RESUMO
Venezuelan equine encephalitis virus (VEEV) is a disease typically confined to South and Central America, whereby human disease is characterised by a transient systemic infection and occasionally severe encephalitis, which is associated with lethality. Using an established mouse model of VEEV infection, the encephalitic aspects of the disease were analysed to identify biomarkers associated with inflammation. Sequential sampling of lethally challenged mice (infected subcutaneously) confirmed a rapid onset systemic infection with subsequent spread to the brain within 24 h of the challenge. Changes in inflammatory biomarkers (TNF-α, CCL-2, and CCL-5) and CD45+ cell counts were found to correlate strongly to pathology (R>0.9) and present previously unproven biomarkers for disease severity in the model, more so than viral titre. The greatest level of pathology was observed within the olfactory bulb and midbrain/thalamus. The virus was distributed throughout the brain/encephalon, often in areas not associated with pathology. The principal component analysis identified five principal factors across two independent experiments, with the first two describing almost half of the data: (1) confirmation of a systemic Th1-biased inflammatory response to VEEV infection, and (2) a clear correlation between specific inflammation of the brain and clinical signs of disease. Targeting strongly associated biomarkers of deleterious inflammation may ameliorate or even eliminate the encephalitic syndrome of this disease.
Assuntos
Vírus da Encefalite Equina Venezuelana , Encefalomielite Equina Venezuelana , Humanos , Cavalos , Camundongos , Animais , Fator de Necrose Tumoral alfa , Vírus da Encefalite Equina Venezuelana/fisiologia , Encéfalo , Inflamação/patologia , Quimiocinas , LeucócitosAssuntos
Adjuvantes Imunológicos/administração & dosagem , Antivirais/administração & dosagem , Quimioprevenção/métodos , Vírus da Encefalite Equina Venezuelana/efeitos dos fármacos , Encefalomielite Equina Venezuelana/prevenção & controle , Oligodesoxirribonucleotídeos/administração & dosagem , Administração Intranasal , Animais , Modelos Animais de Doenças , Feminino , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos BALB C , Oligonucleotídeos , Análise de SobrevidaRESUMO
An adenovirus-based (ad-based) vaccine delivering antigens from the Alphavirus Venezuelan equine encephalitis virus (VEEV) is a strategy that offers clinical potential. A vaccine against VEEV is desirable because of the re-emerging nature of this virus, and also the potential that it may be used as a biological weapon. This study was designed to investigate whether the co-administration of CpG oligodeoxynucleotides (ODNs) with an ad-based VEEV vaccine could enhance the protective efficacy of the vaccine. We report that the co-administration of CpG ODN was unable to increase VEEV-specific antibody responses in mice, and was unable to increase the protective efficacy of the vaccine against aerosol challenge with virulent VEEV. However, it was noted that antibody responses directed against the adenovirus vaccine vector were increased, which may be detrimental, particularly in the context of homologous boosting.