RESUMEN
Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is an important model of the progressive disability caused by irreversible CNS tissue injury, and provides an example of how a CNS pathogen can cause inflammation, demyelination, and neuronal damage. We were interested in which molecules, especially inflammatory mediators, might be upregulated in the CNS throughout TMEV-IDD. We quantitated by a real-time RT-PCR multi-gene system the expression of a pathway-focused panel of genes at 30 and 165 days post infection, characterizing both the early inflammatory and the late neurodegenerative stages of TMEV-IDD. Also, we measured 32 cytokines/chemokines by multiplex Luminex analysis in CSF specimens from early and late TMEV-IDD as well as sham-treated mice. Results indicate that, in the later stage of TMEV-IDD, activation of the innate immune response is most prominent: TLRs, type I IFN response genes, and innate immunity-associated cytokines were highly expressed in late TMEV-IDD compared to sham (p ≤ 0.0001) and early TMEV-IDD (p < 0.05). Conversely, several molecular mediators of adaptive immune response were highly expressed in early TMEV-IDD (all p ≤ 0.001). Protein detection in the CSF was broadly concordant with mRNA abundance of the corresponding gene measured by real-time RT-PCR in the spinal cord, since several cytokines/chemokines were increased in the CSF of TMEV-IDD mice. Results show a clear shift from adaptive to innate immunity from early to late TMEV-IDD, indicating that adaptive and innate immune pathways are likely involved in the development and progression of the disease to different extents. CSF provides an optimal source of biomarkers of CNS neuroinflammation.
Asunto(s)
Inmunidad Adaptativa , Infecciones por Cardiovirus/inmunología , Enfermedades Desmielinizantes/inmunología , Interacciones Huésped-Patógeno , Inmunidad Innata , Animales , Infecciones por Cardiovirus/líquido cefalorraquídeo , Infecciones por Cardiovirus/genética , Infecciones por Cardiovirus/virología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/virología , Citocinas/líquido cefalorraquídeo , Citocinas/genética , Citocinas/inmunología , Enfermedades Desmielinizantes/líquido cefalorraquídeo , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/virología , Progresión de la Enfermedad , Regulación de la Expresión Génica , Inflamación , Ratones , Anotación de Secuencia Molecular , ARN Mensajero/líquido cefalorraquídeo , ARN Mensajero/genética , ARN Mensajero/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Theilovirus/crecimiento & desarrollo , Theilovirus/inmunología , Theilovirus/patogenicidad , Factores de Tiempo , Receptores Toll-Like/genética , Receptores Toll-Like/inmunologíaRESUMEN
The first human virus in the genus Cardiovirus was described in 2007 and named Saffold virus (SAFV). Cardioviruses can cause severe infections of the myocardium and central nervous system in animals, but SAFV has not yet been convincingly associated with disease in humans. To study a possible association between SAFV and infections in the human central nervous system, we designed a real-time PCR for SAFV and tested cerebrospinal fluid (CSF) samples from children <4 years of age. SAFV was detected in 2 children: in the CSF and a fecal sample from 1 child with monosymptomatic ataxia caused by cerebellitis; and in the CSF, blood, and myocardium of another child who died suddenly with no history of illness. Virus from each child was sequenced and shown to be SAFV type 2. These findings demonstrate that SAFV can cause serious invasive infection in children.
Asunto(s)
Infecciones por Cardiovirus/patología , Cardiovirus/aislamiento & purificación , Infecciones del Sistema Nervioso Central/virología , Cardiovirus/clasificación , Cardiovirus/genética , Infecciones por Cardiovirus/líquido cefalorraquídeo , Infecciones del Sistema Nervioso Central/patología , Preescolar , Resultado Fatal , Heces/virología , Femenino , Genoma Viral , Humanos , Lactante , Masculino , Filogenia , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Cardioviruses cause myocarditis and encephalomyelitis in rodents; human cardioviruses have not been ascribed to any disease. We screened 6,854 cerebrospinal fluid and 10 myocardium specimens from children and adults. A genotype 2 cardiovirus was detected from a child who died of sudden infant death syndrome, and 2 untypeable cardioviruses were detected from 2 children with meningitis.