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101 Publications visible to you, out of a total of 101
Antiviral activity of brequinar against African swine fever virus infection in vitro.

Abstract (Expand)

African swine fever virus (ASFV) is a double-stranded DNA virus that causes an acute and hemorrhagic disease in domestic swine, resulting in significant economic losses to the global porcine industry. … The lack of vaccines and antiviral drugs highlights the urgent need for antiviral studies against ASFV. Here, we report that brequinar (BQR), which is a specific inhibitor of dihydroorotate dehydrogenase, robustly inhibits ASFV replication in Vero cells, as well as in porcine macrophages. We demonstrate that BQR exerts its antiviral activity in a dose-dependent manner through the depletion of pyrimidine pool. Although BQR does not affect the synthesis of an early viral protein, pI215L, the synthesis of late viral proteins, p17 and p72, is suppressed in the presence of BQR. We also show that BQR is able to induce cellular antiviral response in ASFV-infected macrophages by enhancing the expression of interferon-stimulated genes. Taken together, our study reveals that targeting nucleotide biosynthesis represents a promising strategy for developing antiviral agents against ASFV.

Authors: Rafayela Grigoryan, Erik Arabyan, Roza Izmailyan, Zaven Karalyan, Nuno Jordão, Fernando Ferreira, Hovakim Zakaryan

Date Published: 23rd May 2022

Publication Type: Journal

Molecular Analysis of SARS-CoV-2 Lineages in Armenia

Abstract (Expand)

The sequencing of SARS-CoV-2 provides essential information on viral evolution, transmission, and epidemiology. In this paper, we performed the whole-genome sequencing of SARS-CoV-2 using nanopore and … Illumina sequencing to describe the circulation of the virus lineages in Armenia. The analysis of 145 full genomes identified six clades (19A, 20A, 20B, 20I, 21J, and 21K) and considerable intra-clade PANGO lineage diversity. Phylodynamic and transmission analysis allowed to attribute specific clades as well as infer their importation routes. Thus, the first two waves of positive case increase were caused by the 20B clade, the third peak caused by the 20I (Alpha), while the last two peaks were caused by the 21J (Delta) and 21K (Omicron) variants. The functional analyses of mutations in sequences largely affected epitopes associated with protective HLA loci and did not cause the loss of the signal in PCR tests targeting ORF1ab and N genes as confirmed by RT-PCR. We also compared the performance of nanopore and Illumina short-read sequencing and showed the utility of nanopore sequencing as an efficient and affordable alternative for large-scale molecular epidemiology research. Thus, our paper describes new data on the genomic diversity of SARS-CoV-2 variants in Armenia in the global context of the virus molecular genomic surveillance.

Authors: Diana Avetyan, Siras Hakobyan, Maria Nikoghosyan, Lilit Ghukasyan, Gisane Khachatryan, Tamara Sirunyan, Nelli Muradyan, Roksana Zakharyan, Andranik Chavushyan, Varduhi Hayrapetyan, Anahit Hovhannisyan, Shah A. Mohamed Bakhash, Keith R. Jerome, Pavitra Roychoudhury, Alexander L. Greninger, Lyudmila Niazyan, Mher Davidyants, Gayane Melik-Andreasyan, Shushan Sargsyan, Lilit Nersisyan, Arsen Arakelyan

Date Published: 17th May 2022

Publication Type: Journal

HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity

Abstract (Expand)

The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte … antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), Pbonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).

Authors: Anahit Hovhannisyan, Vergine Madelian, Sevak Avagyan, Mihran Nazaretyan, Armine Hyussyan, Alina Sirunyan, Rubina Arakelyan, Zorayr Manukyan, Levon Yepiskoposyan, Karine R. Mayilyan, Frieda Jordan

Date Published: 3rd Feb 2022

Publication Type: Journal

Emerging Role of Exosomal Long Non-coding RNAs in Spaceflight-Associated Risks in Astronauts

Abstract (Expand)

During spaceflight, astronauts are exposed to multiple unique environmental factors, particularly microgravity and ionizing radiation, that can cause a range of harmful health consequences. Over the … past decades, increasing evidence demonstrates that the space environment can induce changes in gene expression and RNA processing. Long non-coding RNA (lncRNA) represent an emerging area of focus in molecular biology as they modulate chromatin structure and function, the transcription of neighboring genes, and affect RNA splicing, stability, and translation. They have been implicated in cancer development and associated with diverse cardiovascular conditions and associated risk factors. However, their role on astronauts' health after spaceflight remains poorly understood. In this perspective article, we provide new insights into the potential role of exosomal lncRNA after spaceflight. We analyzed the transcriptional profile of exosomes isolated from peripheral blood plasma of three astronauts who flew on various Shuttle missions between 1998-2001 by RNA-sequencing. Computational analysis of the transcriptome of these exosomes identified 27 differentially expressed lncRNAs with a Log2 fold change, with molecular, cellular, and clinical implications.

Authors: Malik Bisserier, Nathaniel Saffran, Agnieszka Brojakowska, Aimy Sebastian, Angela Clare Evans, Matthew A. Coleman, Kenneth Walsh, Paul J. Mills, Venkata Naga Srikanth Garikipati, Arsen Arakelyan, Lahouaria Hadri, David A. Goukassian

Date Published: 17th Jan 2022

Publication Type: Journal

Cell‐Free Mitochondrial DNA as a Potential Biomarker for Astronauts' Health

Abstract (Expand)

Background: Space travel–associated stressors such as microgravity or radiation exposure have been reported in astronauts after short‐ and long‐duration missions aboard the International Space Station. … Despite risk mitigation strategies, adverse health effects remain a concern. Thus, there is a need to develop new diagnostic tools to facilitate early detection of physiological stress. Methods and Results: We measured the levels of circulating cell‐free mitochondrial DNA in blood plasma of 14 astronauts 10 days before launch, the day of landing, and 3 days after return. Our results revealed a significant increase of cell‐free mitochondrial DNA in the plasma on the day of landing and 3 days after return with vast ~2 to 355‐fold interastronaut variability. In addition, gene expression analysis of peripheral blood mononuclear cells revealed a significant increase in markers of inflammation, oxidative stress, and DNA damage. Conclusions: Our study suggests that cell‐free mitochondrial DNA abundance might be a biomarker of stress or immune response related to microgravity, radiation, and other environmental factors during space flight.

Authors: Malik Bisserier, Santhanam Shanmughapriya, Amit Kumar Rai, Carolina Gonzalez, Agnieszka Brojakowska, Venkata Naga Srikanth Garikipati, Muniswamy Madesh, Paul J. Mills, Kenneth Walsh, Arsen Arakelyan, Raj Kishore, Lahouaria Hadri, David A. Goukassian

Date Published: 2nd Nov 2021

Publication Type: Journal

Flavonoid Library Screening Reveals Kaempferol as a Potential Antiviral Agent Against African Swine Fever Virus.

Abstract (Expand)

Naturally occurring plant flavonoids are a promising class of antiviral agents to inhibit African swine fever virus (ASFV), which causes highly fatal disease in pigs and is a major threat to the swine … industry. Currently known flavonoids with anti-ASFV activity demonstrate a wide range of antiviral mechanisms, which motivates exploration of new antiviral candidates within this class. The objective of this study was to determine whether other flavonoids may significantly inhibit ASFV infection <i>in vitro</i>. We performed a cell-based library screen of 90 flavonoids. Our screening method allowed us to track the development of virus-induced cytopathic effect by MTT in the presence of tested flavonoids. This screening method was shown to be robust for hit identification, with an average Z-factor of 0.683. We identified nine compounds that inhibit ASFV Ba71V strain in Vero cells. Among them, kaempferol was the most potent and exhibited dose-dependent inhibition, which occurred through a virostatic effect. Time-of-addition studies revealed that kaempferol acts on the entry and post-entry stages of the ASFV replication cycle and impairs viral protein and DNA synthesis. It was further identified that kaempferol induces autophagy in ASFV-infected Vero cells, which is related to its antiviral activity and could be partially abrogated by the addition of an autophagy inhibitor. Kaempferol also exhibited dose-dependent inhibition of a highly virulent ASFV Arm/07 isolate in porcine macrophages. Together, these findings support that kaempferol is a promising anti-ASFV agent and has a distinct antiviral mechanism compared to other anti-ASFV flavonoids.

Authors: Erik Arabyan, Astghik Hakobyan, Tamara Hakobyan, Rafaella Grigoryan, Roza Izmailyan, Aida Avetisyan, Zaven Karalyan, Joshua A Jackman, Fernando Ferreira, Charles C Elrod, Hovakim Zakaryan

Date Published: 21st Oct 2021

Publication Type: Journal

The Evolving Faces of the SARS-CoV-2 Genome

Abstract (Expand)

Surveillance of the evolving SARS-CoV-2 genome combined with epidemiological monitoring and emerging vaccination became paramount tasks to control the pandemic which is rapidly changing in time and … space. Genomic surveillance must combine generation and sharing sequence data with appropriate bioinformatics monitoring and analysis methods. We applied molecular portrayal using self-organizing maps machine learning (SOM portrayal) to characterize the diversity of the virus genomes, their mutual relatedness and development since the beginning of the pandemic. The genetic landscape obtained visualizes the relevant mutations in a lineage-specific fashion and provides developmental paths in genetic state space from early lineages towards the variants of concern alpha, beta, gamma and delta. The different genes of the virus have specific footprints in the landscape reflecting their biological impact. SOM portrayal provides a novel option for ‘bioinformatics surveillance’ of the pandemic, with strong odds regarding visualization, intuitive perception and ‘personalization’ of the mutational patterns of the virus genomes.

Authors: Maria Schmidt, Mamoona Arshad, Stephan H. Bernhart, Siras Hakobyan, Arsen Arakelyan, Henry Loeffler-Wirth, Hans Binder

Date Published: 3rd Sep 2021

Publication Type: Journal

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