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Biomedicines
Special Issues
Encephalitis and Viral Infection: Mechanisms and Therapies
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Encephalitis and Viral Infection: Mechanisms and Therapies

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 5887

Special Issue Editors

Dr. Bradley S. Hollidge

E-Mail Website
Guest Editor
REGENXBIO Inc., Rockville, MD, USA
Interests: neurovirology; gene therapy; neuroinflammation; arboviruses
Dr. Samantha S. Soldan

E-Mail Website
Guest Editor
Wistar Institute, Philadelphia, PA, USA
Interests: T lymphocytes; microbiology; pathogenesis; virology; B lymphocytes; human herpesvirus 4; EBV-encoded nuclear antigen 1; epstein–barr virus and multiple sclerosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue offers a platform for researchers to delve into the intricate relationship between neurovirology, encephalitis, and efficient therapies. Neurovirology and encephalitis are complex and often intertwined fields that are informative to the gene therapy field for treating neurologic diseases. In addition, recent advancements in gene therapies have opened new avenues for understanding and treating these encephalitic and neurologic diseases. This Special Issue acts as a bridge, fostering interdisciplinary collaboration and advancing medical knowledge.

We invite original research articles and reviews that contribute to the understanding of the following aspects within the scope of this Special Issue:

Neurovirology: Investigations into the molecular mechanisms underlying neurotropic viral infections, their impact on neural function, and the development of antiviral strategies.

Encephalitis: Studies on the etiology, pathogenesis, diagnosis, and management of encephalitis, with a focus on both infectious and autoimmune forms.

Gene therapy: Research on the development and application of gene therapies for neurologic diseases, including the use of viral vectors, gene editing techniques, and immunomodulatory approaches.

Interdisciplinary approaches: Contributions that bridge the gap between neurovirology, encephalitis, and gene therapies, offering novel insights, therapeutic strategies, and potential translational applications.

By bringing together experts from these diverse fields, this Special Issue seeks to foster collaboration, stimulate innovative research, and ultimately contribute to the development of novel therapeutic interventions for neuroviral infections, encephalitis, and neurologic diseases. We welcome manuscripts that explore the intersections of these disciplines, providing a holistic view of the challenges and opportunities in this critical area of biomedical science.

Dr. Bradley S. Hollidge
Dr. Samantha S. Soldan
Guest Editors

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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

  • neurovirology
  • encephalitis
  • gene therapy
  • viral vectors
  • virology
  • immunology
  • neuroscience
  • gene editing

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Published Papers (4 papers)

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Research

Jump to: Review, Other

16 pages, 1887 KiB  
Article
Post-Herpetic Anti-NMDAR Encephalitis in Denmark: Current Status and Future Challenges
by Anna Søgaard, Charlotte Aaberg Poulsen, Nadia Zeeberg Belhouche, Alberte Thybo, Siv Tonje Faret Hovet, Lykke Larsen, Christine Nilsson, Morten Blaabjerg and Mette Scheller Nissen
Biomedicines 2024, 12(9), 1953; https://doi.org/10.3390/biomedicines12091953 - 27 Aug 2024
Viewed by 1173
Abstract
It is well known that N-methyl-D-aspartate receptor encephalitis (NMDARE) can be triggered by infectious encephalitis such as herpes simplex virus 1 encephalitis (HSE). However, the incidence of post-HSE NMDARE in Denmark is unknown. We reviewed literature cases and compared these to retrospectively [...] Read more.
It is well known that N-methyl-D-aspartate receptor encephalitis (NMDARE) can be triggered by infectious encephalitis such as herpes simplex virus 1 encephalitis (HSE). However, the incidence of post-HSE NMDARE in Denmark is unknown. We reviewed literature cases and compared these to retrospectively identified cases of post-HSE NMDARE in Denmark, using a national cohort database of autoimmune encephalitis (AE) and two regional databases of infectious encephalitis patients. We identified 80 post-HSE NMDARE cases in the literature, 66% being children, who more often presented movement disorders, decreased consciousness, and sleep disturbances compared to adults. Eight patients with post-HSE NMDARE were identified from the national cohort database of AE, none being children. Forty-four HSE patients were identified from the regional infectious encephalitis databases. Of these, 16 (36%) fulfilled the Graus criteria for probable/definite NMDARE, and eight (18%) presented a prolonged/relapsing disease course. Ten (23%) were tested for AE during hospitalization. Six (14%) had leftover cerebrospinal fluid available for retrospective autoantibody testing. One out of these six patients (17%) harbored NMDARE antibodies. Thus, in total, nine post-HSE NMDARE patients have been identified in Denmark from 2009 to 2021. Comparing the adult Danish patients to the literature, Danish patients were older, but the clinical phenotype and paraclinical findings were similar. Overall, the incidence of adult post-HSE NMDARE in the Region of Southern Denmark was 0.17 per million people per year and only 7% of adult HSE patients in the region were diagnosed with post-HSE NMDARE. Our findings suggest that adult patients are still underdiagnosed and the absence of pediatric cases diagnosed with post-HSE NMDARE in Denmark is highly concerning. Full article
(This article belongs to the Special Issue Encephalitis and Viral Infection: Mechanisms and Therapies)
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Figure 1
<p>Sixty papers were identified; 29 were considered irrelevant, resulting in 31 papers providing 126 relevant cases. Due to insufficient data/duplicate cases, 46 cases were excluded. A total of 80 cases were included and divided based on age of onset into: children (&lt;18 years) and adults (≥18 years). Abbreviations: post-HSE NMDARE, post-Herpes Simplex Virus 1 <span class="html-italic">N</span>-methyl-D-Aspartate Receptor Encephalitis.</p> Full article ">Figure 2
<p>Pie chart displaying the distribution of post-HSE NMDARE symptoms in children and adult literature cases. Abbreviations: HSE, herpes simplex encephalitis. NMDARE, <span class="html-italic">N</span>-Methyl-D-Aspartate receptor encephalitis.</p> Full article ">Figure 3
<p>Overview of screening of national and regional databases for post-HSE NMDARE patients. The Danish National NMDARE Cohort (left) was screened for patients with preceding HSE; a total of eight patients developed NMDARE after HSE infection. Two regional infectious encephalitis databases (right) were screened for patients with HSE; 44 patients were found. Of these, one additional patient developing NMDARE after HSE was identified. Abbreviations: HSE, Herpes Simplex Virus Encephalitis. NMDARE, <span class="html-italic">N</span>-Methyl-D-Aspartate receptor Encephalitis; VZE, Varicella Zoster Virus Encephalitis; VZV. Varicella Zoster Virus. * No data available for 2014.</p> Full article ">Figure 4
<p>Bar chart illustrating patients admitted with HSE (blue), patients with relapsing/prolonged disease course (black) and the total number of tests for AE autoantibodies in CSF performed (light blue) in the Region of Southern Denmark 2009–2021. Abbreviations: AE, Autoimmune Encephalitis; <span class="html-italic">HSE</span>, Herpes Simplex Encephalitis.</p> Full article ">
19 pages, 4187 KiB  
Article
SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin
by Moon Han Chang, Jung Hyun Park, Hye Kyung Lee, Ji Young Choi and Young Ho Koh
Biomedicines 2024, 12(6), 1223; https://doi.org/10.3390/biomedicines12061223 - 31 May 2024
Cited by 3 | Viewed by 2110
Abstract
Abnormal aggregation of α-synuclein is the hallmark of neurodegenerative diseases, classified as α-synucleinopathies, primarily occurring sporadically. Their onset is associated with an interaction between genetic susceptibility and environmental factors such as neurotoxins, oxidative stress, inflammation, and viral infections. Recently, evidence has suggested an [...] Read more.
Abnormal aggregation of α-synuclein is the hallmark of neurodegenerative diseases, classified as α-synucleinopathies, primarily occurring sporadically. Their onset is associated with an interaction between genetic susceptibility and environmental factors such as neurotoxins, oxidative stress, inflammation, and viral infections. Recently, evidence has suggested an association between neurological complications in long COVID (sometimes referred to as ‘post-acute sequelae of COVID-19’) and α-synucleinopathies, but its underlying mechanisms are not completely understood. In this study, we first showed that SARS-CoV-2 Spike protein 1 (S1) induces α-synuclein aggregation associated with activation of microglial cells in the rodent model. In vitro, we demonstrated that S1 increases aggregation of α-synuclein in BE(2)M-17 dopaminergic neurons via BV-2 microglia-mediated inflammatory responses. We also identified that S1 directly affects aggregation of α-synuclein in dopaminergic neurons through increasing mitochondrial ROS, though only under conditions of sufficient α-Syn accumulation. In addition, we observed a synergistic effect between S1 and the neurotoxin MPP+ S1 treatment. Combined with a low dose of MPP+, it boosted α-synuclein aggregation and mitochondrial ROS production compared to S1 or the MPP+ treatment group. Furthermore, we evaluated the therapeutic effects of metformin. The treatment of metformin suppressed the S1-induced inflammatory response and α-synucleinopathy. Our findings demonstrate that S1 promotes α-synucleinopathy via both microglia-mediated inflammation and mitochondrial ROS, and they provide pathological insights, as well as a foundation for the clinical management of α-synucleinopathies and the onset of neurological symptoms after the COVID-19 outbreak. Full article
(This article belongs to the Special Issue Encephalitis and Viral Infection: Mechanisms and Therapies)
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Figure 1

Figure 1
<p>SARS-CoV-2 S1 increases α-Syn aggregation in a rat brain. (<b>A</b>) Experimental timeline for SARS-CoV-2 treatment. A single dose (0.5 g of S1 or PBS) was intranasally administered to 8-week-old male rats, and brains were collected at 6 weeks after administration. (<b>B</b>) Representative images of immunohistochemistry using aggregated α-Syn (5G4) specific antibody in substantia nigra. (<b>C</b>) Representative immunoblot images for protein levels of aggregated α-Syn (5G4). (<b>D</b>) Western blot quantification for protein levels of aggregated α-Syn (5G4) in rat brain striatum. (<b>E</b>) Immunofluorescence staining of Iba-1, representing markers for active microglia cells, and aggregated α-Syn (5G4) in substantia nigra of vehicle and S1-treated rat brain. (Green: α-Syn (5G4) and red: Iba-1) (Scale bar: 100 μm). Data are presented as mean ± standard error of the mean (<span class="html-italic">n</span> = 3–4 mice per group, * <span class="html-italic">p</span> &lt; 0.05).</p> Full article ">Figure 2
<p>SARS-CoV-2 S1 increases aggregation and monomers of α-Syn via a microglia pro-inflammatory response. (<b>A</b>) A schematic diagram showing BE(2)M-17 dopaminergic neuron cells stimulated by S1 protein-activated glia-conditioned media (CM). BV-2 cells were incubated for 24 h in serum-free DMEM (untreated controls) or serum-free DMEM containing S1 (200 ng/mL) with or without 5 μM JSH-23. BE(2)M-17 cells were treated with collected BV-2 CM for 24 h. Further details are provided in <a href="#sec2-biomedicines-12-01223" class="html-sec">Section 2</a>. (<b>B</b>) Representative images of immunoblot analysis using specific antibodies for aggregated α-Syn (5G4), phospho-α-Syn (Ser129), and monomeric α-Syn. (<b>C</b>–<b>E</b>) Quantification of immunoblot analysis for aggregated α-Syn (5G4), phospho-α-Syn (Ser129), and monomeric α-Syn. (<b>F</b>) Multiplex cytokine analysis from conditioned media of BV-2 cells in response to S1 (200 ng/mL) with or without 5 μM JSH-23. (<b>G</b>) Representative images of immunoblot analysis using specific antibodies for TNF-α, mature IL-1β, Iba-1, and CD163. (<b>H</b>–<b>K</b>) Quantification of immunoblot analysis for TNF-α, mature IL-1β, Iba-1, and CD163. All data are presented as mean ± standard error of the mean (<span class="html-italic">n</span> = 3–5 per group, * <span class="html-italic">p</span> &lt; 0.05 and *** <span class="html-italic">p</span> &lt; 0.001, ND; Not Detected, ns; no significance).</p> Full article ">Figure 3
<p>SARS-CoV-2 S1 directly increases aggregation of α-Syn above a threshold. α-Syn overexpressed BE(2)M-17 cells were incubated for 24 h in DMEM/F12 (untreated controls) or DMEM/F12 containing S1 (500 ng/mL), with or without 10 μM MitoTEMPO. (<b>A</b>) Representative images of immunoblot analysis using specific antibody for aggregated α-Syn (5G4) and (<b>B</b>) quantification of data. (<b>C</b>) Mitochondrial damage analyzed using JC-1 dye and (<b>D</b>) quantification data of JC1 determined using fluorescence microscope (green: whole mitochondria, red: damaged mitochondria). (<b>E</b>) Representative image of MitoSOX red staining for mitochondrial ROS and (<b>F</b>) quantification of data. All data are presented as mean ± standard error of the mean (<span class="html-italic">n</span> = 3–5 per group, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001). (Scale bar: 50 μm).</p> Full article ">Figure 4
<p>SARS-CoV-2 S1-induced microglial activation enhances MPP-induced cytotoxicity and α-Syn aggregation, with the moderating effects of metformin. (<b>A</b>) A schematic diagram showing BE(2)M-17 dopaminergic neuron cells stimulated by S1 protein-activated BV-2-conditioned media (CM). BV-2 cells were incubated for 24 h in serum-free DMEM (untreated controls) or serum-free DMEM containing S1 (200 ng/mL), with or without 1 mM metformin. BE(2)M-17 cells were treated with collected BV-2 CM with or without MPP+ for 24 h. Further details are provided in <a href="#sec2-biomedicines-12-01223" class="html-sec">Section 2</a>. (<b>B</b>) The effects of MPP+, 200 ng/mL S1-activated BV-2 CM, and metformin (alone and in combination) on the cell viability (% of control) of BE(2)M-17 cells for 24 h. (<b>C</b>) Representative images of immunoblot analysis using specific antibodies for aggregated α-Syn (5G4), phospho-α-Syn (Ser129), and monomeric α-Syn. (<b>D</b>–<b>F</b>) Quantification of immunoblot analysis for aggregated α-Syn (5G4), phospho-α-Syn (Ser129), and monomeric α-Syn. (<b>G</b>) Multiplex cytokine analysis from conditioned media of BV-2 cells in response to S1 (200 ng/mL) with or without 1 mM metformin. (<b>H</b>) Representative images of immunoblot analysis using specific antibodies for TNF-α, mature IL-1β, Iba-1, and CD163. (<b>I</b>–<b>L</b>) Quantification of immunoblot analysis for TNF-α, mature IL-1β, Iba-1, and CD163. All data are presented as mean ± standard error of the mean (<span class="html-italic">n</span> = 3–5 per group, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001, ND; Not Detected, ns; no significance).</p> Full article ">Figure 5
<p>SARS-CoV-2 S1 directly enhances MPP-induced cytotoxicity, with moderating effects of metformin. (<b>A</b>) The effects of MPP+ (0, 250, 500 μM) and S1 (0, 250, 500 ng/mL) (alone and in combination) on the cell viability (% of control) of α-Syn-overexpressed BE(2)M-17 cells for 24 h. (<b>B</b>–<b>H</b>) α-Syn-overexpressed BE(2)M-17 cells were incubated for 24 h in DMEM/F12 (untreated controls) or DMEM/F12 containing S1 (500 ng/mL) with or without 1 mM metformin to identify moderating effects of metformin. (<b>B</b>) MTT assays were performed to identify moderating effects of metformin on S1 with MPP+ treatment-induced cytotoxicity. (<b>C</b>) Representative images of immunoblot analysis using specific antibody for aggregated α-Syn (5G4) and (<b>D</b>) quantification of data. (<b>E</b>) Mitochondrial damage analyzed using JC-1 dye and (<b>F</b>) quantification data of JC1 (green: whole mitochondria, red: damaged mitochondria). (<b>G</b>) Representative image of MitoSOX red staining for mitochondrial ROS and (<b>H</b>) quantification of data. All data are presented as mean ± standard error of the mean (<span class="html-italic">n</span> = 3–5 per group, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001) (Scale bar: 50 μm).</p> Full article ">Figure 6
<p>Proposal model of this study.</p> Full article ">

Review

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10 pages, 221 KiB  
Review
Harnessing the Power of AI to Improve Detection, Monitoring, and Public Health Interventions for Japanese Encephalitis
by Junhua Xiao, Evie Kendal and Faith A. A. Kwa
Biomedicines 2025, 13(1), 42; https://doi.org/10.3390/biomedicines13010042 - 27 Dec 2024
Viewed by 744
Abstract
Japanese Encephalitis (JE) is the leading cause of viral encephalitis in regions with endemic Japanese Encephalitis Virus (JEV) infections. Background/Objectives: The aim of this review is to consider the potential role of artificial intelligence (AI) to improve detection, monitoring and public health interventions [...] Read more.
Japanese Encephalitis (JE) is the leading cause of viral encephalitis in regions with endemic Japanese Encephalitis Virus (JEV) infections. Background/Objectives: The aim of this review is to consider the potential role of artificial intelligence (AI) to improve detection, monitoring and public health interventions for JE. Discussion: As climate change continues to impact mosquito population growth patterns, more regions will be affected by mosquito-borne diseases, including JE. Improving diagnosis and surveillance, while continuing preventive measures, such as widespread vaccination campaigns in endemic regions, will be essential to reduce morbidity and mortality associated with JEV. Conclusions: With careful integration, AI mathematical and mechanistic models could be useful tools for combating the growing threat of JEV infections globally. Full article
(This article belongs to the Special Issue Encephalitis and Viral Infection: Mechanisms and Therapies)

Other

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14 pages, 739 KiB  
Case Report
Fatal Fulminant Epstein–Barr Virus (EBV) Encephalitis in Immunocompetent 5.5-Year-Old Girl—A Case Report with the Review of Diagnostic and Management Dilemmas
by Magdalena Mierzewska-Schmidt, Anna Piwowarczyk, Krystyna Szymanska, Michal Ciaston, Edyta Podsiadly, Maciej Przybylski and Izabela Pagowska-Klimek
Biomedicines 2024, 12(12), 2877; https://doi.org/10.3390/biomedicines12122877 - 18 Dec 2024
Viewed by 936
Abstract
Introduction: Epstein–Barr virus (EBV) usually causes mild, self-limiting, or asymptomatic infection in children, typically infectious mononucleosis. The severe course is more common in immunocompromised patients. Neurological complications of primary infection, reactivation of the latent infection, or immune-mediated are well-documented. However, few published cases [...] Read more.
Introduction: Epstein–Barr virus (EBV) usually causes mild, self-limiting, or asymptomatic infection in children, typically infectious mononucleosis. The severe course is more common in immunocompromised patients. Neurological complications of primary infection, reactivation of the latent infection, or immune-mediated are well-documented. However, few published cases of fatal EBV encephalitis exist. Case presentation We report a case of a 5.5-year-old immunocompetent girl with fulminant EBV encephalitis fulfilling the criteria for the recently proposed subtype Acute Fulminant Cerebral Edema: (AFCE). The child presented with fever, vomiting, altered mental status, and ataxia. Her initial brain CT (computed tomography) scan was normal. On day 2 she developed refractory status epilepticus requiring intubation, ventilation, and sedation for airway protection and seizure control. Magnetic resonance imaging (MRI) scan showed cytotoxic brain edema. Despite intensive treatment, including acyclovir, ceftriaxone, hyperosmotic therapy (3% NaCl), intravenous immunoglobulins (IVIG), corticosteroids, as well as supportive management, on day 5 she developed signs of impending herniation. Intensification of therapy (hyperventilation, deepening sedation, mannitol) was ineffective, and a CT scan demonstrated generalized brain edema with tonsillar herniation. EBV primary infection was confirmed by serology and qPCR in blood samples and post-mortem brain tissue. An autopsy was consistent with the early phase of viral encephalitis. Conclusions This case confirms that normal or non-specific CT and MRI scans do not exclude encephalitis diagnosis if clinical presentation fulfills the diagnostic criteria. The implementation of prophylactic anticonvulsants could improve outcomes. Intracranial pressure (ICP) monitoring should be considered in AFCE for better ICP management. Decompressive craniectomy might be a life-saving option in refractory cases. An encephalitis management algorithm is proposed. Full article
(This article belongs to the Special Issue Encephalitis and Viral Infection: Mechanisms and Therapies)
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Figure 1
<p>Initial CT scan (<b>A</b>) performed at the emergency department on the day of admission shows no abnormalities in the brain parenchyma, with no signs of edema, hemorrhage, or mass effect. Follow-up CT scan (<b>B</b>), performed 5 days later due to clinical deterioration and suspicion of tonsillar herniation, reveals diffuse cerebral edema with complete loss of cerebrospinal fluid reserve and evidence of tonsillar herniation through the foramen magnum.</p> Full article ">Figure 2
<p>MRI DWI (<b>B</b>) sequence reveals diffuse areas of restricted diffusion in the cortical regions of both cerebral hemispheres, consistent with cytotoxic edema. No abnormalities are observed in the T2-FLAIR (<b>A</b>) sequence or other performed sequences. These findings suggest a status epilepticus origin rather than an inflammatory process. The pattern is not typical for EBV encephalitis. No areas of abnormal intracranial enhancement were visualized.</p> Full article ">
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