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Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 18449

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Prof. Dr. Wolfgang Baumgärtner

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Department of Pathology, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany
Interests: viral pathogenesis; host range; virus-host cell-tropism and interactions;, virus discovery; models for multiple sclerosis; intervention strategies; neuroinfectiology
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Special Issue Information

Dear Colleagues,

This Special Issue is the third volume of our previous Special Issue, “Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection” and "Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 2.0". In recent years, reported cases of viral pathogens causing infection of the central nervous system (CNS) as emerging and re-emerging diseases have been increasing, particularly noticeable in humans and animals. Some viruses will infect only the CNS, others cause a systemic spread and affection of the nervous systems and are noticed in a small percentage of individuals. Still, a substantial number of possible viral CNS diseases remain etiologically undetermined so far. The burden of infectious CNS diseases is reinforced by the fact that survivors may suffer from life-long neurological and psychiatric complications. A sensu stricto definition of neuroinfectiology would refer to a direct pathogen–host cell effect, resulting in cytolysis and inflammation. However, the cellular functions may remain impaired, despite cell survival, especially in the CNS. Such an impaired organ function may be due to a derailment of immune responses, epitope spreading, and molecular mimicry, even after the elimination of the causing viral pathogen. Similarly, predisposing factors, including concurrent diseases and immune deficiencies, may increase susceptibility to viral infection. Therefore, a broader definition of neuroinfectiology should include predisposing mechanisms, acute host–pathogen interactions, and long-term, delayed disturbances and disabilities.

Mechanisms that govern the neuropathogenesis of viral infections will be highlighted in this Special Issue, entitled “Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 3.0”.

Prof. Dr. Wolfgang Baumgärtner
Guest Editor

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Keywords

neuroinfection
acute neuropathogenesis
long-term pathogenesis
neurotoxicity
host–glial cell interactions
virus discover
host range
transmission
neuro-immunopathology
viral persistence
demyelination
axonopathy
delayed neurological symptoms
neurocognitive disorders
intervention strategies

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Published Papers (7 papers)

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Research

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21 pages, 8468 KiB

Open AccessArticle

Tumor Necrosis Factor-α Receptor 1 Mediates Borna Disease Virus 1-Induced Changes in Peroxisomal and Mitochondrial Dynamics in Neurons

by Dominic Osei, Eveline Baumgart-Vogt, Barbara Ahlemeyer and Christiane Herden

Int. J. Mol. Sci. 2024, 25(3), 1849; https://doi.org/10.3390/ijms25031849 - 3 Feb 2024

Cited by 2 | Viewed by 1359

Abstract

Borna disease virus 1 (BoDV1) causes a persistent infection in the mammalian brain. Peroxisomes and mitochondria play essential roles in the cellular antiviral immune response, but the effect of BoDV1 infection on peroxisomal and mitochondrial dynamics and their respective antioxidant capacities is still not clear. Using different mouse lines—i.e., tumor necrosis factor-α transgenic (TNFTg; to pro-inflammatory status), TNF receptor-1 knockout (TNFR1ko), and TNFR2ko mice in comparison to wild-type (Wt) mice—we analyzed the abundances of both organelles and their main antioxidant enzymes, catalase and superoxide dismutase 2 (SOD2), in neurons of the hippocampal, cerebral, and cerebellar cortices. In TNFTg mice, a strong increase in mitochondrial (6.9-fold) and SOD2 (12.1-fold) abundances was detected; meanwhile, peroxisomal abundance increased slightly (1.5-fold), but that of catalase decreased (2.9-fold). After BoDV1 infection, a strong decrease in mitochondrial (2.1–6.5-fold), SOD2 (2.7–9.1-fold), and catalase (2.7–10.3-fold) abundances, but a slight increase in peroxisomes (1.3–1.6-fold), were detected in Wt and TNFR2ko mice, whereas no changes occurred in TNFR1ko mice. Our data suggest that the TNF system plays a crucial role in the biogenesis of both subcellular organelles. Moreover, TNFR1 signaling mediated the changes in peroxisomal and mitochondrial dynamics after BoDV1 infection, highlighting new mechanisms by which BoDV1 may achieve immune evasion and viral persistence. Full article

(This article belongs to the Special Issue Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 3.0)

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16 pages, 3238 KiB

Open AccessArticle

Intact Type I Interferon Receptor Signaling Prevents Hepatocellular Necrosis but Not Encephalitis in a Dose-Dependent Manner in Rift Valley Fever Virus Infected Mice

by Lukas Mathias Michaely, Lukas Schuwerk, Lisa Allnoch, Kathleen Schön, Inken Waltl, Pia-Katharina Larsen, Andreas Pavlou, Chittappen Kandiyil Prajeeth, Guus F. Rimmelzwaan, Stefanie C. Becker, Ulrich Kalinke, Wolfgang Baumgärtner and Ingo Gerhauser

Int. J. Mol. Sci. 2022, 23(20), 12492; https://doi.org/10.3390/ijms232012492 - 18 Oct 2022

Cited by 5 | Viewed by 2115

Abstract

Rift Valley fever (RVF) is a zoonotic and emerging disease, caused by the RVF virus (RVFV). In ruminants, it leads to “abortion storms” and enhanced mortality rates in young animals, whereas in humans it can cause symptoms like severe hemorrhagic fever or encephalitis. The role of the innate and adaptive immune response in disease initiation and progression is still poorly defined. The present study used the attenuated RVFV strain clone 13 to investigate viral spread, tissue tropism, and histopathological lesions after intranasal infection in C57BL/6 wild type (WT) and type I interferon (IFN-I) receptor I knockout (IFNAR^−/−) mice. In WT mice, 10⁴ PFU RVFV (high dose) resulted in a fatal encephalitis, but no hepatitis 7–11 days post infection (dpi), whereas 10³ PFU RVFV (low dose) did not cause clinical disease or significant histopathological lesions in liver and the central nervous system (CNS). In contrast, IFNAR^−/− mice infected with 10³ PFU RVFV developed hepatocellular necrosis resulting in death at 2–5 dpi and lacked encephalitis. These results show that IFNAR signaling prevents systemic spread of the attenuated RVFV strain clone 13, but not the dissemination to the CNS and subsequent fatal disease. Consequently, neurotropic viruses may be able to evade antiviral IFN-I signaling pathways by using the transneuronal instead of the hematogenous route. Full article

(This article belongs to the Special Issue Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 3.0)

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18 pages, 5487 KiB

Open AccessArticle

Viral Clearance and Neuroinflammation in Acute TMEV Infection Vary by Host Genetic Background

by Koedi S. Lawley, Raquel R. Rech, Aracely A. Perez Gomez, Laura Hopkins, Gang Han, Katia Amstalden, C. Jane Welsh, Colin R. Young, Yava Jones-Hall, David W. Threadgill and Candice L. Brinkmeyer-Langford

Int. J. Mol. Sci. 2022, 23(18), 10482; https://doi.org/10.3390/ijms231810482 - 9 Sep 2022

Cited by 8 | Viewed by 2470

Abstract

A wide range of viruses cause neurological manifestations in their hosts. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the brain, depending in part on host genetic background. The interaction between host genetic background, neurological response to viral infection, and subsequent clinical manifestations remains poorly understood. In the present study, we used the genetically diverse Collaborative Cross (CC) mouse resource to better understand how differences in genetic background drive clinical signs and neuropathological manifestations of acute Theiler’s murine encephalomyelitis virus (TMEV) infection. For the first time, we characterized variations of TMEV viral tropism and load based on host genetic background, and correlated viral load with microglial/macrophage activation. For five CC strains (CC002, CC023, CC027, CC057, and CC078) infected with TMEV, we compared clinical signs, lesion distribution, microglial/macrophage response, expression, and distribution of TMEV mRNA, and identified genetic loci relevant to the early acute (4 days post-infection [dpi]) and late acute (14 dpi) timepoints. We examined brain pathology to determine possible causes of strain-specific differences in clinical signs, and found that fields CA1 and CA2 of the hippocampal formation were especially targeted by TMEV across all strains. Using Iba-1 immunolabeling, we identified and characterized strain- and timepoint-specific variation in microglial/macrophage reactivity in the hippocampal formation. Because viral clearance can influence disease outcome, we used RNA in situ hybridization to quantify viral load and TMEV mRNA distribution at both timepoints. TMEV mRNA expression was broadly distributed in the hippocampal formation at 4 dpi in all strains but varied between radiating and clustered distribution depending on the CC strain. We found a positive correlation between microglial/macrophage reactivity and TMEV mRNA expression at 4 dpi. At 14 dpi, we observed a dramatic reduction in TMEV mRNA expression, and localization to the medial portion of field CA1 and field CA2. To better understand how host genetic background can influence pathological outcomes, we identified quantitative trait loci associated with frequency of lesions in a particular brain region and with microglial/macrophage reactivity. These QTL were located near several loci of interest: lysosomal trafficking regulator (Lyst) and nidogen 1 (Nid1), and transmembrane protein 106 B (Tmem106b). Together, these results provide a novel understanding about the influences of genetic variation on the acute neuropathological and immunopathological environment and viral load, which collectively lead to variable disease outcomes. Our findings reveal possible avenues for future investigation which may lead to more effective intervention strategies and treatment regimens. Full article

(This article belongs to the Special Issue Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 3.0)

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15 pages, 2188 KiB

Open AccessArticle

Rubella Virus Triggers Type I Interferon Antiviral Response in Cultured Human Neural Cells: Involvement in the Control of Viral Gene Expression and Infectious Progeny Production

by Sayuri Sakuragi, Huanan Liao, Kodai Yajima, Shigeyoshi Fujiwara and Hiroyuki Nakamura

Int. J. Mol. Sci. 2022, 23(17), 9799; https://doi.org/10.3390/ijms23179799 - 29 Aug 2022

Cited by 5 | Viewed by 3106

Abstract

The type I interferon (IFN) response is one of the primary defense systems against various pathogens. Although rubella virus (RuV) infection is known to cause dysfunction of various organs and systems, including the central nervous system, little is known about how human neural cells evoke protective immunity against RuV infection, leading to controlling RuV replication. Using cultured human neural cells experimentally infected with RuV RA27/3 strain, we characterized the type I IFN immune response against the virus. RuV infected cultured human neural cell lines and induced IFN-β production, leading to the activation of signal transducer and activator of transcription 1 (STAT1) and the increased expression of IFN-stimulated genes (ISGs). Melanoma-differentiation-associated gene 5 (MDA5), one of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, is required for the RuV-triggered IFN-β mRNA induction in U373MG cells. We also showed that upregulation of RuV-triggered ISGs was attenuated by blocking IFN-α/β receptor subunit 2 (IFNAR2) using an IFNAR2-specific neutralizing antibody or by repressing mitochondrial antiviral signaling protein (MAVS) expression using MAVS-targeting short hairpin RNA (shRNA). Furthermore, treating RuV-infected cells with BX-795, a TANK-binding kinase 1 (TBK1)/I kappa B kinase ε (IKKε) inhibitor, robustly reduced STAT1 phosphorylation and expression of ISGs, enhancing viral gene expression and infectious virion production. Overall, our findings suggest that the RuV-triggered type I IFN-mediated antiviral response is essential in controlling RuV gene expression and viral replication in human neural cells. Full article

(This article belongs to the Special Issue Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 3.0)

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17 pages, 3327 KiB

Open AccessArticle

CARD9 Deficiency Increases Hippocampal Injury Following Acute Neurotropic Picornavirus Infection but Does Not Affect Pathogen Elimination

by Suvarin Pavasutthipaisit, Melanie Stoff, Tim Ebbecke, Malgorzata Ciurkiewicz, Sabine Mayer-Lambertz, Theresa Störk, Kevin D. Pavelko, Bernd Lepenies and Andreas Beineke

Int. J. Mol. Sci. 2021, 22(13), 6982; https://doi.org/10.3390/ijms22136982 - 29 Jun 2021

Cited by 7 | Viewed by 2900

Abstract

Neurotropic viruses target the brain and contribute to neurologic diseases. Caspase recruitment domain containing family member 9 (CARD9) controls protective immunity in a variety of infectious disorders. To investigate the effect of CARD9 in neurotropic virus infection, CARD9^−/− and corresponding C57BL/6 wild-type control mice were infected with Theiler’s murine encephalomyelitis virus (TMEV). Brain tissue was analyzed by histology, immunohistochemistry and molecular analyses, and spleens by flow cytometry. To determine the impact of CARD9 deficiency on T cell responses in vitro, antigen presentation assays were utilized. Genetic ablation of CARD9 enhanced early pro-inflammatory cytokine responses and accelerated infiltration of T and B cells in the brain, together with a transient increase in TMEV-infected cells in the hippocampus. CARD9^−/− mice showed an increased loss of neuronal nuclear protein⁺ mature neurons and doublecortin⁺ neuronal precursor cells and an increase in β-amyloid precursor protein⁺ damaged axons in the hippocampus. No effect of CARD9 deficiency was found on the initiation of CD8⁺ T cell responses by flow cytometry and co-culture experiments using virus-exposed dendritic cells or microglia-enriched glial cell mixtures, respectively. The present study indicates that CARD9 is dispensable for the initiation of early antiviral responses and TMEV elimination but may contribute to the modulation of neuroinflammation, thereby reducing hippocampal injury following neurotropic virus infection. Full article

(This article belongs to the Special Issue Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 3.0)

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Review

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16 pages, 278 KiB

Open AccessReview

The Significance of COVID-19 Immunological Status in Severe Neurological Complications and Multiple Sclerosis—A Literature Review

by Joanna Kulikowska, Agnieszka Kulczyńska-Przybik, Barbara Mroczko and Alina Kułakowska

Int. J. Mol. Sci. 2021, 22(11), 5894; https://doi.org/10.3390/ijms22115894 - 31 May 2021

Cited by 4 | Viewed by 3114

Abstract

SARS-CoV-2/Coronavirus 2019 (COVID-19) is responsible for the pandemic, which started in December 2019. In addition to the typical respiratory symptoms, this virus also causes other severe complications, including neurological ones. In diagnostics, serological and polymerase chain reaction tests are useful not only in detecting past infections but can also predict the response to vaccination. It is now believed that an immune mechanism rather than direct viral neuroinvasion is responsible for neurological symptoms. For this reason, it is important to assess the presence of antibodies not only in the serum but also in the cerebrospinal fluid (CSF), especially in the case of neuro-COVID. A particular group of patients are people with multiple sclerosis (MS) whose disease-modifying drugs weaken the immune system and lead to an unpredictable serological response to SARS-CoV-2 infection. Based on available data, the article summarizes the current serological information concerning COVID-19 in CSF in patients with severe neurological complications and in those with MS. Full article

(This article belongs to the Special Issue Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 3.0)

Other

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10 pages, 1160 KiB

Open AccessBrief Report

Tamoxifen Application Is Associated with Transiently Increased Loss of Hippocampal Neurons following Virus Infection

by Kirsten Hülskötter, Fred Lühder, Alexander Flügel, Vanessa Herder and Wolfgang Baumgärtner

Int. J. Mol. Sci. 2021, 22(16), 8486; https://doi.org/10.3390/ijms22168486 - 6 Aug 2021

Cited by 1 | Viewed by 2148

Abstract

Tamoxifen is frequently used in murine knockout systems with CreER/LoxP. Besides possible neuroprotective effects, tamoxifen is described as having a negative impact on adult neurogenesis. The present study investigated the effect of a high-dose tamoxifen application on Theiler’s murine encephalomyelitis virus (TMEV)-induced hippocampal damage. Two weeks after TMEV infection, 42% of the untreated TMEV-infected mice were affected by marked inflammation with neuronal loss, whereas 58% exhibited minor inflammation without neuronal loss. Irrespective of the presence of neuronal loss, untreated mice lacked TMEV antigen expression within the hippocampus at 14 days post-infection (dpi). Interestingly, tamoxifen application 0, 2 and 4, or 5, 7 and 9 dpi decelerated virus elimination and markedly increased neuronal loss to 94%, associated with increased reactive astrogliosis at 14 dpi. T cell infiltration, microgliosis and expression of water channels were similar within the inflammatory lesions, regardless of tamoxifen application. Applied at 0, 2 and 4 dpi, tamoxifen had a negative impact on the number of doublecortin (DCX)-positive cells within the dentate gyrus (DG) at 14 dpi, without a long-lasting effect on neuronal loss at 147 dpi. Thus, tamoxifen application during a TMEV infection is associated with transiently increased neuronal loss in the hippocampus, increased reactive astrogliosis and decreased neurogenesis in the DG. Full article

(This article belongs to the Special Issue Neuroinfectiology: Molecular and Cellular Mechanisms of Neurotropic Virus Infection 3.0)

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