Encephalitis induced by reovirus serotype 3 (T3) strains results from the apoptotic death of infected neurons. Extrinsic apoptotic signaling is activated in reovirus-infected neurons in vitro and in vivo, but the role of intrinsic apoptosis signaling during encephalitis is largely unknown. Bax plays a key role in intrinsic apoptotic signaling in neurons by allowing the release of mitochondrial cytochrome c. We found Bax activation and cytochrome c release in neurons following infection of neonatal mice with T3 reoviruses. Bax ؊/؊ mice infected with T3 Abney (T3A) have reduced central nervous system (CNS) tissue injury and decreased apoptosis, despite viral replication that is similar to that in wild-type (WT) Bax ؉/؉ mice. In contrast, in the heart, T3A-infected Bax ؊/؊ mice have viral growth, caspase activation, and injury comparable to those in WT mice, indicating that the role of Bax in pathogenesis is organ specific. Nonmyocarditic T3 Dearing (T3D)-infected Bax ؊/؊ mice had delayed disease and enhanced survival compared to WT mice. T3D-infected Bax ؊/؊ mice had significantly lower viral titers and levels of activated caspase 3 in the brain despite unaffected transneuronal spread of virus. Cytochrome c and Smac release occurred in some reovirus-infected neurons in the absence of Bax; however, this was clearly reduced compared to levels seen in Bax ؉/؉ wild-type mice, indicating that Bax is necessary for efficient activation of proapoptotic mitochondrial signaling in infected neurons. Our studies suggest that Bax is important for reovirus growth and pathogenesis in neurons and that the intrinsic pathway of apoptosis, mediated by Bax, is important for full expression of disease, CNS tissue injury, apoptosis, and viral growth in the CNS of reovirus-infected mice.
Objective Patients with established rheumatoid arthritis (RA) demonstrate altered immune responses to Epstein‐Barr virus (EBV), but the presence and roles of EBV have not been fully explored during the pre–clinical disease period. This study was undertaken to determine if EBV infection, as evidenced by an altered anti‐EBV antibody response, either plays an important role in driving the development of RA or is a result of expanded RA‐related autoimmunity. Methods A total of 83 subjects with RA according to the 1987 American College of Rheumatology (ACR) criteria and 83 age‐, sex‐, and race‐matched control subjects without RA were included in our study. We collected sera from RA subjects and matched controls during the pre–RA and post–RA diagnosis periods and tested the sera for the presence of 5 anti‐EBV antibodies (anti–EBV nuclear antigen 1 IgG isotype, anti–viral capsid antigen [anti‐VCA] isotypes IgG and IgA, and anti–early antigen [EA] isotypes IgG and IgA), 7 RA‐related autoantibodies (rheumatoid factor measured by nephelometry [RF‐Neph] as well as isotype‐specific IgA‐RF, IgM‐RF, and IgG‐RF, and anti–cyclic citrullinated peptide [anti‐CCP] antibodies, including anti‐CCP2, anti‐CCP3, and anti‐CCP3.1), 22 cytokines/chemokines, 36 individual anti–citrullinated protein antibodies, and IgG–cytomegalovirus (CMV) antibodies. Random forest classification, mixed modeling, and joint mixed modeling were used to determine differences in anti‐EBV antibody levels between RA subjects and controls. Results Random forest analysis identified the presence of preclinical EBV antibodies in the serum that differentiated RA subjects from controls without RA. Specifically, IgG‐EA antibody levels were higher in RA subjects (mean ± SD 0.82 ± 0.72 international standardized ratio [ISR]) compared to controls (mean ± SD 0.49 ± 0.28 ISR). In subjects with RA, elevated serum IgG‐EA levels in the preclinical period before seroconversion were significantly correlated with increased serum IgM‐RF levels (P = 0.007), whereas this correlation was not seen in control subjects without RA (P = 0.15). IgG‐CMV antibody levels did not differ between groups. Conclusion Subjects whose serum IgG‐EA antibody levels are elevated in the preclinical period will eventually develop RA, which suggests that EBV reactivation cycles are increased during the preclinical period of RA. A combination of RF and EBV reactivation may play an important role in the development of RA.
Objective.We investigated the association of age and anticyclic citrullinated peptide antibodies (anti-CCP) in subjects without rheumatoid arthritis (RA).Methods.Serum was tested for anti-CCP3.1 (IgG/IgA) in 678 first-degree relatives (FDR) of patients with RA and 330 patients with osteoarthritis (OA). Individual isotypes (anti–CCP-IgA and anti–CCP-IgG) were also tested in all FDR.Results.In FDR, increasing age was significantly associated with positivity for anti-CCP3.1 (per year, OR 1.03) and anti–CCP-IgA (per year, OR 1.05) but not anti–CCP-IgG. In FDR and OA subjects, anti-CCP3.1 prevalence was significantly increased after age 50 years.Conclusion.Increasing age in individuals without RA should be considered in the interpretation of anti-CCP3.1 positivity.
The tumor suppressor p53 plays a critical part in determining cell fate both as a regulator of the transcription of several proapoptotic genes and through its binding interactions with Bcl-2 family proteins at mitochondria. We now demonstrate that p53 protein levels are increased in infected brains during reovirus encephalitis. This increase occurs in the cytoplasm of reovirus-infected neurons and is associated with the activation of caspase 3. Increased levels of p53 in reovirus-infected brains are not associated with increased expression levels of p53 mRNA, suggesting that p53 regulation occurs at the protein level. Increased levels of p53 are also not associated with the increased expression levels of p53-regulated, proapoptotic genes. In contrast, upregulated p53 accumulates in mitochondria. Previous reports demonstrated that the binding of p53 to Bak at mitochondria causes Bak activation and results in apoptosis. We now show that Bak is activated and that activated Bak is bound to p53 during reovirus encephalitis. In addition, survival is enhanced in reovirus-infected Bak ؊/؊ mice compared to controls, demonstrating a role for Bak in reovirus pathogenesis. Inhibition of the mitochondrial translocation of p53 with pifithrin prevents the formation of p53/Bak complexes following reovirus infection of ex vivo brain slice cultures and results in decreased apoptosis and tissue injury. These results suggest that the mitochondrial localization of p53 regulates reovirus-induced pathogenesis in the central nervous system (CNS) through its interactions with Bak. IMPORTANCEThere are virtually no specific treatments of proven efficacy for virus-induced neuroinvasive diseases. A better understanding of the pathogenesis of virus-induced CNS injury is crucial for the rational development of novel therapies. Our studies demonstrate that p53 is activated in the brain following reovirus infection and may provide a therapeutic target for virus-induced CNS disease. V iral encephalitis causes morbidity and mortality throughout the world (1, 2). New therapies, including those targeting specific mechanisms of virus-induced central nervous system (CNS) injury, are urgently needed. Intracerebral injection of neonatal mice with type 3 (T3) strains of reovirus is a well-characterized experimental model for studying viral pathogenesis within the CNS. Reovirus specifically targets neurons within the hippocampus, thalamus, and cortex, causing lethal encephalitis. We and others have previously shown that apoptosis of infected neurons is an important pathogenic mechanism during reovirus encephalitis and that reovirus-induced neuronal apoptosis involves the activation of both extrinsically (death receptor) and intrinsically (mitochondrial) mediated pathways, leading to the activation of cellular caspases (3-7).The tumor suppressor p53 plays a critical role in cell death signaling following a variety of insults (8, 9), including infection of BHK-21 cells with avian reovirus (10) and during reovirus oncolysis (11). Increased levels of...
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