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Article: Toll-like Receptors in Viral Encephalitis

Gern, Olivia Luise / Mulenge, Felix / Pavlou, Andreas / Ghita, Luca / Steffen, Imke / Stangel, Martin / Kalinke, Ulrich

Viruses. 2021 Oct. 14, v. 13, no. 10

2021

Abstract: Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important ... ...

Abstract	Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear. On one hand, TLRs can affect the physiology of neurons during neuronal progenitor cell differentiation and neurite outgrowth, whereas under conditions of infection, the complex interplay between TLR stimulated neurons, astrocytes and microglia is just on the verge of being understood. In this review, we summarize the current knowledge about which TLRs are expressed by cell subsets of the CNS. Furthermore, we specifically highlight functional implications of TLR stimulation in neurons, astrocytes and microglia. After briefly illuminating some examples of viral evasion strategies from TLR signaling, we report on the current knowledge of primary immunodeficiencies in TLR signaling and their consequences for viral encephalitis. Finally, we provide an outlook with examples of TLR agonist mediated intervention strategies and potentiation of vaccine responses against neurotropic virus infections.
Keywords	Flaviviridae ; Human alphaherpesvirus 3 ; Paramyxoviridae ; Rhabdoviridae ; agonists ; astrocytes ; cell differentiation ; herpes simplex ; immunosuppression ; neurites ; physiology ; stem cells ; vaccines ; viral encephalitis ; viruses
Language	English
Dates of publication	2021-1014
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13102065
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Toll-like Receptors in Viral Encephalitis.

Gern, Olivia Luise / Mulenge, Felix / Pavlou, Andreas / Ghita, Luca / Steffen, Imke / Stangel, Martin / Kalinke, Ulrich

Viruses

2021 Volume 13, Issue 10

Abstract	Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear. On one hand, TLRs can affect the physiology of neurons during neuronal progenitor cell differentiation and neurite outgrowth, whereas under conditions of infection, the complex interplay between TLR stimulated neurons, astrocytes and microglia is just on the verge of being understood. In this review, we summarize the current knowledge about which TLRs are expressed by cell subsets of the CNS. Furthermore, we specifically highlight functional implications of TLR stimulation in neurons, astrocytes and microglia. After briefly illuminating some examples of viral evasion strategies from TLR signaling, we report on the current knowledge of primary immunodeficiencies in TLR signaling and their consequences for viral encephalitis. Finally, we provide an outlook with examples of TLR agonist mediated intervention strategies and potentiation of vaccine responses against neurotropic virus infections.
MeSH term(s)	Animals ; Astrocytes/virology ; Central Nervous System/immunology ; Central Nervous System/metabolism ; Encephalitis, Viral/immunology ; Herpes Simplex/immunology ; Host Microbial Interactions ; Humans ; Immunity, Innate ; Microglia/virology ; Neurons ; Signal Transduction ; Simplexvirus ; Toll-Like Receptors/immunology ; Toll-Like Receptors/metabolism
Chemical Substances	Toll-Like Receptors
Language	English
Publishing date	2021-10-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13102065
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage.

Waltl, Inken / Käufer, Christopher / Gerhauser, Ingo / Chhatbar, Chintan / Ghita, Luca / Kalinke, Ulrich / Löscher, Wolfgang

Brain, behavior, and immunity

2018 Volume 74, Page(s) 186–204

Abstract: In the central nervous system (CNS), innate immune surveillance is mainly coordinated by microglia. These CNS resident myeloid cells are assumed to help orchestrate the immune response against infections of the brain. However, their specific role in this ...

Abstract	In the central nervous system (CNS), innate immune surveillance is mainly coordinated by microglia. These CNS resident myeloid cells are assumed to help orchestrate the immune response against infections of the brain. However, their specific role in this process and their interactions with CNS infiltrating immune cells, such as blood-borne monocytes and T cells are only incompletely understood. The recent development of PLX5622, a specific inhibitor of colony-stimulating factor 1 receptor that depletes microglia, allows studying the role of microglia in conditions of brain injury such as viral encephalitis, the most common form of brain infection. Here we used this inhibitor in a model of viral infection-induced epilepsy, in which C57BL/6 mice are infected by a picornavirus (Theiler's murine encephalomyelitis virus) and display seizures and hippocampal damage. Our results show that microglia are required early after infection to limit virus distribution and persistence, most likely by modulating T cell activation. Microglia depletion accelerated the occurrence of seizures, exacerbated hippocampal damage, and led to neurodegeneration in the spinal cord, which is normally not observed in this mouse strain. This study enhances our understanding of the role of microglia in viral encephalitis and adds to the concept of microglia-T cell crosstalk.
MeSH term(s)	Animals ; Brain/immunology ; Central Nervous System/immunology ; Disease Models, Animal ; Encephalitis/immunology ; Encephalitis, Viral/immunology ; Encephalitis, Viral/virology ; Epilepsy/physiopathology ; Female ; Hippocampus/immunology ; Macrophages/immunology ; Mice ; Mice, Inbred C57BL ; Microglia/immunology ; Microglia/physiology ; Monocytes/immunology ; Organic Chemicals/pharmacology ; Seizures/physiopathology ; Theilovirus/immunology
Chemical Substances	Organic Chemicals ; PLX5622
Keywords	covid19
Language	English
Publishing date	2018-09-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639219-2
ISSN	1090-2139 ; 0889-1591
ISSN (online)	1090-2139
ISSN	0889-1591
DOI	10.1016/j.bbi.2018.09.006
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Book ; Online: Toll-like Receptors in Viral Encephalitis.

Gern, Olivia Luise / Mulenge, Felix / Pavlou, Andreas / Ghita, Luca / Steffen, Imke / Stangel, Martin / Kalinke, Ulrich

13 ; 10 ; Viruses ; Switzerland

2021

Abstract	Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear. On one hand, TLRs can affect the physiology of neurons during neuronal progenitor cell differentiation and neurite outgrowth, whereas under conditions of infection, the complex interplay between TLR stimulated neurons, astrocytes and microglia is just on the verge of being understood. In this review, we summarize the current knowledge about which TLRs are expressed by cell subsets of the CNS. Furthermore, we specifically highlight functional implications of TLR stimulation in neurons, astrocytes and microglia. After briefly illuminating some examples of viral evasion strategies from TLR signaling, we report on the current knowledge of primary immunodeficiencies in TLR signaling and their consequences for viral encephalitis. Finally, we provide an outlook with examples of TLR agonist mediated intervention strategies and potentiation of vaccine responses against neurotropic virus infections.
Keywords	CNS ; Toll-like receptors ; astrocytes ; microglia ; neurons ; viral encephalitis ; viruses
Subject code	572
Language	English
Publishing date	2021-10-14
Publisher	MDPI
Publishing country	de
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.

Karim, Marwah / Mishra, Manjari / Lo, Chieh-Wen / Saul, Sirle / Cagirici, Halise Busra / Tran, Do Hoang Nhu / Agrawal, Aditi / Ghita, Luca / Ojha, Amrita / East, Michael P / Gammeltoft, Karen Anbro / Sahoo, Malaya Kumar / Johnson, Gary L / Das, Soumita / Jochmans, Dirk / Cohen, Courtney A / Gottwein, Judith / Dye, John / Neff, Norma /

Pinsky, Benjamin A / Laitinen, Tuomo / Pantsar, Tatu / Poso, Antti / Zanini, Fabio / Jonghe, Steven De / Asquith, Christopher R M / Einav, Shirit

bioRxiv : the preprint server for biology

2024

Abstract: In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the ... ...

Abstract	In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Advanced lipidomics revealed alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and linked its antiviral effect with functional PIP4K2C and PIKfyve inhibition. We discovered PIP4K2C's roles in SARS-CoV-2 entry, RNA replication, and assembly/egress, validating it as a druggable antiviral target. Integrating proteomics, single-cell transcriptomics, and functional assays revealed that PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced impairment of autophagic flux. Reversing this autophagic flux impairment is a mechanism of antiviral action of RMC-113. These findings reveal virus-induced autophagy regulation via PIP4K2C, an understudied kinase, and propose dual inhibition of PIP4K2C and PIKfyve as a candidate strategy to combat emerging viruses.
Language	English
Publishing date	2024-04-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.15.589676
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: MyD88 signaling by neurons induces chemokines that recruit protective leukocytes to the virus-infected CNS.

Ghita, Luca / Spanier, Julia / Chhatbar, Chintan / Mulenge, Felix / Pavlou, Andreas / Larsen, Pia-Katharina / Waltl, Inken / Lueder, Yvonne / Kohls, Moritz / Jung, Klaus / Best, Sonja M / Förster, Reinhold / Stangel, Martin / Schreiner, Dietmar / Kalinke, Ulrich

Science immunology

2021 Volume 6, Issue 60

Abstract: Viral encephalitis initiates a series of immunological events in the brain that can lead to brain damage and death. Astrocytes express IFN-β in response to neurotropic infection, whereas activated microglia produce proinflammatory cytokines and ... ...

Abstract	Viral encephalitis initiates a series of immunological events in the brain that can lead to brain damage and death. Astrocytes express IFN-β in response to neurotropic infection, whereas activated microglia produce proinflammatory cytokines and accumulate at sites of infection. Here, we observed that neurotropic vesicular stomatitis virus (VSV) infection causes recruitment of leukocytes into the central nervous system (CNS), which requires MyD88, an adaptor of Toll-like receptor and interleukin-1 receptor signaling. Infiltrating leukocytes, and in particular CD8
MeSH term(s)	Adaptor Proteins, Vesicular Transport/genetics ; Adaptor Proteins, Vesicular Transport/metabolism ; Animals ; CD8-Positive T-Lymphocytes/immunology ; Chemokines/metabolism ; Disease Models, Animal ; Encephalitis, Viral/immunology ; Encephalitis, Viral/pathology ; Encephalitis, Viral/virology ; Female ; Humans ; Male ; Mice ; Mice, Knockout ; Myeloid Differentiation Factor 88/genetics ; Myeloid Differentiation Factor 88/metabolism ; Neurons/metabolism ; Olfactory Bulb/cytology ; Olfactory Bulb/immunology ; Olfactory Bulb/pathology ; Olfactory Bulb/virology ; Rhabdoviridae Infections/immunology ; Rhabdoviridae Infections/pathology ; Rhabdoviridae Infections/virology ; Signal Transduction/immunology ; Vesiculovirus/immunology
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Chemokines ; Myd88 protein, mouse ; Myeloid Differentiation Factor 88 ; TICAM-1 protein, mouse
Language	English
Publishing date	2021-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abc9165
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Article ; Online: Sequential MAVS and MyD88/TRIF signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes.

Ghita, Luca / Breitkopf, Veronika / Mulenge, Felix / Pavlou, Andreas / Gern, Olivia Luise / Durán, Verónica / Prajeeth, Chittappen Kandiyil / Kohls, Moritz / Jung, Klaus / Stangel, Martin / Steffen, Imke / Kalinke, Ulrich

Journal of neuroscience research

2021 Volume 99, Issue 10, Page(s) 2478–2492

Abstract: Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is typically transmitted upon tick bite and can cause meningitis and encephalitis in humans. In TBEV-infected mice, mitochondrial antiviral-signaling protein (MAVS), the ... ...

Abstract	Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is typically transmitted upon tick bite and can cause meningitis and encephalitis in humans. In TBEV-infected mice, mitochondrial antiviral-signaling protein (MAVS), the downstream adaptor of retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) signaling, is needed to induce early type I interferon (IFN) responses and to confer protection. To characterize the brain-resident cell subset that produces protective IFN-β in TBEV-infected mice, we isolated neurons, astrocytes, and microglia from mice and exposed these cell types to TBEV in vitro. Under such conditions, neurons showed the highest percentage of infected cells, whereas astrocytes and microglia were infected to a lesser extent. In the supernatant (SN) of infected neurons, IFN-β was not detectable, while infected astrocytes showed high and microglia low IFN-β expression. Transcriptome analyses of astrocytes implied that MAVS signaling was needed early after TBEV infection. Accordingly, MAVS-deficient astrocytes showed enhanced TBEV infection and significantly reduced early IFN-β responses. Nevertheless, at later time points, moderate amounts of IFN-β were detected in the SN of infected MAVS-deficient astrocytes. Transcriptome analyses indicated that MAVS deficiency negatively affected the induction of early anti-viral responses, which resulted in significantly increased TBEV replication. Treatment with MyD88 and TRIF inhibiting peptides reduced only late IFN-β responses of TBEV-infected WT astrocytes and blocked entirely IFN-β responses of infected MAVS-deficient astrocytes. Thus, upon TBEV exposure of brain-resident cells, astrocytes are important IFN-β producers showing biphasic IFN-β induction that initially depends on MAVS and later on MyD88/TRIF signaling.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Adaptor Proteins, Vesicular Transport/metabolism ; Animals ; Astrocytes/metabolism ; Astrocytes/virology ; Encephalitis Viruses, Tick-Borne/metabolism ; Encephalitis, Tick-Borne/metabolism ; Encephalitis, Tick-Borne/prevention & control ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myeloid Differentiation Factor 88/metabolism ; Signal Transduction/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport ; IPS-1 protein, mouse ; Myd88 protein, mouse ; Myeloid Differentiation Factor 88 ; TICAM-1 protein, mouse
Language	English
Publishing date	2021-07-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	195324-2
ISSN	1097-4547 ; 0360-4012
ISSN (online)	1097-4547
ISSN	0360-4012
DOI	10.1002/jnr.24923
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Article ; Online: Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures.

Käufer, Christopher / Chhatbar, Chintan / Bröer, Sonja / Waltl, Inken / Ghita, Luca / Gerhauser, Ingo / Kalinke, Ulrich / Löscher, Wolfgang

Proceedings of the National Academy of Sciences of the United States of America

2018 Volume 115, Issue 38, Page(s) E8929–E8938

Abstract: Viral encephalitis is a major risk factor for the development of seizures, epilepsy, and hippocampal damage with associated cognitive impairment, markedly reducing quality of life in survivors. The mechanisms underlying seizures and hippocampal ... ...

Abstract	Viral encephalitis is a major risk factor for the development of seizures, epilepsy, and hippocampal damage with associated cognitive impairment, markedly reducing quality of life in survivors. The mechanisms underlying seizures and hippocampal neurodegeneration developing during and after viral encephalitis are only incompletely understood, hampering the development of preventive treatments. Recent findings suggest that brain invasion of blood-born monocytes may be critically involved in both seizures and brain damage in response to encephalitis, whereas the relative role of microglia, the brain's resident immune cells, in these processes is not clear. CCR2 and CX3CR1 are two chemokine receptors that regulate the responses of myeloid cells, such as monocytes and microglia, during inflammation. We used
MeSH term(s)	Animals ; CD11b Antigen/immunology ; CD11b Antigen/metabolism ; CX3C Chemokine Receptor 1/genetics ; CX3C Chemokine Receptor 1/immunology ; Disease Models, Animal ; Encephalitis, Viral/immunology ; Encephalitis, Viral/pathology ; Encephalitis, Viral/virology ; Female ; Hippocampus/cytology ; Hippocampus/immunology ; Hippocampus/pathology ; Humans ; Leukocyte Common Antigens/immunology ; Leukocyte Common Antigens/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microglia/cytology ; Microglia/immunology ; Microglia/pathology ; Monocytes/immunology ; Monocytes/pathology ; Neurodegenerative Diseases/immunology ; Neurodegenerative Diseases/pathology ; Neurons/immunology ; Neurons/pathology ; Receptors, CCR2/genetics ; Receptors, CCR2/immunology ; Seizures/immunology ; Seizures/pathology ; Seizures/virology ; Theilovirus/isolation & purification
Chemical Substances	CD11b Antigen ; CX3C Chemokine Receptor 1 ; Ccr2 protein, mouse ; Cx3cr1 protein, mouse ; Receptors, CCR2 ; Leukocyte Common Antigens (EC 3.1.3.48) ; Ptprc protein, mouse (EC 3.1.3.48)
Language	English
Publishing date	2018-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1806754115
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Article ; Online: Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage.

Waltl, Inken / Käufer, Christopher / Gerhauser, Ingo / Chhatbar, Chintan / Ghita, Luca / Kalinke, Ulrich / Löscher, Wolfgang

Brain, behavior, and immunity

2018

Abstract	In the central nervous system (CNS), innate immune surveillance is mainly coordinated by microglia. These CNS resident myeloid cells are assumed to help orchestrate the immune response against infections of the brain. However, their specific role in this process and their interactions with CNS infiltrating immune cells, such as blood-borne monocytes and T cells are only incompletely understood. The recent development of PLX5622, a specific inhibitor of colony-stimulating factor 1 receptor that depletes microglia, allows studying the role of microglia in conditions of brain injury such as viral encephalitis, the most common form of brain infection. Here we used this inhibitor in a model of viral infection-induced epilepsy, in which C57BL/6 mice are infected by a picornavirus (Theiler's murine encephalomyelitis virus) and display seizures and hippocampal damage. Our results show that microglia are required early after infection to limit virus distribution and persistence, most likely by modulating T cell activation. Microglia depletion accelerated the occurrence of seizures, exacerbated hippocampal damage, and led to neurodegeneration in the spinal cord, which is normally not observed in this mouse strain. This study enhances our understanding of the role of microglia in viral encephalitis and adds to the concept of microglia-T cell crosstalk.
Keywords	Hippocampus ; Monocytes ; Neuroinflammation ; Seizures ; Spinal cord ; T cells
Subject code	572
Publishing date	2018-11-01
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage.

Waltl, Inken / Käufer, Christopher / Gerhauser, Ingo / Chhatbar, Chintan / Ghita, Luca / Kalinke, Ulrich / Löscher, Wolfgang

Brain, behavior, and immunity

2018

Abstract	In the central nervous system (CNS), innate immune surveillance is mainly coordinated by microglia. These CNS resident myeloid cells are assumed to help orchestrate the immune response against infections of the brain. However, their specific role in this process and their interactions with CNS infiltrating immune cells, such as blood-borne monocytes and T cells are only incompletely understood. The recent development of PLX5622, a specific inhibitor of colony-stimulating factor 1 receptor that depletes microglia, allows studying the role of microglia in conditions of brain injury such as viral encephalitis, the most common form of brain infection. Here we used this inhibitor in a model of viral infection-induced epilepsy, in which C57BL/6 mice are infected by a picornavirus (Theiler's murine encephalomyelitis virus) and display seizures and hippocampal damage. Our results show that microglia are required early after infection to limit virus distribution and persistence, most likely by modulating T cell activation. Microglia depletion accelerated the occurrence of seizures, exacerbated hippocampal damage, and led to neurodegeneration in the spinal cord, which is normally not observed in this mouse strain. This study enhances our understanding of the role of microglia in viral encephalitis and adds to the concept of microglia-T cell crosstalk.
Keywords	Hippocampus ; Monocytes ; Neuroinflammation ; Seizures ; Spinal cord ; T cells
Subject code	572
Publishing date	2018-11-01
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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