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Molecular Aspects of Viral Pathogenesis: From Infection to Host Response

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A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Microbiology".

Deadline for manuscript submissions: 30 November 2026 | Viewed by 7701

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Dr. Quang Duy Trinh

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Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
Interests: infectious disease; medicine; viral infections in pregnancy
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Special Issue Information

Dear Colleagues,

Understanding viral pathogenesis, especially the molecular mechanisms underlying viral infections, is essential for developing effective prevention and treatment strategies. Viruses interact with host cells in complex and dynamic ways, manipulating cellular machinery to ensure replication, evade immune responses, spread within the host, and cause diseases. Whether studying long-recognized viruses responsible for chronic infections or newly identified pathogens with epidemic/pandemic potential, uncovering these molecular pathways remains a central focus in virology and infectious disease research.

This Special Issue aims to bring together cutting-edge studies that elucidate the molecular basis of viral infection, host immune responses, and virus–host interactions. We welcome submissions exploring, but not limited to, topics such as viral entry, replication, latency, host cell signaling, immune evasion strategies, and inflammation. Contributions involving both well-established and novel viruses, as well as interdisciplinary approaches incorporating molecular biology, immunology, structural biology, and omics technologies, are particularly encouraged. Through this collection, we seek to promote deeper insights into viral diseases and contribute to the development of new diagnostic tools, vaccines, and antiviral therapies.

Dr. Quang Duy Trinh
Guest Editor

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Keywords

viruses
viral pathogenesis
virus–host interaction
molecular virology
immunity
viral entry
viral replication
emerging viruses
infectious diseases
inflammation

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Published Papers (6 papers)

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Research

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44 pages, 29598 KB

Open AccessArticle

Experimental Analysis of HPV16 L1/L2 Chimeric VLP Internalization by Human Peripheral Blood Leukocytes

by Aurora Marques Cianciarullo, Dirce Sakauchi, Erica Akemi Kavati Sasaki, Tania Matiko Hosoda, Primavera Borelli and Willy Beçak

Int. J. Mol. Sci. 2026, 27(15), 6968; https://doi.org/10.3390/ijms27156968 - 3 Aug 2026

Viewed by 471

Abstract

Human papillomavirus type 16 (HPV16) is a major etiological agent of cervical and other epithelial cancers, yet the mechanisms underlying host–pathogen interactions remain incompletely understood. In this study, we investigated the responses of human peripheral blood leukocytes to engineered HPV16 L1/L2 chimeric virus-like particles (VLPs), produced in suspension by HEK 293-F cells. These VLPs were designed to mimic native viral structures while incorporating chimeric features that enhance stability and immunogenicity. Through experimental assays, we characterized leukocyte engagement, primarily involving leukocyte phenotyping, VLP internalization, confocal colocalization, and endocytic pathway analyses. We demonstrated that recombinant L1/L2 proteins assembled into structured VLPs capable of interacting with mononuclear cells, including lymphocytes and monocytes, but not with polymorphonuclear cells, such as neutrophils, eosinophils and basophils. Uptake occurred via the CD71 transferrin receptor-mediated pathway, in addition to other endocytic routes analyzed, as confirmed by blockage assays using chlorpromazine, rCTB, filipin, nystatin, liquemine, and sodium azide. Confocal colocalization and endocytic pathway analyses further supported receptor-mediated uptake. These findings demonstrate that HPV16 L1/L2 chimeric VLPs interact with and are internalized by human peripheral blood mononuclear cells through CD71-associated and other endocytic pathways. The study provides new insights into HPV16 VLP–leukocyte interactions and contributes to a better understanding of the cellular mechanisms involved in VLP uptake, which may be relevant for future studies on HPV biology and VLP-based vaccine development. Full article

(This article belongs to the Special Issue Molecular Aspects of Viral Pathogenesis: From Infection to Host Response)

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21 pages, 6031 KB

Open AccessArticle

Molecular Characterization of Influenza A(H3N2) Hemagglutinin Variants Circulating in Western Mexico, 2022

by Karen M Hernandez-Gonzalez, Ahtziri Socorro Carranza-Aranda, José Francisco Muñoz-Valle, Luis Alfonso Muñoz-Miranda, Alejandra Natali Vega-Magaña, Ana Laura Pereira-Suárez and Cesar Arturo Nava-Valdivia

Int. J. Mol. Sci. 2026, 27(15), 6833; https://doi.org/10.3390/ijms27156833 - 30 Jul 2026

Viewed by 472

Abstract

Influenza A(H3N2) remains a significant public health threat due to its rapid antigenic drift, which often compromises vaccine effectiveness. This study characterized the molecular and epidemiological profile of hemagglutinin (HA) variants circulating in Western Mexico throughout 2022. Among 476 positive cases, A(H3N2) was the predominant subtype (88%), with infection peaks during epidemiological weeks (EW) 1, 45, and 46. Sanger sequencing of the HA gene identified 64 amino acid substitutions, with 85.9% of the substitutions located in the HA1 subunit, primarily within the receptor-binding domain (RBD). Homology modeling and molecular docking were performed on five representative variants: C156S, D158N, Y159N, C136S, and L227P. All variants exhibited a slight decrease in binding affinity for sialic acid compared to the 1HGE reference. Notably, while mutations such as D158N and Y159N remodeled the interaction network, Glu190 and His183 remained critical for stabilizing the HA-ligand complex through hydrogen bonds and non-covalent interactions in the structural models. These structural findings suggest that contemporary mutations in the RBD may contribute to changes in receptor-binding interactions while preserving key structural features associated with host cell attachment. Full article

(This article belongs to the Special Issue Molecular Aspects of Viral Pathogenesis: From Infection to Host Response)

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22 pages, 14207 KB

Open AccessArticle

Potato Virus Y NIb Multifunctional Protein Suppresses Antiviral Defense by Interacting with Several Protein Components of the RNA Silencing Pathway

by Prakash M. Niraula, Saniyaa Howell, Chase A. Stratton, Michael T. Moore, Matthew B. Dopler, Muhammad I. Abeer, Michael A. Gitcho and Vincent N. Fondong

Int. J. Mol. Sci. 2026, 27(3), 1208; https://doi.org/10.3390/ijms27031208 - 25 Jan 2026

Cited by 2 | Viewed by 1057

Abstract

Potyvirus genomes are expressed as a single large open reading frame, which is translated into a polyprotein that is post-translationally cleaved by three virus-encoded proteases into 10 functional proteins. Several of these potyviral proteins, including nuclear inclusion protein b (NIb), are multifunctional. Here, using the classic GFP silencing in Nicotiana benthamiana gfp-transgenic plants, we show that potato virus Y (PVY) NIb, in addition to its canonical role as the viral RNA-dependent RNA polymerase (RdRP), functions as a suppressor of RNA silencing. Mutational analyses reveal a previously unreported NIb nuclear localization signal (NLS) consisting of a triple-lysine motif. NIb suppression of RNA silencing activity was lost when the NLS was mutated, suggesting that nuclear localization is required for NIb suppression of RNA silencing activity. Analysis of sequenced GFP siRNAs revealed three reproducible hotspot regions at ≈175 nt, ≈320–330 nt, and a broader 3′-proximal region spanning ≈560–700 nt that contains multiple local maxima. These data show differences in the positional distribution of siRNAs between samples expressing NIb and those expressing NIb^Del3×2, the NIb null mutant that does not suppress RNA silencing. However, the positional distribution of GFP-derived small RNAs across the transgene differed modestly between NIb and NIb^Del3×2, while both treatments showed the same three reproducible hotspot regions. Furthermore, NIb was found to interact with four key RNA silencing pathway proteins—AGO4, HSP70, HSP90, and SGS3. Except for HSP90, each of these proteins showed degradation products that were absent in NIb mutants that did not suppress RNA silencing. These findings support a role for NIb in countering host defense during virus infection. Full article

(This article belongs to the Special Issue Molecular Aspects of Viral Pathogenesis: From Infection to Host Response)

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Review

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19 pages, 1478 KB

Open AccessReview

Glutamine-Linked Cellular Stress Responses in Viral Infection: Mechanisms, Crosstalk, and Future Perspectives

by Ngan Thi Kim Pham, Quang Duy Trinh, Hiroshi Ushijima, Shihoko Komine-Aizawa and Kazuaki Yoshimune

Int. J. Mol. Sci. 2026, 27(11), 4717; https://doi.org/10.3390/ijms27114717 - 23 May 2026

Viewed by 694

Abstract

Glutamine is the most abundant amino acid in human plasma and tissues and plays essential roles in cellular metabolism, biosynthesis, and redox homeostasis. Beyond these canonical functions, glutamine availability and utilization have emerged as key regulators of multiple cellular stress responses, including the integrated stress response, endoplasmic reticulum stress, metabolic checkpoint signaling, and autophagy. During viral infection, host glutamine metabolism is frequently reprogrammed to meet the energetic and biosynthetic demands of viral replication, thereby inducing or reshaping glutamine-linked stress pathways. Increasing evidence indicates that these stress responses are not merely secondary consequences of infection but actively influence key stages of the viral life cycle, including viral entry, genome replication, protein synthesis, and host antiviral responses. In this review, we summarize current advances in understanding how glutamine metabolism regulates cellular stress responses in the context of both viral and non-viral infections, and how these pathways, in turn, modulate viral pathogenesis and host defense. We discuss the context-dependent roles of glutamine-linked stress signaling in either promoting viral replication or restricting infection, depending on viral species, host cell type, and metabolic conditions. Finally, we highlight emerging concepts and unresolved questions, including the potential of targeting glutamine metabolism and associated stress pathways as host-directed antiviral strategies. A deeper understanding of the interplay between glutamine metabolism, cellular stress responses, and viral infection may provide new insights into disease mechanisms and inform the development of novel therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Aspects of Viral Pathogenesis: From Infection to Host Response)

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20 pages, 1128 KB

Open AccessReview

Molecular Aspects of Viral Pathogenesis in Emerging SARS-CoV-2 Variants: Evolving Mechanisms of Infection and Host Response

by Sofia Teodora Muntean, Andreea-Raluca Cozac-Szoke, Andreea Cătălina Tinca, Irina Bianca Kosovski, Silviu Vultur, Mara Vultur, Ovidiu Simion Cotoi and Anca Ileana Sin

Int. J. Mol. Sci. 2026, 27(2), 891; https://doi.org/10.3390/ijms27020891 - 15 Jan 2026

Cited by 2 | Viewed by 1980

Abstract

Although the SARS-CoV-2 pandemic no longer poses a global emergency, the virus continues to diversify and acquire immunoevasive properties. Understanding the molecular pathways that shape SARS-CoV-2 pathogenesis has become essential. In this paper, we summarize the most recent current evidence on how the spike protein structurally evolves, on changes in key non-structural proteins, such as nsp14, and on host factors, such as TMPRSS2 and neuropilin-1. These changes, together, shape viral entry, replication fidelity and interferon antagonism. Given the emerging Omicron variants of SARS-CoV-2, recent articles in the literature, cryo-EM analyses, and artificial intelligence-assisted mutational modeling were analyzed to infer and contextualize mutation-driven mechanisms. It is through these changes that the virus adapts and evolves, such as optimizing angiotensin-converting enzyme binding, modifying antigenic surfaces, and accumulating mutations that affect CD8⁺ T-cell recognition. Multi-omics data studies further support SARS-CoV-2 pathogenesis through convergent evidence linking viral adaptation to host immune and metabolic reprogramming, as occurs in myocarditis, liver injury, and acute kidney injury. By integrating proteomic, transcriptomic, and structural findings, this work presents how the virus persists and dictates disease severity through interferon antagonism (ORF6, ORF9b, and nsp1), adaptive immune evasion, and metabolic rewiring. All these insights underscore the need for next-generation interventions that provide a multidimensional framework for understanding the evolution of SARS-CoV-2 and guiding future antiviral strategies. Full article

(This article belongs to the Special Issue Molecular Aspects of Viral Pathogenesis: From Infection to Host Response)

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17 pages, 1251 KB

Open AccessReview

Mechanistic Insights into Hepatic Pathogenesis of Dengue Virus Serotype-2: Host–Virus Interactions, Immune Dysregulation, and Therapeutic Perspectives

by Tharshni Naidu A. Rama Ravo and Wei Boon Yap

Int. J. Mol. Sci. 2025, 26(22), 10904; https://doi.org/10.3390/ijms262210904 - 10 Nov 2025

Cited by 5 | Viewed by 2350

Abstract

Dengue virus serotype 2 (DENV-2) is a predominant cause of severe dengue and a key determinant of dengue-associated liver injury. This review integrates recent findings on the molecular and cellular mechanisms of DENV-2 hepatotropism, focusing on viral replication, cellular stress responses, and immune-mediated damage. The interplay between hepatocytes, Kupffer cells, and innate and adaptive immune responses, culminating in cytokine storm and immune-mediated hepatocyte apoptosis, is dissected. Integrating in vitro and in vivo findings, this review highlights how viral replication and immune dysregulation converge to cause hepatic injury. Future research should prioritize antiviral, immunomodulatory, and hepatoprotective approaches aimed at reducing the risk of dengue-associated liver failure. Full article

(This article belongs to the Special Issue Molecular Aspects of Viral Pathogenesis: From Infection to Host Response)

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