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Genetic Insights into Host-Viral Response and Pathogenesis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 July 2023) | Viewed by 18599

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Special Issue Editor

Prof. Dr. Peggy Marconi

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Guest Editor

Department of Chemical, Pharmaceutical and Agricultural Sciences (DOCPAS), University of Ferrara, Via Fossato di Mortara 64/A, 44121 Ferrara, Italy
Interests: herpes simplex; in vitro molecular studies; virus-host interaction pathways
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Numerous evidences show that genetics play a leading role in influencing the course of many infectious diseases and the probability of developing the disease. The clearance of the microbial agent is strictly dependent on genetic factors, capable of influencing organ susceptibility and / or the effectiveness of the immune response. For this reason, it is important to understand how viruses, at the molecular level, can dynamically influence chromatin remodeling to allow the regulation of gene expression and other processes that require access to cellular DNA, and how these host-pathogen interactions can influence the genetic diversity of both organisms. Infections are perhaps one of the main selective pressures acting on humans. Knowledge of the virus-host molecular interactions and the identification of the key factors that modify the cellular genome, gene expression and epigenetic modifications are essential for understanding the fate of infections, viral diseases and their pathogenesis.

A better understanding of these interactions at the molecular level, which still remain unknown and unexplored for most viruses, are critical to provide some new perspectives for prevention and drug-treatments and vaccine development.

This special issue focuses on the research field of host virus interaction and welcomes original research articles, short communications and review papers dealing with the molecular and genetic mechanisms on host virus response and pathogenesis.

Prof. Dr. Peggy Marconi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

viruses
host-virus interaction
genetics
molecular aspects
epigenetics
immunity
prevention
drug-treatments
vaccine development

Published Papers (10 papers)

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Research

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13 pages, 2708 KiB

Open AccessArticle

TREX1 531C/T Polymorphism and Autoantibodies Associated with the Immune Status of HIV-1-Infected Individuals

by Maria Alice Freitas Queiroz, Tuane Carolina Ferreira Moura, Carlos David Araújo Bichara, Lorena Leticia Peixoto de Lima, Allysson Quintino Tenório de Oliveira, Ranilda Gama de Souza, Samara Tatielle Monteiro Gomes, Ednelza da Silva Graça Amoras and Antonio Carlos Rosário Vallinoto

Int. J. Mol. Sci. 2023, 24(11), 9660; https://doi.org/10.3390/ijms24119660 - 2 Jun 2023

Cited by 2 | Viewed by 1079

Abstract

Autoimmune diseases can develop during HIV-1 infection, mainly related to the individual’s immune competence. The study investigated the association of the TREX1 531C/T polymorphism and antinuclear antibodies (ANA) in HIV-1 infection and the time of antiretroviral therapy (ART) used. Cross-sectional and longitudinal assessments were carried out in 150 individuals, divided into three groups: ART-naïve, 5 years and 10 years on ART; ART-naïve individuals were evaluated for 2 years after initiation of treatment. The individuals’ blood samples were submitted to indirect immunofluorescence tests, real-time PCR and flow cytometry. The TREX1 531C/T polymorphism was associated with higher levels of TCD4⁺ lymphocytes and IFN-α in individuals with HIV-1. Individuals on ART had a higher frequency of ANA, higher levels of T CD4⁺ lymphocytes, a higher ratio of T CD4⁺/CD8⁺ lymphocytes and higher levels of IFN-α than therapy-naïve individuals (p < 0.05). The TREX1 531C/T polymorphism was associated with better maintenance of the immune status of individuals with HIV-1 and ANA with immune restoration in individuals on ART, indicating the need to identify individuals at risk of developing an autoimmune disease. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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19 pages, 2046 KiB

Open AccessArticle

CCR5∆32 and SDF1 3′A: Gene Variants, Expression and Influence on Biological Markers for the Clinical Progression to AIDS among HIV-1 Virus Controllers in a Mixed Population of the Amazon Region of Brazil

by Érica Ribeiro Gomes Lima, Maria Alice Freitas Queiroz, Sandra Souza Lima, Luiz Fernando Almeida Machado, Izaura Maria Vieira Cayres-Vallinoto, Antonio Carlos Rosário Vallinoto, Fernanda Andreza de Pinho Lott Figueiredo, João Farias Guerreiro, Marluísa de Oliveira Guimarães Ishak and Ricardo Ishak

Int. J. Mol. Sci. 2023, 24(5), 4958; https://doi.org/10.3390/ijms24054958 - 4 Mar 2023

Viewed by 1799

Abstract

CCR5Δ32 and SDF1-3′A polymorphisms were investigated in a cohort of viremia controllers, without the use of therapy, along with their influence on CD4+ T lymphocytes (TLs), CD8+ TLs, and plasma viral load (VL). The samples were analyzed from 32 HIV-1-infected individuals classified as viremia controllers 1 and 2 and viremia non-controllers, from both sexes, mostly heterosexuals, paired with 300 individuals from a control group. CCR5∆32 polymorphism was identified by PCR amplification of a fragment of 189 bp for the wild-type allele and 157 bp for the allele with the ∆32 deletion. SDF1-3′A polymorphism was identified by PCR, followed by enzymatic digestion (restriction fragment length polymorphism) with the Msp I enzyme. The relative quantification of gene expression was performed by real-time PCR. The distribution of allele and genotype frequencies did not show significant differences between the groups. The gene expression of CCR5 and SDF1 was not different between the profiles of AIDS progression. There was no significant correlation between the progression markers (CD4+ TL/CD8+ TL and VL) and the CCR5∆32 polymorphism carrier status. The 3′A allele variant was associated with a marked loss of CD4+ TLs and a higher plasma VL. Neither CCR5∆32 nor SDF1-3′A was associated with viremia control or the controlling phenotype. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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12 pages, 1212 KiB

Open AccessArticle

Adiponectin, Leptin, and Resistin Are Dysregulated in Patients Infected by SARS-CoV-2

by Fabio Perrotta, Filippo Scialò, Marta Mallardo, Giuseppe Signoriello, Vito D’Agnano, Andrea Bianco, Aurora Daniele and Ersilia Nigro

Int. J. Mol. Sci. 2023, 24(2), 1131; https://doi.org/10.3390/ijms24021131 - 6 Jan 2023

Cited by 18 | Viewed by 1577

Abstract

Obesity, through adipose tissue (AT) inflammation and dysregulation, represents a critical factor for COVID-19; here, we investigated whether serum levels of adiponectin, HMW oligomers, leptin, and resistin are modulated and/or correlated with clinical and biochemical parameters of severe COVID-19 patients. This study included 62 severe COVID-19 patients; 62 age and sex-matched healthy subjects were recruited as a control group. Anthropometric and biochemical parameters were obtained and compared. Adiponectin, HMW oligomers, leptin, and resistin were analyzed by ELISA. The adiponectin oligomerization state was visualized by Western blotting. When compared to healthy subjects, total adiponectin levels were statistically lower in severe COVID-19 while, in contrast, the levels of leptin and resistin were statistically higher. Interestingly, HMW adiponectin oligomers negatively correlated with leptin and were positively associated with LUS scores. Resistin showed a positive association with IL-6, IL-2R, and KL-6. Our data strongly support that adipose tissue might play a functional role in COVID-19. Although it needs to be confirmed in larger cohorts, adiponectin HMW oligomers might represent a laboratory resource to predict patient seriousness. Whether adipokines can be integrated as a potential additional tool in the evolving landscape of biomarkers for the COVID-19 disease is still a matter of debate. Other studies are needed to understand the molecular mechanisms behind adipokine’s involvement in COVID-19. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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15 pages, 20810 KiB

Open AccessArticle

Puumala Orthohantavirus Reassortant Genome Variants Likely Emerging in the Watershed Forests

by Emmanuel Kabwe, Anton F. Shamsutdinov, Setora Suleimanova, Ekaterina V. Martynova, Ruzilya K. Ismagilova, Venera G. Shakirova, Tatiana A. Savitskaya, Guzel S. Isaeva, Albert A. Rizvanov, Svetlana F. Khaiboullina, Sergey P. Morzunov and Yuriy N. Davidyuk

Int. J. Mol. Sci. 2023, 24(2), 1018; https://doi.org/10.3390/ijms24021018 - 5 Jan 2023

Cited by 2 | Viewed by 1338

Abstract

Hemorrhagic fever with renal syndrome (HFRS) remains a prevalent zoonosis in the Republic of Tatarstan (RT), Russian Federation. Puumala orthohantavirus (PUUV), carried by bank voles (Myodes glareolus), is the principal zoonotic pathogen of HFRS in the RT. In this study, we sought to demonstrate the similarity of the PUUV genetic sequences detected in HFRS case patients and bank vole samples previously collected in some areas of the RT. Furthermore, we intended to identify the reassortant PUUV genomes and locate a potential site for their emergence. During 2019 outbreaks, the PUUV genome sequences of the S and M segments from 42 HFRS cases were analysed and compared with the corresponding sequences from bank voles previously trapped in the RT. Most of the PUUV strains from HFRS patients turned out to be closely related to those isolated from bank voles captured near the site of the human infection. We also found possible reassortant PUUV genomes in five patients while they were absent in bank voles. The location of the corresponding HFRS infection sites suggests that reassortant PUUV genomes could emerge in the bank voles that inhabit the forests on the watershed between the Kazanka River and Myosha River. These findings could facilitate the search for the naturally occurring reassortants of PUUV in bank vole populations. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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16 pages, 1615 KiB

Open AccessArticle

Variants of HCMV UL18 Sequenced Directly from Clinical Specimens Associate with Antibody and T-Cell Responses to HCMV

by Shelley Waters, Silvia Lee, Ibnu Ariyanto, Shay Leary, Kylie Munyard, Silvana Gaudieri, Ashley Irish, Richard J. N. Allcock and Patricia Price

Int. J. Mol. Sci. 2022, 23(21), 12911; https://doi.org/10.3390/ijms232112911 - 26 Oct 2022

Viewed by 1436

Abstract

Around 80% of adults worldwide carry human cytomegaloviris (HCMV). The HCMV gene UL18 is a homolog of HLA class I genes and encodes a protein with high affinity for the NK and T-cell cytotoxicity inhibitor LIR-1. UL18 was deep sequenced from blood, saliva or urine from Indonesian people with HIV (PWH) (n = 28), Australian renal transplant recipients (RTR) (n = 21), healthy adults (n = 7) and neonates (n = 4). 95% of samples contained more than one variant of HCMV UL18, as defined by carriage of nonsynonymous variations. When aligned with immunological markers of the host’s burden of HCMV, the S318N variation associated with high levels of antibody reactive with HCMV lysate in PWH over 12 months on antiretroviral therapy. The A107T variation associated with HCMV antibody levels and inflammatory biomarkers in PWH at early timepoints. Variants D32G, D248N, V250A and E252D aligned with elevated HCMV antibody levels in RTR, while M191K, E196Q and F165L were associated with HCMV-reactive T-cells and proportions of Vδ2⁻ γδ T-cells—populations linked with high burdens of HCMV. We conclude that UL18 is a highly variable gene, where variation may alter the persistent burden of HCMV and/or the host response to that burden. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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Review

Jump to: Research

21 pages, 1109 KiB

Open AccessReview

HIV-1–Host Interaction in Gut-Associated Lymphoid Tissue (GALT): Effects on Local Environment and Comorbidities

by Sonia Moretti, Ivan Schietroma, Giuseppe Sberna, Maria Teresa Maggiorella, Leonardo Sernicola, Stefania Farcomeni, Marta Giovanetti, Massimo Ciccozzi and Alessandra Borsetti

Int. J. Mol. Sci. 2023, 24(15), 12193; https://doi.org/10.3390/ijms241512193 - 30 Jul 2023

Cited by 1 | Viewed by 2049

Abstract

HIV-1 replication in the gastrointestinal (GI) tract causes severe CD4+ T-cell depletion and disruption of the protective epithelial barrier in the intestinal mucosa, causing microbial translocation, the main driver of inflammation and immune activation, even in people living with HIV (PLWH) taking antiretroviral drug therapy. The higher levels of HIV DNA in the gut compared to the blood highlight the importance of the gut as a viral reservoir. CD4+ T-cell subsets in the gut differ in phenotypic characteristics and differentiation status from the ones in other tissues or in peripheral blood, and little is still known about the mechanisms by which the persistence of HIV is maintained at this anatomical site. This review aims to describe the interaction with key subsets of CD4+ T cells in the intestinal mucosa targeted by HIV-1 and the role of gut microbiome and its metabolites in HIV-associated systemic inflammation and immune activation that are crucial in the pathogenesis of HIV infection and related comorbidities. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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24 pages, 1437 KiB

Open AccessReview

Genetic Variants within SARS-CoV-2 Human Receptor Genes May Contribute to Variable Disease Outcomes in Different Ethnicities

by Theolan Adimulam, Thilona Arumugam, Anmol Gokul and Veron Ramsuran

Int. J. Mol. Sci. 2023, 24(10), 8711; https://doi.org/10.3390/ijms24108711 - 13 May 2023

Cited by 6 | Viewed by 2189

Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic, with an alarming infectivity and mortality rate. Studies have examined genetic effects on SARS-CoV-2 disease susceptibility and severity within Eurasian populations. These studies identified contrasting effects on the severity of disease between African populations. Genetic factors can explain some of the diversity observed within SARS-CoV-2 disease susceptibility and severity. Single nucleotide polymorphisms (SNPs) within the SARS-CoV-2 receptor genes have demonstrated detrimental and protective effects across ethnic groups. For example, the TT genotype of rs2285666 (Angiotensin-converting enzyme 2 (ACE2)) is associated with the severity of SARS-CoV-2 disease, which is found at higher frequency within Asian individuals compared to African and European individuals. In this study, we examined four SARS-CoV-2 receptors, ACE2, Transmembrane serine protease 2 (TMPRSS2), Neuropilin-1 (NRP1), and Basigin (CD147). A total of 42 SNPs located within the four receptors were reviewed: ACE2 (12), TMPRSS2 (10), BSG (CD147) (5), and NRP1 (15). These SNPs may be determining factors for the decreased disease severity observed within African individuals. Furthermore, we highlight the absence of genetic studies within the African population and emphasize the importance of further research. This review provides a comprehensive summary of specific variants within the SARS-CoV-2 receptor genes, which can offer a better understanding of the pathology of the SARS-CoV-2 pandemic and identify novel potential therapeutic targets. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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17 pages, 1906 KiB

Open AccessReview

Genetic Insight into the Interaction of IBDV with Host—A Clue to the Development of Novel IBDV Vaccines

by Hui Gao, Yongqiang Wang, Li Gao and Shijun J. Zheng

Int. J. Mol. Sci. 2023, 24(9), 8255; https://doi.org/10.3390/ijms24098255 - 4 May 2023

Cited by 2 | Viewed by 1988

Abstract

Infectious bursal disease virus (IBDV) is an immunosuppressive pathogen causing enormous economic losses to the poultry industry across the globe. As a double-stranded RNA virus, IBDV undergoes genetic mutation or recombination in replication during circulation among flocks, leading to the generation and spread of variant or recombinant strains. In particular, the recent emergence of variant IBDV causes severe immunosuppression in chickens, affecting the efficacy of other vaccines. It seems that the genetic mutation of IBDV during the battle against host response is an effective strategy to help itself to survive. Therefore, a comprehensive understanding of the viral genome diversity will definitely help to develop effective measures for prevention and control of infectious bursal disease (IBD). In recent years, considerable progress has been made in understanding the relation of genetic mutation and genomic recombination of IBDV to its pathogenesis using the reverse genetic technique. Therefore, this review focuses on our current genetic insight into the IBDV’s genetic typing and viral genomic variation. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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18 pages, 2722 KiB

Open AccessReview

Unlocking STING as a Therapeutic Antiviral Strategy

by Annalaura Paulis and Enzo Tramontano

Int. J. Mol. Sci. 2023, 24(8), 7448; https://doi.org/10.3390/ijms24087448 - 18 Apr 2023

Cited by 2 | Viewed by 2079

Abstract

Invading pathogens have developed weapons that subvert physiological conditions to weaken the host and permit the spread of infection. Cells, on their side, have thus developed countermeasures to maintain cellular physiology and counteract pathogenesis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) is a pattern recognition receptor that recognizes viral DNA present in the cytosol, activating the stimulator of interferon genes (STING) protein and leading to the production of type I interferons (IFN-I). Given its role in innate immunity activation, STING is considered an interesting and innovative target for the development of broad-spectrum antivirals. In this review, we discuss the function of STING; its modulation by the cellular stimuli; the molecular mechanisms developed by viruses, through which they escape this defense system; and the therapeutical strategies that have been developed to date to inhibit viral replication restoring STING functionality. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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13 pages, 838 KiB

Open AccessReview

Regulatory Role of Ribonucleotide Reductase Subunit M2 in Hepatocyte Growth and Pathogenesis of Hepatitis C Virus

by Bouchra Kitab and Kyoko Tsukiyama-Kohara

Int. J. Mol. Sci. 2023, 24(3), 2619; https://doi.org/10.3390/ijms24032619 - 30 Jan 2023

Cited by 1 | Viewed by 2084

Abstract

Hepatitis C virus (HCV) frequently causes chronic infection in the human liver, which may progress to advanced hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. HCV primarily infects highly differentiated quiescent hepatocytes and can modulate cell cycle-regulatory genes and proliferation pathways, which ultimately contribute to persistent infection and pathogenesis. On the other hand, several studies have shown differential regulation of HCV RNA and viral protein expression levels, depending on the proliferation state of hepatocytes and the phase of the cell cycle. HCV typically requires factors provided by host cells for efficient and persistent viral replication. Previously, we found that HCV infection upregulates the expression of ribonucleotide reductase subunit M2 (RRM2) in quiescent hepatocytes. RRM2 is a rate-limiting protein that catalyzes de novo synthesis of deoxyribonucleotide triphosphates, and its expression is highly regulated during various phases of the cell cycle. RRM2 functions as a pro-viral factor essential for HCV RNA synthesis, but its functional role in HCV-induced liver diseases remains unknown. Here, we present a comprehensive review of the role of the hepatocyte cell cycle, in correlation with RRM2 expression, in the regulation of HCV replication. We also discuss the potential relevance of this protein in the pathogenesis of HCV, particularly in the development of hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Genetic Insights into Host-Viral Response and Pathogenesis)

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