A 46-year-old woman with relapsing-remitting multiple sclerosis died from progressive multifocal leukoencephalopathy (PML) after having received 37 doses of natalizumab (300 mg every four weeks) as part of a clinical trial of natalizumab and interferon beta-1a. PML was diagnosed on the basis of the finding of JC viral DNA in cerebrospinal fluid on polymerase-chain-reaction assay and was confirmed at autopsy. Nearly every tissue section from bilateral cerebral hemispheres contained either macroscopic or microscopic PML lesions. There was extensive tissue destruction and cavitation in the left frontoparietal area, large numbers of bizarre astrocytes, and inclusion-bearing oligodendrocytes, which were positive for JC virus DNA on in situ hybridization.
Since 1999, there have been nearly 20,000 cases of confirmed symptomatic West Nile virus (WNV) infection in the United States, and it is likely that more than 1 million people have been infected by the virus. WNV is now the most common cause of epidemic viral encephalitis in the United States, and it will likely remain an important cause of neurological disease for the foreseeable future. Clinical syndromes produced by WNV infection include asymptomatic infection, West Nile Fever, and West Nile neuroinvasive disease (WNND). WNND includes syndromes of meningitis, encephalitis, and acute flaccid paralysis/poliomyelitis. The clinical, laboratory, and diagnostic features of these syndromes are reviewed here. Many patients with WNND have normal neuroimaging studies, but abnormalities may be present in areas including the basal ganglia, thalamus, cerebellum, and brainstem. Cerebrospinal fluid invariably shows a pleocytosis, with a predominance of neutrophils in up to half the patients. Diagnosis of WNND depends predominantly on demonstration of WNV-specific IgM antibodies in cerebrospinal fluid. Recent studies suggest that some WNV-infected patients have persistent WNV IgM serum and/or cerebrospinal fluid antibody responses, and this may require revision of current serodiagnostic criteria. Although there is no proven therapy for WNND, several vaccines and antiviral therapy with antibodies, antisense oligonucleotides, and interferon preparations are currently undergoing human clinical trials. Recovery from neurological sequelae of WNV infection including cognitive deficits and weakness may be prolonged and incomplete.
The Toll-like receptor (TLR) family functions to recognize conserved microbial and viral structures with the purpose of activating signal pathways to instigate immune responses against infections by these organisms. For example, in vitro studies reveal that the TLR3 ligand is a double-stranded RNA (dsRNA), a product of viral infections. From this observation, it has been proposed that TLR3 is likely an important first signal for virus infections. We approached this issue by investigating the role of TLR3 in four different infectious viral models (lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), murine cytomegalovirus (MCMV), and reovirus) and in TLR3 genetically deficient ((-/-)) mice. Our results indicate that TLR3 is not universally required for the generation of effective antiviral responses because the absence of TLR3 does not alter either viral pathogenesis or impair host's generation of adaptive antiviral responses to these viruses.
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