Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

Mott, Kevin R.; Zandian, Mandana; Allen, Sariah J.; Ghiasi, Homayon

doi:10.1128/jvi.02241-13

Cited by 15 publications

(16 citation statements)

References 50 publications

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“…HSV-IL-2 infection of WT mice causes CNS demyelination, whereas infection of mice with parental virus does not ( Dumitrascu et al., 2014 ; Mott et al., 2013 ; Zandian et al., 2009 , 2011a , 2011b ). Based on MS and experimental autoimmune encephalomyelitis (EAE) published studies, we investigated the roles of selected Pdcd1 (PD1), CSF2 (GM-CSF), IL-5, IL-6, IFNgr1, CCL5 (RANTES), CXCL10, Tnfrsf9 (4-1BB/CD137), HIF1α, CSF2rb, Havcr2 (Tim-3), and CTLA4 genes in CNS demyelination in vivo .…”

Section: Resultsmentioning

confidence: 99%

“…(3) Similar to the MS condition, female mice were more susceptible to HSV-IL-2-induced demyelination than were male mice ( Zandian et al., 2009 ). (4) We detected CNS demyelination after delivering IL-2 into the mouse brain using osmotic mini-pumps or by injecting mice with rIL-2 protein, IL-2 DNA, or IL-2 synthetic peptides prior to infection with the WT HSV-1 strains McKrae and KOS ( Mott et al., 2013 ). (5) A single mutation in the IL-2 open reading frame (T27A) completely blocked CNS demyelination in this model ( Mott et al., 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…Mice that were ocularly infected with HSV-IL-2 developed optic neuropathy as determined by changes in visual-evoked cortical potentials (VECPs) ( Zandian et al., 2009 ) and pathologic changes in the ON and CNS ( Osorio et al., 2005 ; Zandian et al., 2009 ), whereas recombinant HSV viruses expressing IL-4, IFN-γ, IL-12p35, IL-12p40, or IL-12p70 did not induce optic neuropathy or CNS pathology ( Ghiasi et al., 2001 , 2002a ). Similarly, delivery of IL-2 into the brains of mice using Alzet osmotic mini-pumps prior to ocular infection with wild-type (WT) HSV-1 produced eye disease and CNS pathology whereas WT HSV-1 alone did not, nor did injection of IL-2 DNA, IL-2 protein, or IL-2 peptides into other mouse strains prior to infection with wt HSV-1 ( Mott et al., 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Type 2 Innate Lymphoid Cells Induce CNS Demyelination in an HSV-IL-2 Mouse Model of Multiple Sclerosis

et al. 2020

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Summary We previously reported that infection of different mouse strains with a recombinant HSV-1 expressing IL-2 (HSV-IL-2) caused CNS demyelination. Histologic examination of infected IL-2rα −/− , IL-2rβ −/− , and IL-2rγ −/− mice showed demyelination in the CNS of IL-2rα −/− and IL-2rβ −/− mice but not in the CNS of IL-2rγ −/− -infected mice. No demyelination was detected in mice infected with control virus. IL-2rγ −/− mice that lack type 2 innate lymphoid cells (ILC2s) and ILCs, play important roles in host defense and inflammation. We next infected ILC1 −/− , ILC2 −/− , and ILC3 −/− mice with HSV-IL-2 or wild-type (WT) HSV-1. In contrast to ILC1 −/− and ILC3 −/− mice, no demyelination was detected in the CNS of ILC2 −/− -sinfected mice. However, transfer of ILC2s from WT mice to ILC2 −/− mice restored demyelination in infected recipient mice. CNS demyelination correlated with downregulation of CCL5 and CXCL10. This study demonstrates that ILC2s contribute to HSV-IL-2-induced CNS demyelination in a mouse model of multiple sclerosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Type 2 Innate Lymphoid Cells Induce CNS Demyelination in an HSV-IL-2 Mouse Model of Multiple Sclerosis

et al. 2020

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“…Furthermore, glutamate recycling via the GLT-1 transporter and the GS enzyme, rather than glutamate synthesis, appears to be the key factor in glutamate homeostasis dysregulation that may lead to the motor dysfunctions and paralytic disease induced in mice following infection with HCoV-OC43. Even though we are aware of the potential limitations of studying a human virus in a mouse model and we are interpreting our results accordingly, we believe that this approach is relevant and important for predicting how a virus could interact with humans, as shown for several other human viruses used in mouse models (82)(83)(84)(85)(86). Our results also strongly suggest that memantine could be used as both a prophylactic and a therapeutic antiviral agent against neuroinvasive and neurotropic human viruses that cause viral encephalitis or meningitis or neurological diseases in which the etiology could involve viruses.…”

Section: Discussionmentioning

confidence: 99%

Novel Treatment with Neuroprotective and Antiviral Properties against a Neuroinvasive Human Respiratory Virus

Brison

Jacomy

Desforges

et al. 2014

J Virol

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Human coronaviruses (HCoVs) are recognized respiratory pathogens with neuroinvasive and neurotropic properties in mice and humans. HCoV strain OC43 (HCoV-OC43) can infect and persist in human neural cells and activate neuroinflammatory and neurodegenerative mechanisms, suggesting that it could be involved in neurological disease of unknown etiology in humans. Moreover, we have shown that HCoV-OC43 is neurovirulent in susceptible mice, causing encephalitis, and that a viral mutant with a single point mutation in the viral surface spike (S) protein induces a paralytic disease that involves glutamate excitotoxicity in susceptible mice. Herein, we show that glutamate recycling via the glial transporter 1 protein transporter and glutamine synthetase are central to the dysregulation of glutamate homeostasis and development of motor dysfunctions and paralytic disease in HCoV-OC43-infected mice. Moreover, memantine, an N-methyl-D-aspartate receptor antagonist widely used in the treatment of neurological diseases in humans, improved clinical scores related to paralytic disease and motor disabilities by partially restoring the physiological neurofilament phosphorylation state in virus-infected mice. Interestingly, memantine attenuated mortality rates and body weight loss and reduced HCoV-OC43 replication in the central nervous system in a dose-dependent manner. This novel action of memantine on viral replication strongly suggests that it could be used as an antiviral agent to directly limit viral replication while improving neurological symptoms in various neurological diseases with a viral involvement. IMPORTANCEMutations in the surface spike (S) protein of human respiratory coronavirus OC43 appear after persistent infection of human cells of the central nervous system, a possible viral adaptation to this environment. Furthermore, a single amino acid change in the viral S protein modulated virus-induced neuropathology in mice from an encephalitis to a neuropathology characterized by flaccid paralysis, which involves glutamate excitotoxicity. We now show that memantine, a drug that is used for alleviating symptoms associated with neuropathology, such as Alzheimer's disease, can partially restore the physiological state of infected mice by limiting both neurodegeneration and viral replication. This suggests that memantine could be used as an antiviral agent while improving neurological symptoms in various neurological diseases with a viral involvement.

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“…Viruses, specifically HSV-1, might not operate as unique causative agents, but rather as risk factors, and indeed genetic susceptibility and the immune system are also crucial in demyelinating pathologies. For instance, when a recombinant HSV-1 constitutively expressing interleukin-2 (IL-2) was inoculated into mice, it provoked CNS demyelination and optic neuropathy, whereas infection with recombinant viruses expressing IL-4, gamma interferon, IL-12p35, IL-12p40, or IL-12p70 did not induce this effect [ 131 ]. On the other hand, donor-dependent differences in resistance to infection with HSV-1 were established in primary cultures of human OLs [ 115 ].…”

Section: Hsv-1 and Demyelinationmentioning

confidence: 99%

The Role of Herpes Simplex Virus Type 1 Infection in Demyelination of the Central Nervous System

Bello-Morales

Andreu

Löpez‐Guerrero

2020

IJMS

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Herpes simplex type 1 (HSV-1) is a neurotropic virus that infects the peripheral and central nervous systems. After primary infection in epithelial cells, HSV-1 spreads retrogradely to the peripheral nervous system (PNS), where it establishes a latent infection in the trigeminal ganglia (TG). The virus can reactivate from the latent state, traveling anterogradely along the axon and replicating in the local surrounding tissue. Occasionally, HSV-1 may spread trans-synaptically from the TG to the brainstem, from where it may disseminate to higher areas of the central nervous system (CNS). It is not completely understood how HSV-1 reaches the CNS, although the most accepted idea is retrograde transport through the trigeminal or olfactory tracts. Once in the CNS, HSV-1 may induce demyelination, either as a direct trigger or as a risk factor, modulating processes such as remyelination, regulation of endogenous retroviruses, or molecular mimicry. In this review, we describe the current knowledge about the involvement of HSV-1 in demyelination, describing the pathways used by this herpesvirus to spread throughout the CNS and discussing the data that suggest its implication in demyelinating processes.

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Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

Cited by 15 publications

References 50 publications

Type 2 Innate Lymphoid Cells Induce CNS Demyelination in an HSV-IL-2 Mouse Model of Multiple Sclerosis

Type 2 Innate Lymphoid Cells Induce CNS Demyelination in an HSV-IL-2 Mouse Model of Multiple Sclerosis

Novel Treatment with Neuroprotective and Antiviral Properties against a Neuroinvasive Human Respiratory Virus

The Role of Herpes Simplex Virus Type 1 Infection in Demyelination of the Central Nervous System

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