ABSTRACT
Prior exposure to social disruption (SDR) stress exacerbates Theiler's murine encephalomyelitis virus (TMEV) infection, a model of multiple sclerosis. Here we examined the impact of SDR on T cell responses to TMEV infection in SJL mice. SDR impaired viral clearance and exacerbated acute disease. Moreover, TMEV infection alone increased CD4 and CD8 mRNA expression in brain and spleen while SDR impaired this response. SDR decreased both CD4(+) and CD8(+) virus-specific T cells in CNS, but not spleen. These findings suggest that SDR-induced suppression of virus-specific T cell responses contributes to impairments in viral clearance and exacerbation of acute disease.
Subject(s)
Adaptive Immunity/physiology , Cardiovirus Infections/immunology , Cardiovirus Infections/physiopathology , Poliomyelitis/immunology , Poliomyelitis/physiopathology , Stress, Psychological/physiopathology , Acute Disease , Animals , Brain/immunology , Brain/metabolism , Brain/virology , CD4 Antigens/genetics , CD4 Antigens/metabolism , CD4-Positive T-Lymphocytes/pathology , CD8 Antigens/genetics , CD8 Antigens/metabolism , CD8-Positive T-Lymphocytes/pathology , Disease Models, Animal , Gene Expression Regulation, Viral/physiology , Male , Mice , Mice, Inbred Strains , RNA, Messenger/metabolism , Spleen/immunology , Spleen/metabolism , Spleen/virology , Stress, Psychological/immunology , Theilovirus/pathogenicityABSTRACT
Theiler's murine encephalomyelitis virus (TMEV) infection is a well-characterized model of multiple sclerosis (MS). Previous research has shown that chronic restraint stress (RS) during early TMEV infection exacerbates behavioral signs of the disease. The present data suggest that RS-induced increases in CNS inflammation, demyelination, and axonal degeneration may underlie this exacerbation. In addition, we report that males exhibit greater CNS inflammation and higher numbers of demyelinating lesions while females show greater susceptibility to RS-induced exacerbation. These findings indicate that RS during early TMEV infection increases CNS lesion formation during the late phase and suggest that the effects of RS are sex-dependent.
Subject(s)
Cardiovirus Infections/immunology , Central Nervous System/immunology , Demyelinating Autoimmune Diseases, CNS/immunology , Encephalomyelitis/immunology , Stress, Psychological/immunology , Theilovirus/immunology , Animals , Axons/immunology , Axons/pathology , Axons/virology , Cardiovirus Infections/physiopathology , Central Nervous System/pathology , Central Nervous System/virology , Chronic Disease , Demyelinating Autoimmune Diseases, CNS/physiopathology , Demyelinating Autoimmune Diseases, CNS/virology , Disease Models, Animal , Disease Progression , Encephalomyelitis/physiopathology , Encephalomyelitis/virology , Female , Male , Mice , Nerve Fibers, Myelinated/immunology , Nerve Fibers, Myelinated/pathology , Nerve Fibers, Myelinated/virology , Restraint, Physical/adverse effects , Restraint, Physical/psychology , Severity of Illness Index , Sex Characteristics , Stress, Psychological/physiopathology , Wallerian Degeneration/immunology , Wallerian Degeneration/pathology , Wallerian Degeneration/virologyABSTRACT
OBJECTIVES: Multiple sclerosis is a degenerative disease of the CNS with a pathology consistent with immunological mediation. Although its cause is unknown, multiple factors are thought to influence both the onset and exacerbation of the disease, including both genetic background as well as environmental factors. METHODS: We are interested in the effect of psychological stress on the onset and exacerbation of Theiler's virus-induced demyelinating disease (TVID), a murine model of MS in which viral persistence facilitates demyelination. In the current study, we determined whether chronic restraint stress (RS)-induced immunosuppression could result in the establishment of a persistent CNS infection in the normally TVID-resistant C57BL/6 mouse strain, resulting in demyelination. RESULTS: Our data indicated that RS repeated over the course of 7 days was not sufficient to cause decreases in virus-specific adaptive immunity, and did not significantly alter CNS viral levels. Furthermore, chronic repeated RS lasting until 4 weeks after infection altered neither the development of virus-specific IgG nor motor function determined by Rotarod analysis. In addition, histological analysis of the CNS of stressed mice indicated no inflammation or demyelination on day 193 after infection. CONCLUSION: These results suggest that stress alone is not sufficient to overcome genetic resistance to TVID in the C57BL/6 mouse strain.
Subject(s)
Cardiovirus Infections/immunology , Demyelinating Autoimmune Diseases, CNS/immunology , Disease Susceptibility/immunology , Immune Tolerance/immunology , Stress, Psychological/immunology , Theilovirus/immunology , Adaptive Immunity/immunology , Animals , Cardiovirus Infections/psychology , Central Nervous System/immunology , Central Nervous System/pathology , Central Nervous System/virology , Demyelinating Autoimmune Diseases, CNS/physiopathology , Demyelinating Autoimmune Diseases, CNS/psychology , Disease Models, Animal , Disease Susceptibility/psychology , Female , Genetic Predisposition to Disease/genetics , Immune Tolerance/genetics , Mice , Mice, Inbred C57BL , Movement Disorders/immunology , Movement Disorders/physiopathology , Nerve Fibers, Myelinated/immunology , Nerve Fibers, Myelinated/pathology , Nerve Fibers, Myelinated/virology , Neurons/immunology , Neurons/pathology , Neurons/virology , Restraint, Physical/adverse effects , Restraint, Physical/psychology , Viral Load/immunologyABSTRACT
Multiple sclerosis (MS) is a devastating CNS disease of unknown origin. Multiple factors including genetic background, infection, and psychological stress affect the onset or progression of MS. Theiler's murine encephalomyelitis virus (TMEV) infection is an animal model of MS in which aberrant immunity leads to viral persistence and subsequently results in demyelination that resembles MS. Here, we examined how stress during acute TMEV infection altered virus-specific cell mediated responses. Using immunodominant viral peptides specific for either CD4(+) or CD8(+) T cells, we found that stress reduced IFN-gamma producing virus-specific CD4(+) and CD8(+) T cells in the spleen and CD8(+) T cells CNS. Cytokine production by cells isolated from the CNS or spleens following stimulation with virus or viral peptides, indicated that stress decreased both type 1 and type 2 responses. Glucocorticoids were implicated in the decreased T cell function as the effects of stress were partially reversed by concurrent RU486 administration but mimicked by dexamethasone. As T cells mediate viral clearance in this model, our data support the hypothesis that stress-induced immunosuppression may provide a mechanism for enhanced viral persistence within the CNS.
Subject(s)
Cardiovirus Infections/immunology , Cardiovirus Infections/psychology , Immunity, Cellular/physiology , Stress, Psychological/immunology , Stress, Psychological/psychology , Theilovirus/immunology , Acute Disease , Animals , Blotting, Western , Body Weight/physiology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cytokines/metabolism , Female , Flow Cytometry , GATA3 Transcription Factor/immunology , Immune Tolerance/immunology , Immune Tolerance/physiology , Mice , Restraint, Physical , Reverse Transcriptase Polymerase Chain Reaction , Th1 Cells/metabolism , Th2 Cells/immunology , Theilovirus/isolation & purification , Viral Plaque AssayABSTRACT
Previous research has shown that chronic restraint stress exacerbates Theiler's virus infection, a murine model for CNS inflammation and multiple sclerosis. The current set of experiments was designed to evaluate the potential role of glucocorticoids in the deleterious effects of restraint stress on acute CNS inflammatory disease. Exposure to chronic restraint stress resulted in elevated levels of corticosterone as well as increased clinical scores and weight loss (Experiment 1). In addition, corticosterone administration alone exacerbated behavioral signs of TMEV-induced sickness (i.e. decreased body weight, increased symptoms of encephalitis, and increased mortality) and reduced inflammation in the CNS (Experiment 2). Infected subjects receiving exogenous corticosterone showed exacerbation of acute phase measures of sickness and severe mortality as well as decreased viral clearance from CNS (Experiment 3). These findings indicate that corticosterone exposure alone is sufficient to exacerbate acute CNS inflammatory disease.
Subject(s)
Cardiovirus Infections/etiology , Cardiovirus Infections/physiopathology , Glucocorticoids/administration & dosage , Theilovirus/pathogenicity , Animals , Body Weight/drug effects , Body Weight/physiology , Cardiovirus Infections/metabolism , Cardiovirus Infections/mortality , Central Nervous System/drug effects , Central Nervous System/pathology , Central Nervous System/virology , Glucocorticoids/metabolism , Male , Meningitis/etiology , Meningitis/pathology , Meningitis/virology , Mice , Mice, Inbred CBA , Mortality , Severity of Illness Index , Stress, Psychological/physiopathology , Survival AnalysisABSTRACT
Prior exposure to social disruption stress (SDR) exacerbates both the acute and chronic phase of Theiler's murine encephalomyelitis virus infection (TMEV; [Johnson, R.R., Storts, R., Welsh, T.H., Jr., Welsh, C.J., Meagher, M.W., 2004. Social stress alters the severity of acute Theiler's virus infection. J. Neuroimmunol. 148, 74--85; Johnson, R.R., Prentice, T.W., Bridegam, P., Young, C.R., Steelman, A.J., Welsh, T.H., Welsh, C.J.R., Meagher, M.W., 2006. Social stress alters the severity and onset of the chronic phase of Theiler's virus infection. J. Neuroimmunol. 175, 39--51]). However, the neuroimmune mechanism(s) mediating this effect have not been determined. The present study examined whether stress-induced increases in the proinflammatory cytokine interleukin-6 (IL-6) contributes to the adverse effects of SDR on acute TMEV infection. Experiment 1 demonstrated that SDR increases central and peripheral levels of IL-6 and that this effect is reversed by intracerebral ventricular infusion of neutralizing antibody to IL-6 prior to each of six SDR sessions. Although SDR reduced the sensitivity of spleen cells to the anti-inflammatory effects of corticosterone, the neutralizing antibody to IL-6 did not alter this effect. To investigate whether stress-induced increases in IL-6 contribute to the exacerbation of acute TMEV infection, Experiment 2 examined whether intracerebral administration of neutralizing antibody to IL-6 during SDR would prevent the subsequent exacerbation of acute TMEV infection. Experiment 3 then replaced the social stress with intracerebral infusion of IL-6 to assess sufficiency. As expected, prior exposure to SDR subsequently increased infection-related sickness behaviors, motor impairment, CNS viral titers, and CNS inflammation. These deleterious effects of SDR were either prevented or significantly attenuated by intracerebral infusion of neutralizing antibody to IL-6 during the stress exposure period. However, infusion of IL-6 alone did not mimic the adverse effects of SDR. We conclude that IL-6 is necessary but not sufficient to exacerbate acute TMEV infection.
Subject(s)
Cardiovirus Infections/immunology , Interleukin-6/immunology , Stress, Psychological/immunology , Theilovirus/immunology , Analysis of Variance , Animals , Brain/immunology , Brain/virology , Cardiovirus Infections/complications , Disease Models, Animal , Exploratory Behavior/physiology , Glucocorticoids/blood , Interleukin-6/blood , Male , Mice , Mice, Inbred BALB C , Motor Activity/immunology , Multiple Sclerosis/immunology , Multiple Sclerosis/psychology , Neuroimmunomodulation , Sick Role , Social Environment , Spinal Cord/immunology , Spinal Cord/virology , Spleen/cytology , Spleen/metabolism , Stress, Psychological/complications , Stress, Psychological/virologyABSTRACT
Theiler's murine encephalomyelitis virus (TMEV), a Picornavirus used as a viral model for multiple sclerosis (MS), causes an acute encephalomyelitis and chronic demyelination. The failure to clear the virus, which can result from stress, is a prerequisite for development of the later disease. Similarly, stressful life events have been associated with the development of MS. In the present study, a restraint stress (RS) model was used to investigate the effect of stress on the systemic dissemination of TMEV during the early stage of disease. Experimental data demonstrated that repeated RS remarkably facilitated the spread of virus from the CNS to such systemic organs as the spleen, lymph nodes, thymus, lungs and heart and compromised the ability of viral clearance within those tissues. RS also altered the pathogenecity of TMEV, enabling it to become cardiotropic, resulting in higher myocardial infectivity. These results demonstrate the profound impact that RS has upon both the tissue and organ dissemination of the virus, and the organ tropism of TMEV. An additional finding associated with stress was hepatic necrosis in the restrained animals, regardless of whether or not they were infected.
Subject(s)
Cardiovirus Infections/virology , Central Nervous System Diseases/virology , Stress, Physiological/virology , Theilovirus/pathogenicity , Animals , Brain/immunology , Brain/virology , Cardiovirus Infections/immunology , Central Nervous System Diseases/immunology , Disease Models, Animal , Heart/virology , Histocytochemistry , Lymphoid Tissue/immunology , Lymphoid Tissue/virology , Male , Mice , Mice, Inbred CBA , Muscle, Skeletal/immunology , Muscle, Skeletal/virology , Restraint, Physical , Specific Pathogen-Free Organisms , Spinal Cord/immunology , Spinal Cord/virology , Stress, Physiological/etiology , Stress, Physiological/immunology , Theilovirus/growth & development , Virus Replication/immunologyABSTRACT
Chronic restraint stress, administered during early infection with Theiler's virus, was found to exacerbate the acute CNS viral infection in male and female mice. During the subsequent demyelinating phase of disease (a model of multiple sclerosis), the effect of stress on disease progression was sex-dependent. Previously stressed male mice had less severe behavioral signs of the chronic phase, better rotarod performance and decreased inflammatory lesions of the spinal cord, while the opposite pattern was observed in females. In addition, mice in all groups developed autoantibodies to MBP, PLP139-151 and MOG33-55.
Subject(s)
Cardiovirus Infections/immunology , Demyelinating Autoimmune Diseases, CNS/immunology , Immune Tolerance/immunology , Stress, Psychological/complications , Stress, Psychological/immunology , Acute Disease , Animals , Autoantibodies/immunology , Behavior, Animal/physiology , Cardiovirus Infections/physiopathology , Chronic Disease , Demyelinating Autoimmune Diseases, CNS/physiopathology , Demyelinating Autoimmune Diseases, CNS/virology , Disease Models, Animal , Female , Male , Mice , Mice, Inbred CBA , Multiple Sclerosis/immunology , Multiple Sclerosis/physiopathology , Multiple Sclerosis/virology , Myelin Proteins/immunology , Nerve Fibers, Myelinated/immunology , Nerve Fibers, Myelinated/pathology , Restraint, Physical , Sex Factors , Spinal Cord/immunology , Spinal Cord/pathology , Spinal Cord/physiopathology , Stress, Psychological/physiopathology , Theilovirus/immunology , Time FactorsABSTRACT
Social stress alters the acute phase of Theiler's virus infection (TMEV), a model of multiple sclerosis. Stress applied prior to infection had deleterious disease outcomes, while stress applied concurrent with infection was protective. The current study examined multiple behavioral (motor impairment, open field activity) and immunological measures (IL-6, antibodies to virus and myelin proteins) in both the acute and chronic phases of TMEV. It was found that stress applied prior to infection exacerbated disease outcomes, while concurrent application was protective in both disease phases.
Subject(s)
Cardiovirus Infections/psychology , Multiple Sclerosis/psychology , Severity of Illness Index , Social Behavior , Stress, Psychological/diagnosis , Theilovirus , Acute Disease , Animals , Behavior, Animal , Cardiovirus Infections/diagnosis , Cardiovirus Infections/immunology , Chronic Disease , Male , Mice , Mice, Inbred BALB C , Multiple Sclerosis/diagnosis , Multiple Sclerosis/immunology , Multiple Sclerosis/virology , Stress, Psychological/immunology , Stress, Psychological/psychology , Stress, Psychological/virology , Theilovirus/immunologyABSTRACT
Chronic restraint stress, administered during early infection with Theiler's virus, was found to exacerbate the acute central nervous system (CNS) viral infection and the subsequent demyelinating phase of disease (an animal model of Multiple Sclerosis (MS)) in SJL male and female mice. During early infection, stressed mice displayed decreased body weights and spontaneous activity; while increased behavioral signs of illness and plasma corticosterone (CORT) levels. During the subsequent chronic demyelinating phase of disease, previously stressed mice had greater behavioral signs of the chronic phase, worsened rotarod performance, and increased inflammatory lesions of the spinal cord. In addition, mice developed autoantibodies to myelin basic protein (MBP), proteolipid protein peptide (PLP139-151), and myelin oligodendrocyte glycoprotein peptide (MOG33-55).
Subject(s)
Demyelinating Autoimmune Diseases, CNS/psychology , Disease Susceptibility/immunology , Immune Tolerance/immunology , Multiple Sclerosis/psychology , Stress, Psychological/immunology , Theilovirus/immunology , Animals , Autoantibodies/immunology , Behavior, Animal/physiology , Body Weight/immunology , Chronic Disease , Corticosterone/blood , Demyelinating Autoimmune Diseases, CNS/immunology , Demyelinating Autoimmune Diseases, CNS/virology , Disease Models, Animal , Eating/immunology , Eating/psychology , Female , Male , Mice , Motor Activity/immunology , Multiple Sclerosis/immunology , Multiple Sclerosis/virology , Myelin Proteins/immunology , Myelitis/immunology , Myelitis/psychology , Myelitis/virology , Restraint, Physical , Stress, Psychological/complications , Stress, Psychological/physiopathologyABSTRACT
Mutations in the Drosophila trol gene cause cell cycle arrest of neuroblasts in the larval brain. Here, we show that trol encodes the Drosophila homolog of Perlecan and regulates neuroblast division by modulating both FGF and Hh signaling. Addition of human FGF-2 to trol mutant brains in culture rescues the trol proliferation phenotype, while addition of a MAPK inhibitor causes cell cycle arrest of the regulated neuroblasts in wildtype brains. Like FGF, Hh activates stem cell division in the larval brain in a Trol-dependent fashion. Coimmunoprecipitation studies are consistent with interactions between Trol and Hh and between mammalian Perlecan and Shh that are not competed with heparin sulfate. Finally, analyses of mutations in trol, hh, and ttv suggest that Trol affects Hh movement. These results indicate that Trol can mediate signaling through both of the FGF and Hedgehog pathways to control the onset of stem cell proliferation in the developing nervous system.