Robin R. Johnson

Social stress alters the severity of acute Theiler's virus infection

Our laboratory has previously shown that restraint stress resulted in decreased Theilers virus-induced CNS inflammation, while exacerbating illness behaviors during the acute phase of disease. In contrast, social disruption stress (SDR) applied prior to infection led to the development of glucocorticoid (GC) resistance, and these animals developed more severe disease course, with increased inflammation. However, when SDR was applied concurrent with infection, GC resistance fails to develop, disease course is less severe and inflammation was moderate. These results suggest that the effects of SDR on Theilers virus infection are dependent upon the timing of SDR application in relation to infection.

Interleukin-6 as a mechanism for the adverse effects of social stress on acute Theiler's virus infection

Prior exposure to social disruption stress (SDR) exacerbates both the acute and chronic phase of Theilers 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 Theilers 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 Theilers 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.

Neonatal Maternal Separation Alters Immune, Endocrine, and Behavioral Responses to Acute Theiler’s Virus Infection in Adult Mice

Previous studies have established a link between adverse early life events and subsequent disease vulnerability. The present study assessed the long-term effects of neonatal maternal separation on the response to Theiler’s murine encephalomyelitis virus infection, a model of multiple sclerosis. Balb/cJ mouse pups were separated from their dam for 180-min/day (180-min MS), 15-min/day (15-min MS), or left undisturbed from postnatal days 2–14. During adolescence, mice were infected with Theiler’s virus and sacrificed at days 14, 21, or 35 post-infection. Prolonged 180-min MS increased viral load and delayed viral clearance in the spinal cords of males and females, whereas brief 15-min MS increased the rate of viral clearance in females. The 15-min and 180-min MS mice exhibited blunted corticosterone responses during infection, suggesting that reduced HPA sensitivity may have altered the immune response to infection. These findings demonstrate that early life events alter vulnerability to CNS infection later in life. Therefore, this model could be used to study gene-environment interactions that contribute to individual differences in susceptibility to infectious and autoimmune diseases of the CNS.

Restraint stress decreases virus-induced pro-inflammatory cytokine mRNA expression during acute Theiler's virus infection.

Stressful life events have been associated with the onset and/or exacerbation of multiple sclerosis (MS). Our previous studies have indicated that restraint stress (RS) reduces inflammation and virus-induced chemokine expression in the Theilers virus-induced demyelination (TVID) model of MS. Here we report that RS significantly reduced the virus-induced interferon-gamma mRNA levels in the brain. Additionally, mRNA levels of lymphotoxin-beta, tumor necrosis factor-alpha, and interferon-gamma in the brain were negatively correlated with viral titers in the brain. These results indicated an immunosuppressive effect of stress during early TVID causing impaired viral clearance, which may be a potential exacerbating factor for later demyelination.

Glucocorticoid exposure alters the pathogenesis of Theiler's murine encephalomyelitis virus during acute infection

Previous research has shown that chronic restraint stress exacerbates Theilers 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.

Neonatal experience interacts with adult social stress to alter acute and chronic Theiler’s virus infection

Previous research has shown that neonatal handling has prolonged protective effects associated with stress resilience and aging, yet little is known about its effect on stress-induced modulation of infectious disease. We have previously demonstrated that social disruption stress exacerbates the acute and chronic phases of the disease when applied prior to Theilers virus infection (PRE-SDR) whereas it attenuates disease severity when applied concurrently with infection (CON-SDR). Here, we asked whether neonatal handling would protect adult mice from the detrimental effects of PRE-SDR and attenuate the protective effects of CON-SDR on Theilers virus infection. As expected, handling alone decreased IL-6 and corticosterone levels, protected the non-stressed adult mice from motor impairment throughout infection and reduced antibodies to myelin components (PLP, MBP) during the autoimmune phase of disease. In contrast, neonatal handling X PRE/CON-SDR elevated IL-6 and reduced corticosterone as well as increased motor impairment during the acute phase of the infection. Neonatal handling X PRE/CON-SDR continued to exacerbate motor impairment during the chronic phase, whereas only neonatal handling X PRE-SDR increased in antibodies to PLP, MOG, MBP and TMEV. Together, these results imply that while handling reduced the severity of later Theilers virus infection in non-stressed mice, brief handling may not be protective when paired with later social stress.

Social Conflict Exacerbates an Animal Model of Multiple Sclerosis

A growing body of evidence suggests that social conflict is associated with inflammatory disease onset and exacerbations in multiple sclerosis (MS) patients and in animal models of MS. This review illustrates how animal research can be used to elucidate the biobehavioral mechanisms underlying the adverse health effects of social conflict. The authors review studies indicating that social conflict exacerbates a virally initiated animal model of MS. This research suggests that the deleterious effects of social conflict may be partially mediated by stress-induced increases in pro-inflammatory cytokine levels in the central nervous system. In addition, they provide evidence that the adverse health effects of social conflict can be prevented by blocking the stress-induced increases in cytokine activity. This suggests that interventions designed to prevent or reverse the stress-induced increases in cytokine activity may be able to prevent or reverse some of the negative health effects of social conflict in humans.

The Effects of Restraint Stress on the Neuropathogenesis of Theiler’s Virus-induced Demyelination: A Murine Model for Multiple Sclerosis

Physical and psychosocial stressors have been shown to compromise immune function (Ader et al., 1991; Kielcolt-Glaser and Glaser, 1995). The immune suppressive effects of stress may be more pronounced in individuals that already have limited immune competence, such as infants, individuals with a predisposition to autoimmune disease, and the elderly (Kielcolt-Glaser and Glaser, 1995). An individual’s response to a stressor is manifested in physiological, hormonal, behavioral, and immunological changes. These stress-induced responses are initiated by the hypothalamus and translated into action by the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Products from these two systems (e.g., corticoid hormones and catecholamines) can directly modulate the activity of various immune effector cells (Ader et al., 1991).

Social stress alters the severity of an animal model of multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) and a leading cause of disability among young adults (Anderson et al., 1992; Jacobson et al., 1997; Noonan et al., 2002; Sorpedra and Martin, 2005). Common symptoms include loss of motor control or sensation in the limbs, loss of bowel or bladder control, neuropathic pain, optic neuritis, sexual dysfunction, and cognitive dysfunction. The etiology of MS remains uncertain; however, considerable evidence suggests that environmental factors interact with genetic factors to cause disease (Kurtzke and Hyllested, 1987; Noseworthy et al., 2000; Sospedra and Martin, 2005). Suspected environmental factors include viral infection and stress.

#62 Possible role for IL-6 in social stress exacerbations of acute Theiler’s virus infection

Background. Rubella virus is a small positive-sense, single-stranded RNA virus that is the sole member of the Rubivirus genus of the Togavirus family. Rubella virus is an important human pathogen that causes a generally benign systemic infection known as Rubella, German measles, or 3-day measles. Rubella virus can act as a teratogen, inducing congenital Rubella syndrome when spread from mother to fetus in the first trimester of pregnancy. Aims and objectives. (1) Determination of Rubella IgG and IgM levels in the serum of infants suspected of having Rubella infection. (2) To evaluate the number of confirmed cases of Rubella registered during 1-year period (January to December 2004) in the Department of Immunology at the Children s Hospital and Institute of Child Health, Lahore. (3) To study the common clinical presentations in children with suspicion of Rubella infection. (4) To assess the complications associated with rubella infection in infants. Setting: research work was conducted in Immunology Department of the Children s Hospital, Lahore. Period: one-year design of study: Prospective, descriptive study. Experimental design. (1) Data collection: For data collection a pro forma was developed. While taking clinical history, following parameters were taken into consideration: General: small for gestational age (SGA), prematurity, failure to thrive. Vital Signs: hypothermia/ hyperthermia, apnea and tachypnea. Skin: petechiae, purpura, pallor, jaundice, and maculopapular rash. Head: microcephaly, large fontanelle, and hydrocephalus. Eyes: chorioretinitis, cataracts, glaucoma, and microphthalmia. Chest: pneumonia. Cardiovascular: structural defects causing murmurs and congestive heart failure. Abdomen: hepatosplenomegaly. CNS: hypotonia/hypertonia, seizures, and microcephaly. (2) Materials and methods: enzyme linked immunosorbent assay (ELISA) was performed to detect Rubella specific IgG and IgM antibodies. Results. The study includes a total of 100 infants suspected of having Rubella infection, who reported to the Department of Immunology in the Children s Hospital Lahore, from January 2004 to December 2004. Serum samples of these infants were tested for Rubella specific IgM and IgG antibodies by ELISA technique. Of the total 100 infants, 63 (63%) were totally negative for Rubella antibodies, 3 (3%) were found to be positive for IgG and IgM antibodies to Rubella virus while 34 (34%) were found to be positive for IgG antibodies only. Rubella IgG positive patients were further categorized on the basis of their age, as follows: 33 (97%) infants were of less than 6 months and only 1 (3%) infant was of more than 6 months. Detection of Rubella specific IgG by ELISA forms the basis of seroprevalence of Rubella IgG antibodies but the test does not discriminate between maternally induced immunity and the infection acquired during early gestation. The common clinical presentations in Rubella positive patients (n = 3) were failure to thrive (100%), cataract (67%), Patent Ductus Arteriosus (67%), microcephaly (67%), intracranial calcification (33%), Buphthalamus (33%), and hepatosplenomegaly (67%). Conclusion. Out of 100 infants, only three children met the definition for confirmed Rubella. Ninety-seven other children had clinical presentation that met the definition for a probable case but when they were tested for Rubella IgM antibodies, the tests were negative. Thirty-four (34%) patients were found to be positive for Rubella IgG antibody. IgG antibody is passed transplacentally from mother to fetus, the titer of virus-specific IgG antibodies in the serum of a neonate or the mother after birth does not prove current active infection. Only when IgG antiviral antibodies persist beyond 4–6 months of age in an infant, one can assume active infection. In the present study, out of 34 patients positive for Rubella IgG, 33 (97%) were less than 6 months of age, therefore as a single sample was tested it cannot be ascertained if it was because of active infection.