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At least 145 records · Page 8Linked to original sources
PubMed2005

Effects of the major histocompatibility complex loci and T-cell receptor beta-chain repertoire on Theiler's virus-induced demyelinating disease.

We have investigated the potential effects of H-2 and T-cell receptor (TCR) V beta family genes on induction of T-cell immunity and susceptibility to virally induced demyelinating disease by using BALB.S (H-2K(s)A(s)D(s)) and BALB.S 3 R (H-2K(s)A(s)D(d)/L(d)) mice. These parameters were compared with those of highly susceptible SJL/J (H-2K(s)A(s)D(s)) mice that contain only one-half of TCR V beta family genes compared with the above-mentioned strains. Our results demonstrate that BALB.S but not BALB.S 3 R mice are susceptible similar to SJL/J mice. Although the level of CD4(+) T-cell infiltration to the CNS was elevated in susceptible mice, virus-specific immune responses restricted with H-2(s) were similar in these mice. No preferential use of V beta families associated with differences in the major histocompatibility complex (MHC) components was apparent. However, the pattern and sequence of CDR 3 distribution shows T-cell clonal accumulation in the CNS associated with the H-2 components. Further anti-CD8 antibody treatment of resistant BALB.S 3 R mice abrogated resistance to demyelinating disease, indicating that CD8(+) T cells restricted with H-2D(d)/L(d) are most likely to exert resistance in BALB.S 3 R mice. These studies indicated that TCR V beta and MHC class II genes are the secondary to a particular MHC class I gene expression in susceptibility to virally induced demyelinating disease.

Animals↗
PubMed2001

The effects of restraint stress on the neuropathogenesis of Theiler's virus infection: I. Acute disease.

Restraint stress was found to have a profound effect on the acute phase of Theiler's virus infection. Increased mortality rates were observed in restrained CBA mice infected with the BeAn strain of Theiler's virus. In addition, restrained mice developed higher CNS viral titers than infected/nonrestrained mice. Thymic atrophy was observed in both infected and uninfected restrained mice. Decreased microgliosis, perivascular cuffing, and astrocytosis were observed in restrained mice compared to nonrestrained infected mice at 7 days postinfection. Restraint-stressed mice also developed decreased numbers of lymphocytes and increased numbers of neutrophils in the blood. The mechanism proposed for these alterations involves stress-induced corticosterone, which causes immunosuppression, decreased trafficking of inflammatory cells in the CNS, and, consequently, increased viral replication.

Acute Disease↗
PubMed1999

Expression and potential role of inducible nitric oxide synthase in the central nervous system of Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Intracerebral inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. We examined the pathogenic roles of nitric oxide (NO) and inducible NO synthase (iNOS) in TMEV-induced demyelinating disease (TMEV-IDD). The presence of iNOS was confirmed in the spinal cords of TMEV-infected mice using immunohistochemical staining with anti-iNOS antibody on day 0 (control) and days 15, 30, 60, and 120. Aminoguanidine (AG), a specific inhibitor of iNOS, was injected intraperitoneally (ip) on 1, 3, 5, 8, 10, and 12 days post-TMEV inoculation as induction phase or 15, 17, 19, 22, 24, and 26 days as effector phase. Control animals in each experiment received phosphate-buffered saline (PBS) ip at similar time intervals. Few iNOS-positive cells were observed in the spinal cords of naive SJL/J mice. In the early phase (day 15) of TMEV-IDD, an increase of iNOS-positive cells was detected in the leptomeninges and perivascular space of the spinal cords. The number of iNOS-positive cells was increased and reached its peak on day 60, when histology of the animals showed peak infiltration with inflammatory cells. The clinical course of TMEV-IDD on each day postintracerebral infection was significantly reduced in mice treated with AG in the effector phase, and there was no significant difference between mice treated with AG in induction phase versus those administered PBS. Thus, NO production via iNOS appears to be a pathogenic factor in the effector phase of TMEV-IDD.

Animals↗
PubMed2002

Amiodarone inhibits interleukin 6 production and attenuates myocardial injury induced by viral myocarditis in mice.

A recent study has shown that amiodarone inhibits the production of cytokines in vitro. This study was performed to examine the effects of amiodarone on survival, heart weight-to-body-weight ratio (HW/BW), myocardial lesions and cytokines production in a murine model of viral myocarditis induced by the encephalomyocarditis virus (EMCV). Four-week-old male DBA/2 mice were inoculated with the EMCV. To examine its effect on survival and HW/BW on day 14, mice were administered oral amiodarone (30 mg/kg) or the vehicle only once daily, starting 4 days before inoculation of the virus. The effects of amiodarone on histopathologic changes in myocardial lesions and myocardial cytokine production were studied in mice treated with amiodarone (10 mg/kg or 30 mg/kg) or vehicle, and killed day 7. The survival rate on day 14 was significantly higher in the amiodarone-treated mice than in the control mice. The HW/BW, histopathologic score of cellular infiltration and myocardial interleukin 6 concentration were significantly lower in the amiodarone-treated group than in the control group. Likewise, myocardial necrotic area was significantly smaller in the amiodarone group than in the control group. This study suggests that the beneficial effects of amiodarone in viral myocarditis may be mediated by decreasing interleukin 6 production in myocardial tissue.

Amiodarone↗
PubMed1999

Quantitative assessment of neurologic deficits in a chronic progressive murine model of CNS demyelination.

The precise factors involved in the development of a progressive motor dysfunction, a hallmark of immune-mediated demyelinating diseases such as multiple sclerosis, are not well defined. The ability to identify neurologic deficits that result in impaired motor performance early in disease may allow for the identification of therapeutic interventions that slow or eliminate the progression toward a permanent dysfunction. Here we describe the use of three objective, quantitative functional assays (spontaneous activity box, rotarod, and footprint analysis) to detect early neurologic deficits following the initiation of a demyelinating disease with Theiler's murine encephalomyelitis virus (TMEV). The results show that the assays are capable of revealing neurologic deficits at the early stages of the demyelinating disease process. These findings are the first to objectively characterize neurologic function in an animal model of progressive CNS demyelination.

Acute Disease↗
PubMed1997

Protective role of interleukin-12 in viral myocarditis.

The co-ordinate action of several cytokines determines the nature, severity and duration of myocarditis. Interleukin (IL)-12 mediates a broad range of effects on both innate and acquired immunity. However, the in vivo role of IL-12 in viral myocarditis remains to be elucidated. To clarify the role of IL-12 in viral myocarditis, we treated mice inoculated with the encephalomyocarditis virus (EMCV), with recombinant IL-12 and neutralizing anti-IL-12 antibody. The successive administration of 10 ng of IL-12 from the day of virus inoculation to 5 days thereafter, reduced mortality, myocardial damage and viral replication in the heart tissue. The gene expression of IL-12p35 and IL-12p40 was enhanced in the hearts of EMCV inoculated mice. Treatment with neutralizing anti-IL-12 resulted in increased mortality of mice inoculated with EMCV. In conclusion, endogenous and exogenous IL-12 play protective roles in murine viral myocarditis.

Animals↗
PubMed2001

Overexpression of interleukin-6 aggravates viral myocarditis: impaired increase in tumor necrosis factor-alpha.

The process of inflammation and immune response is regulated by proinflammatory cytokines. Interleukin-6 (IL-6), one of the proinflammatory cytokines, plays a potentially critical role in viral-induced myocarditis. Our previous work demonstrates that exogenous IL-6 administration, given at the time of encephalomyocarditis virus (EMCV) inoculation in C3H/HeJ mice, has a protective effect on myocardium and improves survival rates. In the present study, we examined whether overexpression of IL-6 modified viral myocarditis. On day 3 and 10 after inoculation with EMCV, the ratio of heart weight to body weight and myocardial injury were significantly increased in IL-6 transgenic mice (IL-6TG). On day 3, a reduction of viral clearance was shown by the presence of elevated viral titers and viral replication in the heart of IL-6TG. The concentrations of serum tumor necrosis factor- alpha (TNF alpha) were dramatically increased in wild-type mice on day 1, in contrast, this change was not observed in IL-6TG. Treatment with recombinant human TNF (2 microg) significantly improved viral clearance in the IL-6TG hearts. Thus, overexpression of IL-6 promotes myocardial injury by interrupting both the cytokine network and viral clearance. These experiments suggest the possibility that IL-6 is one of the factors that accelerates tissue damage, including myocardial injury, in the viral myocarditis.

Animals↗
PubMed2000

HLA-DQ polymorphism influences progression of demyelination and neurologic deficits in a viral model of multiple sclerosis.

The importance of genetic susceptibility in determining the progression of demyelination and neurologic deficits is a major focus in neuroscience. We studied the influence of human leukocyte antigen (HLA)-DQ polymorphisms on disease course and neurologic impairment in virus-induced demyelination. HLA-DQ6 or DQ8 was inserted as a transgene into mice lacking endogenous expression of MHC class I (beta(2)m) and class II (H2-A(beta)) molecules. Following Theiler's murine encephalomyelitis virus (TMEV) infection, we assessed survival, virus persistence, demyelination, and clinical disease. Mice lacking expression of endogenous class I and class II molecules (beta(2)m(o) Abeta(o) mice) died 3 to 4 weeks postinfection (p.i.) due to overwhelming virus replication in neurons. beta(2)m(o) Abeta(o) DQ6 and beta(2)m(o) Abeta(o) DQ8 mice had increased survival and decreased gray matter disease and virus replication compared to nontransgenic littermate controls. Both beta(2)m(o) Abeta(o) DQ6 and beta(2)m(o) Abeta(o) DQ8 mice developed chronic virus persistence in glial cells of the white matter of the spinal cord, with greater numbers of virus antigen-positive cells in beta(2)m(o) Abeta(o) DQ8 than in beta(2)m(o) Abeta(o) DQ6 mice. At day 45 p.i., the demyelinating lesions in the spinal cord of beta(2)m(o) Abeta(o) DQ8 were larger than those in the beta(2)m(o) Abeta(o) DQ6 mice. Earlier and more profound neurologic deficits were observed in beta(2)m(o) Abeta (o) DQ8 mice compared to beta(2)m(o) Abeta(o) DQ6 mice, although by 120 days p.i. both strains of mice showed similar extent of demyelination and neurologic deficits. Delayed-type hypersensitivity and antibody responses to TMEV demonstrated that the mice mounted class II-mediated cellular and humoral immune responses. The results are consistent with the hypothesis that rates of progression of demyelination and neurologic deficits are related to the differential ability of DQ6 and DQ8 transgenes to modulate the immune response and control virus.

Acute Disease↗
PubMed1996

Phosphorylation state of the cap-binding protein eIF4E during viral infection.

The eukaryotic translation initiation factor eIF4E, the cap-binding protein, seems to play an essential role in the establishment of the host shut-off after viral infection. Infection with adenovirus and influenza virus caused dephosphorylation of eIF4E and an involvement of a viral protein was suggested. In this report, we studied several other viruses for their ability to change the phosphorylation state of eIF4E, and we looked for the mechanism of eIF4E dephosphorylation. First, it was shown that after encephalomyocarditis virus (EMCV) and poliovirus infection, dephosphorylation of eIF4E occurred. Dephosphorylation of eIF4E was not observed after Semliki Forest virus and reovirus infection. An artificial increase of the level of phosphorylated eIF4E by treating the cells with the phosphatase inhibitor okadaic acid changed neither the kinetics of EMCV and poliovirus infection, nor that of host shut-off. Infections with the uv-treated EMCV showed that the virus binding or entry into the cell initiates eIF4E dephosphorylation. Besides this entry-induced eIF4E dephosphorylation, dephosphorylation was also induced by blocking protein synthesis with the initiation inhibitor pactamycin, or with the elongation inhibitor cycloheximide. We conclude that eIF4E is dephosphorylated by entry of EMCV, and the effect is strengthened by the decrease in cap-dependent translation.

Alphavirus Infections↗
PubMed1999

Theiler's murine encephalomyelitis virus infection induces early expression of c-fos in astrocytes.

We have determined whether Theiler's murine encephalomyelitis virus (TMEV), a picornavirus that produces demyelination in genetically susceptible strains of mice, induces c-fos in pure quiescent cultures of mouse brain astrocytes. As observed in Northern blots, the expression of this immediate early gene increases in a dose-dependent manner, with its expression peaking at a multiplicity of infection of 100. The expression of c-fos is transient, peaking after 30 min and disappearing 2 h after infection. The virus is quickly internalized at 37 degrees C upon binding to its specific receptor located at the cell surface and is actively replicated in the cytoplasm of the astrocytes, as demonstrated by FACS flow cytometry. Using the same technique, nuclear translation of c-fos mRNA is also shown. The specificity of viral induction is demonstrated by its neutralization with TMEV-specific antibodies and by the fact that only viral particles and not purified protein components VP1, VP2, and VP3 induced proto-oncogene expression. This rapid induction of c-fos in astrocytes could be the first stage in the infection of these central nervous system cell populations by TMEV. The biological relevance of these findings is assessed by the demonstration of c-fos activation after viral infection in vivo.

Animals↗
PubMed2000

The CD4-mediated immune response is critical in determining the outcome of infection using Theiler's viruses with VP1 capsid protein point mutations.

Daniel's strain of Theiler's virus (DA) induces a chronic demyelinating disease in the central nervous system (CNS) of susceptible SJL mice, which serves as an excellent model of multiple sclerosis. We previously demonstrated that point mutations near a putative virus receptor-binding site [VP1 99 (Gly to Ser) or 100 (Gly to Asp)] totally attenuate the ability of DA to persist and induce demyelination in SJL mice. The current studies demonstrate that class II-restricted CD4(+) T cells play a major role in clearing VP1 mutant DA viruses from the CNS to prevent demyelination. Infection of SJL CD4((-/-)) mice with DA-VP1-99(Ser) or DA-VP1-100(Asp) resulted in virus persistence and prominent demyelination in the spinal cord. In contrast, infection of SJL CD8((-/-)) mice with DA-VP1-99(Ser) or DA-VP1-100 did not result in virus persistence or demyelination. In addition, no virus-specific cytotoxicity was observed in CNS-infiltrating lymphocytes following infection of SJL mice with VP1 mutant viruses. The mutant DA-VP1-99(Ser) and DA-VP1(100) viruses were in fact neurovirulent when compared to the wild-type DA virus, as they induced an overwhelming encephalitis and early lethality (2 to 4 days postinfection) in mice deficient in the IFN-alpha/beta receptor. Therefore, the nondemyelinating phenotype observed with DA-VP1-99(Ser) and DA-VP1-100(Asp) viruses is dependent in part on the CD4-mediated host immune response.

Amino Acid Substitution↗
PubMed2000

Differential expression of TGF-beta, IL-2, and other cytokines in the CNS of Theiler's murine encephalomyelitis virus-infected susceptible and resistant strains of mice.

Intracranial inoculation of susceptible SJL mice with Theiler's murine encephalomyelitis virus (TMEV) results in biphasic disease consisting of early acute disease, followed by late chronic demyelinating disease, associated with mononuclear infiltrates and demyelinating lesions. In contrast, resistant C57BL/6 (B6) mice develop only early acute disease. We employed cytokine-specific RT-PCR to determine the expression of cytokine transcripts in the CNS of TMEV-infected SJL and B6 mice. During early acute disease, we have found a strong proinflammatory (Th1) cytokine response in the CNS of both TMEV-infected SJL and B6 mice, demonstrated by the expression of transcripts for IFN-gamma, IL-1, IL-6, IL-12p40, and TNF-alpha. At 8 days postinfection (p.i.), TGF-beta1 and TNF-alpha transcripts were present at significantly higher levels (P < 0.01) in the CNS of SJL susceptible mice in comparison to those found in the CNS of B6 mice. Immunohistochemical staining revealed that TGF-beta protein was expressed in leptomeningeal mononuclear inflammatory cell infiltrates in the brain of SJL mice but not in B6 mice, at 8 days p.i. TGF-beta may be responsible for the failure of SJL mice to develop an effective anti-TMEV CTL response. During late chronic demyelinating disease, high levels of proinflammatory Th1 cytokines were found in the CNS of SJL mice, but not B6 mice. Significantly higher levels (P < 0.01) of anti-inflammatory cytokine transcripts (IL-4, IL-5, and IL-10 (Th2 cytokines) and TGF-beta) were found in the spinal cord of TMEV-infected SJL mice with chronic demyelinating disease than in the spinal cord of B6 mice during the same time period (39 or 60 days p.i.). These anti-inflammatory cytokines may contribute to the downregulation of the proinflammatory response in SJL mice. High levels of IL-2 transcripts and protein appeared transiently in the spinal cord of TMEV-infected SJL mice before the onset of demyelinating disease and coincided with an influx of new T cells into the CNS and/or expansion of remaining T cells that have not been eliminated after viral clearance.

Animals↗
PubMed2001

UDP-galactose transporter is required for Theiler's virus entry into mammalian cells.

Theiler's murine encephalomyelitis viruses (TMEV) are divided into two groups: high-neurovirulence strains, such as GDVII, cause fatal encephalitis, while low-neurovirulence strains, such as BeAn and DA, cause persistent infection and demyelination in mice. Cell surface sialic acid is bound by the low-neurovirulence DA and BeAn viruses, but not by the high-neurovirulence GDVII virus. We have identified a clone from a BHK-21 cell cDNA library that mediates TMEV entry and infection by viruses of both TMEV groups in a receptor-negative BHK-21 cell variant (R26). The sequence of this clone is 96.4% identical to the human UDP-galactose transporter (UGT), which belongs to a family of nucleotide-sugar transporter proteins involved in the biosynthesis of complex carbohydrate structures in the trans-Golgi network. UGT mRNA from R26 cells was found to have a 490-nucleotide deletion involving the C-terminal amino acids 255 to 392 and 81 nucleotides of the 3' noncoding region. These results suggest two possibilities by which UGT may mediate TMEV entry and infection. The most likely one relates to the transporter function of adding galactose to another receptor protein. This possibility suggests the requirement for a specific glycoprotein interaction for GDVII virus cell binding and entry, e.g., galactose for GDVII and sialic acid for BeAn. Alternatively, UGT might be a TMEV receptor itself, acting via UGT cycling to the cell surface.

Amino Acid Sequence↗
PubMed2006

Evolution of virulence in picornaviruses.

The Picornaviridae encompass many positive-strand RNA viruses, all of which share a generally similar genome design and capsid structure, but which induce quite diverse diseases in humans and other animals. Picornavirus strains of the same serotype have been shown to express different virulence (or pathogenic) phenotypes when studied in animal models, demonstrating that key elements of pathogenesis reside in the viral genome. However, the genetics that determine the virulence phenotype of any picornavirus are poorly understood. Picornaviruses do not have virulence genes per se, but the design ofthe capsid andhow it interacts with the virus receptor expressed on the host cell surface, specific sequences within the nontranslated regions of the viral genome, as well as coding sequences that result in different protein sequences may all have a part in determining the virulence phenotype. Virulence may be better understood as a continuum from an apparent inability to induce disease to the ability to cause severe pathogenic changes. Ultimately, the ability of a picornavirus to induce disease depends upon viral genetics and how they are modulated by the host environment.

Animals↗
PubMed1996

In vivo administration of serum thymic factor (FTS) prevents EMC-D virus-induced diabetes and myocarditis in BALB/cAJcl mice.

The effect of serum thymic factor (FTS) on the D-variant of encephalomyocarditis (EMC-D) virus-induced diabetes and myocarditis in BALB/cAJcl mice was investigated. Mice pretreated with 50 or 10 micrograms of FTS were infected with 10 or 10(3) PFU of EMC-D virus. In the mice inoculated with 10 PFU of virus, 40% developed diabetes on post-infection day (PID) 14, whereas those treated with FTS (50 micrograms/administration) on day 2 and 1 before infection did not develop diabetes. FTS (10 micrograms)-pretreated mice developed diabetes. In histological observation, FTS non-treated mice which developed diabetes showed severe necrosis and inflammation of mononuclear cells in the islets of Langerhans and myocardia on 19 PID. Mice pretreated with 50 micrograms of FTS, however, manifested mild islet degeneration without any myocardial inflammation. Furthermore, in FTS non-treated mice, immunohistological staining showed a loss of insulin granules. This loss was markedly reversed and insulin granules remained largely intact in FTS-pretreated mice. Viral titers in pancreas of FTS-pretreated mice approximated well to those of non-treated mice on PID 4, 7 and 19. In mice inoculated with higher titer of EMC-D virus (10(3) PFU), however, 50 micrograms of FTS pretreatment did not change the course of these acute pathological developments (diabetes and myocarditis observed from PID 4).

Animals↗
PubMed1999

Apoptosis in congestive heart failure induced by viral myocarditis in mice.

It has recently been speculated that progressive deterioration of left ventricular function in chronic heart failure is due to the ongoing loss of viable cardiac myocytes. However, as there is little direct evidence of significant apoptosis contributing to the pathogenesis in cardiac myocytes in vivo, the significance of apoptosis in heart failure remains to be clarified. We investigated the role of apoptosis in heart failure induced by encephalomyocarditis virus myocarditis. DBA/2 mice were inoculated with the virus (day 0), then killed, and their hearts were extracted 3 to 28 days later. Internucleosomal DNA fragmentation, chromatin binding dye staining, and in situ terminal transferase deoxyuridine triphosphate (dUTP) end-labeling were used to detect apoptosis. Internucleosomal DNA fragmentation (DNA ladder) was clearly demonstrated on days 5 to 14 in the virus-infected hearts when myocardial necrosis and infiltration of mononuclear cells were prominent in the hearts. Apoptotic cells demonstrated morphological changes typical of apoptosis (condensation of chromatin and nuclear fragmentation). Both Fas antigen and Fas ligand immunoreactivity were detected in the infiltrating mononuclear cells. The in situ terminal transferase dUTP end-labeling method demonstrated condensed nuclei of infiltrating mononuclear cells on day 7. However, nuclei of cardiac myocytes surrounded by the cellular infiltration were absent. The main source of apoptotic cells in the heart in mice with viral myocarditis appeared to be the infiltrating mononuclear cells.

Animals↗