tends to exist as a distribution of mutants. In this review, we aim to explore how genetic events such as spontaneous mutations could [...] Read more.

RNA viruses are known to replicate by low fidelity polymerases and have high mutation rates whereby the resulting virus population tends to exist as a distribution of mutants. In this review, we aim to explore how genetic events such as spontaneous mutations could alter the genomic organization of RNA viruses in such a way that they impact virus replications and plaque morphology. The phenomenon of quasispecies within a viral population is also discussed to reflect virulence and its implications for RNA viruses. An understanding of how such events occur will provide further evidence about whether there are molecular determinants for plaque morphology of RNA viruses or whether different plaque phenotypes arise due to the presence of quasispecies within a population. Ultimately this review gives an insight into whether the intrinsically high error rates due to the low fidelity of RNA polymerases is responsible for the variation in plaque morphology and diversity in virulence. This can be a useful tool in characterizing mechanisms that facilitate virus adaptation and evolution. Full article

(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)

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18 pages, 1019 KiB

Open AccessReview

Mapping the Interactions of HBV cccDNA with Host Factors

by Nur K. Mohd-Ismail, Zijie Lim, Jayantha Gunaratne and Yee-Joo Tan

Int. J. Mol. Sci. 2019, 20(17), 4276; https://doi.org/10.3390/ijms20174276 - 1 Sep 2019

Cited by 35 | Viewed by 9332

Abstract

Hepatitis B virus (HBV) infection is a major health problem affecting about 300 million people globally. Although successful administration of a prophylactic vaccine has reduced new infections, a cure for chronic hepatitis B (CHB) is still unavailable. Current anti-HBV therapies slow down disease [...] Read more.

Hepatitis B virus (HBV) infection is a major health problem affecting about 300 million people globally. Although successful administration of a prophylactic vaccine has reduced new infections, a cure for chronic hepatitis B (CHB) is still unavailable. Current anti-HBV therapies slow down disease progression but are not curative as they cannot eliminate or permanently silence HBV covalently closed circular DNA (cccDNA). The cccDNA minichromosome persists in the nuclei of infected hepatocytes where it forms the template for all viral transcription. Interactions between host factors and cccDNA are crucial for its formation, stability, and transcriptional activity. Here, we summarize the reported interactions between HBV cccDNA and various host factors and their implications on HBV replication. While the virus hijacks certain cellular processes to complete its life cycle, there are also host factors that restrict HBV infection. Therefore, we review both positive and negative regulation of HBV cccDNA by host factors and the use of small molecule drugs or sequence-specific nucleases to target these interactions or cccDNA directly. We also discuss several reporter-based surrogate systems that mimic cccDNA biology which can be used for drug library screening of cccDNA-targeting compounds as well as identification of cccDNA-related targets. Full article

(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)

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21 pages, 3611 KiB

Open AccessReview

Autophagy in Zika Virus Infection: A Possible Therapeutic Target to Counteract Viral Replication

by Rossella Gratton, Almerinda Agrelli, Paola Maura Tricarico, Lucas Brandão and Sergio Crovella

Int. J. Mol. Sci. 2019, 20(5), 1048; https://doi.org/10.3390/ijms20051048 - 28 Feb 2019

Cited by 32 | Viewed by 12166

Abstract

Zika virus (ZIKV) still constitutes a public health concern, however, no vaccines or therapies are currently approved for treatment. A fundamental process involved in ZIKV infection is autophagy, a cellular catabolic pathway delivering cytoplasmic cargo to the lysosome for degradation—considered as a primordial [...] Read more.

Zika virus (ZIKV) still constitutes a public health concern, however, no vaccines or therapies are currently approved for treatment. A fundamental process involved in ZIKV infection is autophagy, a cellular catabolic pathway delivering cytoplasmic cargo to the lysosome for degradation—considered as a primordial form of innate immunity against invading microorganisms. ZIKV is thought to inhibit the Akt-mTOR signaling pathway, which causes aberrant activation of autophagy promoting viral replication and propagation. It is therefore appealing to study the role of autophagic molecular effectors during viral infection to identify potential targets for anti-ZIKV therapeutic intervention. Full article

(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)

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