Interferon regulatory factor 7 modulates virus clearance and immune responses to alphavirus encephalomyelitis.

IMPORTANCE: Viral encephalomyelitis outcome is dependent on host responses to neuronal infection. Interferon (IFN) is an important component of the innate response, and IFN regulatory factor (IRF) 7 is an inducible transcription factor for the synthesis of IFN-α. IRF7-deficient mice develop fatal paralysis after CNS infection with Sindbis virus, while wild-type mice recover. Irf7 -/- mice produce low levels of IFN-α but high levels of IFN-ß with induction of IFN-stimulated genes, so the reason for this difference is not understood. The current study shows that Irf7 -/- mice developed inflammation earlier but failed to clear virus from motor neuron-rich regions of the brainstem and spinal cord. Levels of IFN-γ and virus-specific antibody were comparable, indicating that IRF7 deficiency does not impair expression of these known viral clearance factors. Therefore, IRF7 is either necessary for the neuronal response to currently identified mediators of clearance or enables the production of additional antiviral factor(s) needed for clearance.

Zika Virus Infection in the Developing Mouse Produces Dramatically Different Neuropathology Dependent on Viral Strain.

Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome (CZS). Here we detail how ZIKV infection produces extensive neuropathology in the developing mouse brain and spinal cord of both sexes. Surprisingly, neuropathology differs depending on viral strain with a French Polynesian isolate producing primarily excitotoxicity and a Brazilian isolate being almost exclusively apoptotic but occurring over a prolonged period that is more likely to produce severe hypoplasia. We also show exposure can produce a characteristic pattern of infection that mirrors neuropathology and ultimately results in gross morphological deformities strikingly similar to CZS. This research provides a valuable mouse model mirroring the clinical course of disease that can be used to test potential therapies to improve treatment and gain a better understanding of the disabilities associated with CZS.SIGNIFICANCE STATEMENT Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome. Despite its devastating effects, very little is known about how ZIKV infection produces fetal neuropathology. Here we detail the temporal progression of ZIKV infection in the mouse brain and spinal cord resulting in massive neurodegeneration of infected regions. We also report a ZIKV strain from a region of Brazil with high levels of microcephaly (abnormally small head circumference) produces particularly devastating neuropathology.

Erythropoietin as candidate for supportive treatment of severe COVID-19.

In light of the present therapeutic situation in COVID-19, any measure to improve course and outcome of seriously affected individuals is of utmost importance. We recap here evidence that supports the use of human recombinant erythropoietin (EPO) for ameliorating course and outcome of seriously ill COVID-19 patients. This brief expert review grounds on available subject-relevant literature searched until May 14, 2020, including Medline, Google Scholar, and preprint servers. We delineate in brief sections, each introduced by a summary of respective COVID-19 references, how EPO may target a number of the gravest sequelae of these patients. EPO is expected to: (1) improve respiration at several levels including lung, brainstem, spinal cord and respiratory muscles; (2) counteract overshooting inflammation caused by cytokine storm/ inflammasome; (3) act neuroprotective and neuroregenerative in brain and peripheral nervous system. Based on this accumulating experimental and clinical evidence, we finally provide the research design for a double-blind placebo-controlled randomized clinical trial including severely affected patients, which is planned to start shortly.

Analysis of ALS-related proteins during herpes simplex virus-2 latent infection.

BACKGROUND: Genetics have provided hints on potential molecular pathways involved in neurodegenerative diseases (NDD). However, the number of cases caused exclusively by genetic alterations is low, suggesting an important contribution of environmental factors to NDDs. Among these factors, viruses like herpes simplex viruses (HSV-2), capable of establishing lifelong infections within the nervous system (NS), are being proposed to have a role in NDDs. Despite promising data, there is a significant lack of knowledge on this and an urgent need for more research. METHODS: We have set up a mouse model to study HSV latency and its associated neuroinflammation in the spinal cord. The goal of this model was to observe neuroinflammatory changes caused by HSV latent infections, and if those changes were similar to alterations observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients. RESULTS: In infected spinal cords, we have observed a strong leukocyte infiltration and a severe alteration of microglia close to motor neurons. We have also analyzed ALS-related proteins: we have not found changes in TDP-43 and Fus in neurons, but interestingly, we have found decreased protein levels of C9orf72, of which coding gene is severely altered in some familial forms of ALS and is critical for microglia homeostasis. CONCLUSIONS: Latent infection of HSV in the spinal cord showed altered microglia and leukocyte infiltration. These inflammatory features resembled to those observed in the spinal cord of ALS patients. No changes mimicking ALS neuropathology, such as TDP-43 cytoplasmic inclusions, were found in infected spinal cords, but a decrease in protein levels of C9orf72 was observed. Then, further studies should be required to determine whether HSV-2 has a role in ALS.

Progressive multifocal leukoencephalopathy in an HIV patient was diagnosed by 3 times lumbar punctures and 2 times brain biopsies.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by JC virus (JCV) and is difficult to diagnose. We report on a male HIV-positive patient with PML finally diagnosed by 3 times lumbar punctures and 2 times brain biopsies. Negative results of JCV-PCR in cerebrospinal fluid (CSF) do not rule out the diagnosis of PML when clinical manifestations and neuroimaging features suspected PML. It is necessary to obtain new CSF and make repeat tests and even perform brain biopsy.

Human T-lymphotropic virus type 1 (HTLV-1) and cellular immune response in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is an inflammatory disease of the spinal cord and clinically characterized by progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. The interaction between the host immune response and HTLV-1-infected cells regulates the development of HAM/TSP. HTLV-1 preferentially infects CD4+ T cells and is maintained by proliferation of the infected T cells. HTLV-1-infected cells rarely express viral antigens in vivo; however, they easily express the antigens after short-term culture. Therefore, such virus-expressing cells may lead to activation and expansion of antigen-specific T cell responses. Infected T cells with HTLV-1 and HTLV-1-specific CD8+ cytotoxic T lymphocytes invade the central nervous system and produce various proinflammatory cytokines and chemokines, leading to neuronal damage and degeneration. Therefore, cellular immune responses to HTLV-1 have been considered to play important roles in disease development of HAM/TSP. Recent studies have clarified the viral strategy for persistence in the host through genetic and epigenetic changes by HTLV-1 and host immune responses including T cell function and differentiation. Newly developed animal models could provide the opportunity to uncover the precise pathogenesis and development of clinically effective treatment. Several molecular target drugs are undergoing clinical trials with promising efficacy. In this review, we summarize recent advances in the immunopathogenesis of HAM/TSP and discuss the perspectives of the research on this disease.

The Role of the Spinal Wnt Signaling Pathway in HIV-Related Neuropathic Pain.

Human immunodeficiency virus (HIV)-related neuropathic pain includes HIV-induced neuropathic pain (HNP) and antiretroviral therapy-induced neuropathic pain (ART-NP). A significant amount of evidence from the past few years has shown that the development of HIV-related neuropathic pain is closely related to the activation of the Wnt signaling pathway in the spinal cord. This review summarizes the function of the spinal Wnt signaling pathway in HIV-induced neuropathic pain, focusing on the role of the spinal Wnt signaling pathway in HNP, and provides a theoretical basis for further studies and the exploration of new target drugs.

A mouse model of paralytic myelitis caused by enterovirus D68.

In 2014, the United States experienced an epidemic of acute flaccid myelitis (AFM) cases in children coincident with a nationwide outbreak of enterovirus D68 (EV-D68) respiratory disease. Up to half of the 2014 AFM patients had EV-D68 RNA detected by RT-PCR in their respiratory secretions, although EV-D68 was only detected in cerebrospinal fluid (CSF) from one 2014 AFM patient. Given previously described molecular and epidemiologic associations between EV-D68 and AFM, we sought to develop an animal model by screening seven EV-D68 strains for the ability to induce neurological disease in neonatal mice. We found that four EV-D68 strains from the 2014 outbreak (out of five tested) produced a paralytic disease in mice resembling human AFM. The remaining 2014 strain, as well as 1962 prototype EV-D68 strains Fermon and Rhyne, did not produce, or rarely produced, paralysis in mice. In-depth examination of the paralysis caused by a representative 2014 strain, MO/14-18947, revealed infectious virus, virion particles, and viral genome in the spinal cords of paralyzed mice. Paralysis was elicited in mice following intramuscular, intracerebral, intraperitoneal, and intranasal infection, in descending frequency, and was associated with infection and loss of motor neurons in the anterior horns of spinal cord segments corresponding to paralyzed limbs. Virus isolated from spinal cords of infected mice transmitted disease when injected into naïve mice, fulfilling Koch's postulates in this model. Finally, we found that EV-D68 immune sera, but not normal mouse sera, protected mice from development of paralysis and death when administered prior to viral challenge. These studies establish an experimental model to study EV-D68-induced myelitis and to better understand disease pathogenesis and develop potential therapies.

MRI reveals segmental distribution of enterovirus lesions in the central nervous system: a probable clinical evidence of retrograde axonal transport of EV-A71.

Enterovirus 71 (EV-A71) is a major causative agent for hand, foot, and mouth disease (HFMD), especially severe HFMD characterized by neurologic involvement. The objective of this study is to investigate the relationship between the distribution of neurologic infection and the outcomes of severe HFMD. A total of 139 suspected severe HFMD cases (92 were confirmed as EV-A71 infection) underwent clinical and laboratory diagnosis as well as magnetic resonance imaging (MRI) scans of the nervous system. Only those who were confirmed with EV-A71 infection were included in our study. The image data of severe EV-A71-related HFMD cases were retrospectively analyzed, and they were grouped according to lesion site location indicated by MRI. The distribution of lesions in the central nervous system shown by MRI indicated that there were 47 (51%) in brainstem, 33 (36%) in spinal nerve roots lower than T1 thoracic spine, four (5%) in brainstem plus cervical spinal cord involvement, three (3%) in cervical spinal cord, three (3%) in brainstem plus spinal nerve root lower than T1, and two (2%) in cervical and thoracic spinal cord lower than T1. Our analysis strongly substantiates the hypothesis of retrograde axonal transport (RAT) of EV-A71 pathogenesis, suggesting that the pharyngeal branch of the vagus nerve is a major route to the brainstem, and that ascending transportation via the spinal cord does not occur when spinal nerve roots are infected by EV-A71 via RAT. Graphical abstract ᅟ.

Distribution of Viral Antigen and Inflammatory Lesions in the Central Nervous System of Cockatiels ( Nymphicus hollandicus) Experimentally Infected with Parrot Bornavirus 2.

Neurotropism is a striking characteristic of bornaviruses, including parrot bornavirus 2 (PaBV-2). Our study evaluated the distribution of inflammatory foci and viral nucleoprotein (N) antigen in the brain and spinal cord of 27 cockatiels ( Nymphicus hollandicus) following experimental infection with PaBV-2 by injection into the pectoral muscle. Tissue samples were taken at 12 timepoints between 5 and 114 days post-inoculation (dpi). Each experimental group had approximately 3 cockatiels per group and usually 1 negative control. Immunolabeling was first observed within the ventral horns of the thoracic spinal cord at 20 dpi and in the brain (thalamic nuclei and hindbrain) at 25 dpi. Both inflammation and viral antigen were restricted to the central core of the brain until 40 dpi. The virus then spread quickly at 60 dpi to both gray and white matter of all analyzed sections of the central nervous system (CNS). Encephalitis was most severe in the thalamus and hindbrain, while myelitis was most prominent in the gray matter and equally distributed in the cervical, thoracic, and lumbosacral spinal cord. Our results demonstrate a caudal to rostral spread of virus in the CNS following experimental inoculation of PABV-2 into the pectoral muscle, with the presence of viral antigen and inflammatory lesions first in the spinal cord and progressing to the brain.

Comparison of Theiler's Murine Encephalomyelitis Virus Induced Spinal Cord and Peripheral Nerve Lesions Following Intracerebral and Intraspinal Infection.

Hallmarks of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) include spinal cord (SC) inflammation, demyelination and axonal damage occurring approximately 5-8 weeks after classical intracerebral (i.c.) infection. The aim of this study was to elucidate the consequences of intraspinal (i.s.) TMEV infection and a direct comparison of classical i.c. and intraspinal infection. Swiss Jim Lambert (SJL)-mice were i.s. infected with the BeAn strain of TMEV. Clinical investigations including a scoring system and rotarod analysis were performed on a regular basis. Necropsies were performed at 3, 7, 14, 28 and 63 days post infection (dpi) following i.s. and at 4, 7, 14, 28, 56, 98, 147 and 196 dpi following i.c. infection. Serial sections of formalin-fixed, paraffin-embedded SC and peripheral nerves (PN) were investigated using hematoxylin and eosin (HE) and immunohistochemistry. I.s. infected mice developed clinical signs and a deterioration of motor coordination approximately 12 weeks earlier than i.c. infected animals. SC inflammation, demyelination and axonal damage occurred approximately 6 weeks earlier in i.s. infected animals. Interestingly, i.s. infected mice developed PN lesions, characterized by vacuolation, inflammation, demyelination and axonal damage, which was not seen following i.c. infection. The i.s. infection model offers the advantage of a significantly earlier onset of clinical signs, inflammatory and demyelinating SC lesions and additionally enables the investigation of virus-mediated PN lesions.

Longitudinal Extensive Transverse Myelitis in an Immunocompetent Older Individual-A Rare Complication of Varicella-Zoster Virus Reactivation.

Varicella-zoster virus (VZV) is a human neurotropic herpes virus that causes chickenpox in children. After becoming latent in dorsal root ganglia, it can reactivate to cause dermatological manifestations, the most common one being shingles or herpes zoster. Severe neurologic dysfunctions can occur in immunocompromised patients such as encephalitis, meningitis, myelitis and neuropathy. Longitudinal extensive transverse myelitis (LETM) is an unusual neurological complication mainly described in immunocompromised patients, with very few cases described in immunocompetent ones. We hereby report a case of VZV-induced LETM in an immunocompetent older adult-a situation rarely described in the literature. LETM is a rare complication of VZV and its pathogenesis; therapeutic interventions and prognosis are far from being fully clarified. However, a prompt diagnosis is needed to allow a rapid initialization of treatment and ensure a better outcome. Although the therapeutic lines are not clear, immunosuppressive agents may have their place in cases of unsuccessful results and/or relapses following acyclovir coupled with a well conducted methylprednisolone therapy. Further studies are highly needed to improve the current understanding of the disease course and mechanisms, and to optimize therapeutic strategies.

Dynamic changes and molecular analysis of cell death in the spinal cord of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus.

Theiler's murine encephalomyelitis (TME) is caused by the TME virus (TMEV) and represents an important animal model for multiple sclerosis (MS). Oligodendroglial apoptosis and reduced apoptotic elimination of encephalitogenic leukocytes seem to participate in autoimmune demyelination in MS. The present study quantified apoptotic cells in BeAn-TMEV-induced spinal cord white matter lesions at 14, 42, 98, and 196 days post infection (dpi) using immunostaining. Apoptotic cells were identified by transmission electron microscopy and double-immunofluorescence. The mRNA expression of apoptosis-related genes was investigated using microarray analysis. Oligodendroglial apoptosis was already detected in the predemyelinating phase at 14 dpi. Apoptotic cell numbers peaked at 42 dpi and decreased until 196 dpi partly due to reduced T cell apoptosis. In addition to genes involved in the classical pathways of apoptosis induction, microarray analysis detected the expression of genes related to alternative mechanisms of cell death such as pyroptosis, necroptosis, and endoplasmic reticulum stress. Consequently, oligodendroglial apoptosis is involved in the initiation of the TME demyelination process, whereas the development of apoptosis resistance of T cells potentially favors the maintenance of inflammation and myelin loss.

Zika virus-induced acute myelitis and motor deficits in adult interferon αß/γ receptor knockout mice.

Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barrë syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/ß receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. The severity of hindlimb motor deficits correlated with increased numbers of ZIKV-infected lumbosacral spinal motor neurons and decreased numbers of spinal motor neurons. Electrophysiological compound muscle action potential (CMAP) amplitudes in response to stimulation of the lumbosacral spinal cord were reduced when obvious motor deficits were present. ZIKV immunoreactivity was high, intense, and obvious in tissue sections of the brain and spinal cord. Infection in the brain and spinal cord was also associated with astrogliosis as well as T cell and neutrophil infiltration. CMAP and histological analysis indicated that peripheral nerve and muscle functions were intact. Consequently, motor deficits in these circumstances appear to be primarily due to myelitis and possibly encephalitis as opposed to a peripheral neuropathy or a GBS-like syndrome. Thus, acute ZIKV infection of adult AG129 mice may be a useful model for ZIKV-induced myelitis, encephalitis, and seizure activity.

Persistence of SIV in the brain of SIV-infected Chinese rhesus macaques with or without antiretroviral therapy.

Persistence of HIV-1 reservoirs in the central nervous system (CNS) is an obstacle to cure strategies. However, little is known about residual viral distribution, viral replication levels, and genetic diversity in different brain regions of HIV-infected individuals on combination antiretroviral therapy (cART). Because myeloid cells particularly microglia are likely major reservoirs in the brain, and more microglia exist in white matter than gray matter in a human brain, we hypothesized the major viral reservoirs in the brain are the white matter reflected by higher levels of viral DNA. To address the issue, we used the Chinese rhesus macaque (ChRM) model of SIV infection, and treated 11 SIVmac251-infected animals including long-term nonprogressors with cART for up to 24 weeks. SIV reservoirs were assessed by SIV DNA levels in 16 specific regions of the brain and 4 regions of spinal cord. We found relatively high frequencies of SIV in basal ganglia and brain stem compared to other regions. cART-receiving animals had significantly lower SIV DNA levels in the gray matter than white matter. Moreover, a shortened envelope gp120 with 21 nucleotide deletions and guanine-to-adenine hypermutations were observed. These results demonstrate that SIV enters the CNS in SIV-infected ChRM with a major reservoir in the white matter after cART; the SIV/ChRM/cART is an appropriate model for studying HIV CNS reservoirs and testing new eradication strategies. Further, examining multiple regions of the CNS may be needed when assessing whether an agent is successful in reducing the size of SIV reservoirs in the CNS.

Neuronal Vacuolization in Feline Panleukopenia Virus Infection.

Feline panleukopenia virus (FPV) infections are typically associated with anorexia, vomiting, diarrhea, neutropenia, and lymphopenia. In cases of late prenatal or early neonatal infections, cerebellar hypoplasia is reported in kittens. In addition, single cases of encephalitis are described. FPV replication was recently identified in neurons, although it is mainly found in cells with high mitotic activity. A female cat, 2 months old, was submitted to necropsy after it died with neurologic deficits. Besides typical FPV intestinal tract changes, multifocal, randomly distributed intracytoplasmic vacuoles within neurons of the thoracic spinal cord were found histologically. Next-generation sequencing identified FPV-specific sequences within the central nervous system. FPV antigen was detected within central nervous system cells, including the vacuolated neurons, via immunohistochemistry. In situ hybridization confirmed the presence of FPV DNA within the vacuolated neurons. Thus, FPV should be considered a cause for neuronal vacuolization in cats presenting with ataxia.

Outbreaks of Neuroinvasive Astrovirus Associated with Encephalomyelitis, Weakness, and Paralysis among Weaned Pigs, Hungary.

A large, highly prolific swine farm in Hungary had a 2-year history of neurologic disease among newly weaned (25- to 35-day-old) pigs, with clinical signs of posterior paraplegia and a high mortality rate. Affected pigs that were necropsied had encephalomyelitis and neural necrosis. Porcine astrovirus type 3 was identified by reverse transcription PCR and in situ hybridization in brain and spinal cord samples in 6 animals from this farm. Among tissues tested by quantitative RT-PCR, the highest viral loads were detected in brain stem and spinal cord. Similar porcine astrovirus type 3 was also detected in archived brain and spinal cord samples from another 2 geographically distant farms. Viral RNA was predominantly restricted to neurons, particularly in the brain stem, cerebellum (Purkinje cells), and cervical spinal cord. Astrovirus was generally undetectable in feces but present in respiratory samples, indicating a possible respiratory infection. Astrovirus could cause common, neuroinvasive epidemic disease.

Influenza virus infection exacerbates experimental autoimmune encephalomyelitis disease by promoting type I T cells infiltration into central nervous system.

Multiple sclerosis starts with increased migration of auto-reactive lymphocytes across the blood-brain barrier, resulting in persistent neurodegeneration. Clinical and epidemiological studies indicated upper respiratory viral infections are associated with clinical exacerbation of multiple sclerosis. However, so far there is no any direct evidence to support it. Using the experimental autoimmune encephalomyelitis mice as the model for multiple sclerosis, we demonstrated that mice experienced with influenza virus infection were unable to recover from experimental autoimmune encephalomyelitis with a long-term exacerbation. The exacerbated disease was due to more type I T cells, such as CD45highCD4+CD44high, CD45highCD4+CCR5+, CD45high IFNγ+CD4+, MOG35-55-specific IFNγ+CD4+ and influenza virus-specific IFNγ+CD4+ T cells, infiltrating central nervous system in mice with prior influenza virus infection. Influenza virus infection created a notable inflammatory environment in lung and mediastinal lymph node after influenza virus inoculation, suggesting the lung may constitute an inflammatory niche in which auto-aggressive T cells gain the capacity to enter CNS. Indeed, the early stage of EAE disease was accompanied by increased CCR5+CD4+, CXCR3+CD4+ T cell and MOG35-55 specific CD4+ T cells localized in the lung in influenza virus-infected mice. CCL5/CCR5 might mediate the infiltration of type I T cells into CNS during the disease development after influenza infection. Administration of CCR5 antagonist could significantly attenuate the exacerbated disease. Our study provided the evidence that the prior influenza virus infection may promote the type I T cells infiltration into the CNS, and subsequently cause a long-term exacerbation of experimental autoimmune encephalomyelitis.

Phrenic nerve deficits and neurological immunopathology associated with acute West Nile virus infection in mice and hamsters.

Neurological respiratory deficits are serious outcomes of West Nile virus (WNV) disease. WNV patients requiring intubation have a poor prognosis. We previously reported that WNV-infected rodents also appear to have respiratory deficits when assessed by whole-body plethysmography and diaphragmatic electromyography. The purpose of this study was to determine if the nature of the respiratory deficits in WNV-infected rodents is neurological and if deficits are due to a disorder of brainstem respiratory centers, cervical spinal cord (CSC) phrenic motor neuron (PMN) circuitry, or both. We recorded phrenic nerve (PN) activity and found that in WNV-infected mice, PN amplitude is reduced, corroborating a neurological basis for respiratory deficits. These results were associated with a reduction in CSC motor neuron number. We found no dramatic deficits, however, in brainstem-mediated breathing rhythm generation or responses to hypercapnia. PN frequency and pattern parameters were normal, and all PN parameters changed appropriately upon a CO2 challenge. Histological analysis revealed generalized microglia activation, astrocyte reactivity, T cell and neutrophil infiltration, and mild histopathologic lesions in both the brainstem and CSC, but none of these were tightly correlated with PN function. Similar results in PN activity, brainstem function, motor neuron number, and histopathology were seen in WNV-infected hamsters, except that histopathologic lesions were more severe. Taken together, the results suggest that respiratory deficits in acute WNV infection are primarily due to a lower motor neuron disorder affecting PMNs and the PN rather than a brainstem disorder. Future efforts should focus on markers of neuronal dysfunction, axonal degeneration, and myelination.

Demyelinating strain of mouse hepatitis virus infection bridging innate and adaptive immune response in the induction of demyelination.

The presence of immunoglobulin oligoclonal bands in the cerebrospinal fluid of Multiple Sclerosis (MS) patients supports the hypothesis of an infectious etiology, although the antigenic targets remain elusive. Neurotropic mouse hepatitis virus (MHV) infection in mice provides a useful tool for studying mechanisms of demyelination in a virus-induced experimental model of MS. This study uses Affymetrix microarray analysis to compare differential spinal cord mRNA levels between mice infected with demyelinating and non-demyelinating strains of MHV to identify host immune genes expressed in this demyelinating disease model. The study reveals that during the acute stage of infection, both strains induce inflammatory innate immune response genes, whereas upregulation of several immunoglobulin genes during chronic stage infection is unique to infection with the demyelinating strain. Results suggest that the demyelinating strain induced an innate-immune response during acute infection that may promote switching of Ig isotype genes during chronic infection, potentially playing a role in antibody-mediated progressive demyelination even after viral clearance.