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Cells
Special Issues
Multifaceted Nature of Immune Responses to Viral Infection
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Multifaceted Nature of Immune Responses to Viral Infection

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 30 June 2026 | Viewed by 5059

Special Issue Editors

Prof. Dr. Homayon Ghiasi

E-Mail Website
Guest Editor
Ophthalmology Viral Immunology and Vaccine Laboratory, Cedars-Sinai Health University, Los Angeles, CA 90048, USA
Interests: the role of HSV-1 in herpes-induced corneal scarring; vaccine development against ocular HSV-1 infection; the role of viral infection and cytokines in CNS demyelination
Prof. Dr. Susmit Suvas

E-Mail Website
Guest Editor
School of Medicine, Wayne State University, Detroit, MI, USA
Interests: corneal homeostasis; ocular HSV-1 infection; neuroimmunology of HSV-1 infection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viruses penetrate host organisms and establish infections by replicating within host cells. The means of viral entry into the host are diverse and depend on the virus. In response to viruses entering via different routes, the host employs multiple defense strategies, involving both innate and adaptive immune mechanisms, to counteract infection. These immune responses vary across species and can be complex, underscoring the host immune system's critical role in controlling viral pathogenesis. This Special Issue will characterize the interactions between viral pathogenicity and host defense mechanisms. It will explore various immune signaling pathways, highlight key regulatory processes, and establish connections between different means of viral infection and host responses.

Prof. Dr. Homayon Ghiasi
Prof. Dr. Susmit Suvas
Guest Editors

Manuscript Submission Information

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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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • viral infection
  • innate and adaptive immunity
  • protection
  • RNA and DNA viruses
  • autoimmunity
  • immune escape

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Published Papers (5 papers)

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Research

Jump to: Review

17 pages, 5949 KB  
Article
New Insights into Parthanatos as Programmed Cell Death During Murine Cytomegalovirus or Herpes Simplex Virus Type 1 Productive Replication in Diverse Cell Types
by Jay J. Oh, Xinge Xie and Richard D. Dix
Cells 2026, 15(11), 1009; https://doi.org/10.3390/cells15111009 - 30 May 2026
Viewed by 280
Abstract
Programmed cell death (PCD) pathways of innate immunity serve to protect host cells from invading viruses. Parthanatos is a novel form of PCD triggered by excessive host cell DNA damage that leads to overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) which in turn stimulates poly(ADP-ribose) [...] Read more.
Programmed cell death (PCD) pathways of innate immunity serve to protect host cells from invading viruses. Parthanatos is a novel form of PCD triggered by excessive host cell DNA damage that leads to overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) which in turn stimulates poly(ADP-ribose) (PAR) polymer formation. PAR translocates to the cytoplasm, where it induces release of apoptosis-inducing factor (AIF) from mitochondria, that then travels back to the nucleus, where it mediates large-scale DNA fragmentation and cell death. Little information is available regarding parthanatos as a cell death mechanism to dampen herpesvirus replication at the host cell level. A series of studies were therefore performed to clarify a possible role for parthanatos during productive replication of murine cytomegalovirus (MCMV) and herpes simplex virus type 1 (HSV-1) in diverse cell types. These included mouse embryo fibroblasts, mouse lung fibroblasts, mouse microglial (BV-2) cells, and human retinal pigment epithelial (ARPE-19) cells. We report that PAR protein production is surprisingly cell type specific. Moreover, MCMV or HSV-1 infection may suppress parthanatos as observed for other PCD pathways, such as apoptosis, necroptosis, and pyroptosis, in a dose-dependent and cell type-specific manner. We conclude that the operation of parthanatos at the host cell level during herpesvirus replication is more complex than originally thought but offers new targets for possible therapeutic interventions. Full article
(This article belongs to the Special Issue Multifaceted Nature of Immune Responses to Viral Infection)
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22 pages, 8956 KB  
Article
Zika Virus-Induced Metabolic Reprogramming Drives Lipid Droplet Biogenesis, Promoting Viral Replication and Ocular Pathogenesis
by Prince Kumar, Jieon Kim, Nikhil Deshmukh and Pawan Kumar Singh
Cells 2026, 15(9), 817; https://doi.org/10.3390/cells15090817 - 30 Apr 2026
Viewed by 664
Abstract
Zika virus (ZIKV) remains a significant global public health threat due to its association with severe neurological and ocular abnormalities, including microcephaly and congenital glaucoma in infants. Viruses often exploit host metabolic programs, such as energy and lipid metabolism, to support their replication. [...] Read more.
Zika virus (ZIKV) remains a significant global public health threat due to its association with severe neurological and ocular abnormalities, including microcephaly and congenital glaucoma in infants. Viruses often exploit host metabolic programs, such as energy and lipid metabolism, to support their replication. However, how ZIKV-driven metabolic reprogramming affects the anterior segment of the eye, especially trabecular meshwork (TM) cells, remains poorly defined. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) signaling, fatty acid (FA) metabolism, and lipid droplet (LD) biogenesis in ZIKV-induced ocular pathogenesis using primary human TM cells and an IFNAR1-deficient mouse model. ZIKV infection triggered time-dependent activation of the LKB1-AMPK-ACC signaling axis and significantly increased LD accumulation. Pharmacological activation of AMPK suppressed viral replication, whereas its inhibition enhanced infection, highlighting an antiviral role for AMPK signaling. In contrast, ZIKV promoted LD biogenesis, and inhibition of DGAT1 reduced both LD formation and viral replication, indicating a proviral role for LDs. Modulation of FA metabolism further revealed differential effects on ZIKV infection: saturated FA (palmitate) enhanced viral replication, whereas inhibition of FA oxidation with etomoxir reduced infection. Conversely, unsaturated FAs (oleate and linoleate) suppressed viral replication, in part by impairing viral binding and entry. Collectively, these findings show that ZIKV reshapes host metabolic pathways in TM by differentially engaging AMPK signaling, FA metabolism, and LD biogenesis to promote viral replication and spread in ocular tissue. Targeting these metabolic pathways may offer promising therapeutic avenues for preventing and/or treating ZIKV-associated ocular complications. Full article
(This article belongs to the Special Issue Multifaceted Nature of Immune Responses to Viral Infection)
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16 pages, 2189 KB  
Article
Glucocorticoid Receptor and Cell Cycle Regulator (E2F2) Cooperatively Transactivate a Cis-Regulatory Module in the HSV-1 Infected Cell Protein 0 (ICP0) Promoter
by Kaushalya Jayathilake, Vanessa Claire Santos and Clinton Jones
Cells 2026, 15(5), 445; https://doi.org/10.3390/cells15050445 - 2 Mar 2026
Viewed by 1288
Abstract
Human alpha-herpesvirus 1 (HSV-1) acute infection culminates in life-long latency in sensory neurons in trigeminal ganglia and certain neurons in the central nervous system. Previously, E2F family members and glucocorticoid receptor (GR) were shown to stimulate HSV-1 and bovine herpesvirus 1 (BoHV-1) replication. [...] Read more.
Human alpha-herpesvirus 1 (HSV-1) acute infection culminates in life-long latency in sensory neurons in trigeminal ganglia and certain neurons in the central nervous system. Previously, E2F family members and glucocorticoid receptor (GR) were shown to stimulate HSV-1 and bovine herpesvirus 1 (BoHV-1) replication. Consequently, we hypothesized GR and E2F family members activate certain HSV-l promoters. To test this hypothesis, we determined if four HSV-1 ICP0 cis-regulatory modules (CRM) upstream of the ICP0 promoter were activated by E2F. GR and E2F2, but not E2F1, E2F3a, or E2F3b, cooperatively transactivate the ICP0 CRM-C, but not CRM-A, -B, or -D fragments upstream of a minimal promoter in a luciferase reporter construct. CRM-C sequences contain two E2F consensus binding sites, a GC-rich motif that E2F2 can bind, and a consensus ½ GR response element (GRE) adjacent to the consensus E2F #2 binding site. Mutating the ½ GRE or the 3 E2F binding sites significantly reduced GR- and E2F2-mediated transactivation. Chromatin immunoprecipitation studies revealed E2F2 occupied ICP0 CRM-C sequences during productive infection and mutating the E2F binding sites prevented E2F2 binding. These studies reveal GR and E2F2 transactivate ICP0-promoter activity, which may enhance viral replication in certain cell types. Full article
(This article belongs to the Special Issue Multifaceted Nature of Immune Responses to Viral Infection)
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Review

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28 pages, 4140 KB  
Review
Beyond ATP: Lipid-Driven Plasticity and the Immunometabolism of ILC2s
by Vanessa-Vivien Pesold, Jafar Cain, Steven J. Bensinger and Omid Akbari
Cells 2026, 15(9), 838; https://doi.org/10.3390/cells15090838 - 3 May 2026
Viewed by 803
Abstract
Group 2 innate lymphoid cells (ILC2s) are tissue-resident immune cells that play a central role in type 2 immunity. Beyond cytokine signaling, they integrate inputs from lipids, nutrients, neuroendocrine mediators, and local metabolic cues, establishing cellular metabolism as a key regulator of their [...] Read more.
Group 2 innate lymphoid cells (ILC2s) are tissue-resident immune cells that play a central role in type 2 immunity. Beyond cytokine signaling, they integrate inputs from lipids, nutrients, neuroendocrine mediators, and local metabolic cues, establishing cellular metabolism as a key regulator of their function. Immunometabolism provides a framework to understand how ILC2s adapt to diverse tissue environments such as the lung, adipose tissue, gut, skin, and brain, each defined by distinct nutrient availability, oxygen tension, and inflammatory conditions. Unlike many immune cells that primarily rely on glycolysis, ILC2s dynamically balance glycolysis, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS) depending on activation state and tissue context. Lipids not only serve as energy substrates but also regulate membrane organization, lipid raft–dependent signaling, and the generation of bioactive mediators, including eicosanoids, oxysterols, and sphingolipids. Emerging evidence linking cholesterol biosynthesis, steroid metabolism, and sphingolipid signaling to ILC2 function underscores the importance of lipid-dependent immune regulation. Dysregulation of these pathways contributes to chronic inflammatory diseases such as asthma, metabolic disorders, and fibrosis. Targeting metabolic pathways and checkpoints may therefore offer new strategies to modulate ILC2-driven pathology. This review summarizes current insights into metabolic programs governing ILC2 activation, survival, and plasticity and highlights emerging therapeutic opportunities. Full article
(This article belongs to the Special Issue Multifaceted Nature of Immune Responses to Viral Infection)
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33 pages, 2492 KB  
Review
Neutrophil Extracellular Traps in Viral Infections: Regulation, Immune Consequences, and Pathogenic Outcomes
by Clinton Njinju Asaba, Bella Nyemkuna Gwanyama, Humblenoble Stembridge Ayuk, Thomas Ikechukwu Odo, Razieh Bitazar, Tatiana Noumi, Patrick Labonté and Terence Ndonyi Bukong
Cells 2026, 15(7), 580; https://doi.org/10.3390/cells15070580 - 25 Mar 2026
Viewed by 1517
Abstract
Neutrophils are among the early responders of the innate immune system and play a key role in host defense against viral infections. Beyond their classical antimicrobial functions, neutrophils can engage in a specialized defense mechanism by releasing web-like extracellular DNA known as neutrophil [...] Read more.
Neutrophils are among the early responders of the innate immune system and play a key role in host defense against viral infections. Beyond their classical antimicrobial functions, neutrophils can engage in a specialized defense mechanism by releasing web-like extracellular DNA known as neutrophil extracellular traps (NETs). These extracellular traps are a mesh-like network of chromatin DNA decorated with cellular components, including histones, proteases, and antimicrobial enzymes, that function to contain and limit the spread of pathogens. While NET formation contributes to antiviral immunity, accumulating evidence indicates that excessive or dysregulated NET formation can significantly contribute to immunopathology during viral infections. Thus, depending on the context and outcome, NET formation may be viewed as a double-edged sword. Therefore, understanding the regulatory mechanisms governing NET formation and its harmful effects is critical for developing therapeutic strategies that enhance antiviral defense while minimizing tissue damage. In this review, we provide a comprehensive overview of the molecular mechanisms that drive NET formation and clearance, with a particular focus on how viruses modulate these processes to influence disease outcome. We also discuss the pathways underlying NET formation and subsequent neutrophil cell death (NETosis), including canonical and non-canonical pathways, and highlight key signaling axes involving SYK, MAPKs, and NF-κB. Using SARS-CoV-2 and hepatitis B virus as representative models, we examine how different viral components trigger, exploit, or evade NET targeting and how persistent accumulation of NETs can contribute to hyperinflammation, progressive tissue injury, and post-viral syndromes. We further explore emerging evidence linking impaired NET clearance and neutrophil heterogeneity, particularly low-density neutrophils (LDNs), to chronic inflammation and post-viral sequelae such as long COVID and autoimmune hepatitis. Finally, we summarize current and emerging therapeutic strategies aimed at modulating NET formation or enhancing NET clearance. Altogether, this review underscores the dual nature of NETs in viral infections, highlighting their potential roles in antiviral defense and tissue injury, and provides a framework for the development of targeted interventions to limit virus-induced immunopathology. Full article
(This article belongs to the Special Issue Multifaceted Nature of Immune Responses to Viral Infection)
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