RESUMO
Zika virus (ZIKV) is an Aedes-mosquito-borne flavivirus that causes debilitating congenital and developmental disorders. Improved understanding of ZIKV pathogenesis could assist efforts to fill the therapeutic and vaccine gap. We use several ZIKV strains, including a pair differing by a single phenylalanine-to-leucine substitution (M-F37L) in the membrane (M) protein, coupled with unbiased genomics to demarcate the border between attenuated and pathogenic infection. We identify infection-induced metabolic dysregulation as a minimal set of host alterations that differentiates attenuated from pathogenic ZIKV strains. Glycolytic rewiring results in impaired oxidative phosphorylation and mitochondrial dysfunction that trigger inflammation and apoptosis in pathogenic but not attenuated ZIKV strains. Critically, pyruvate supplementation prevents cell death, in vitro, and rescues fetal development in ZIKV-infected dams. Our findings thus demonstrate dysregulated metabolism as an underpinning of ZIKV pathogenicity and raise the potential of pyruvate supplementation in expectant women as a prophylaxis against congenital Zika syndrome.
Assuntos
Desenvolvimento Fetal , Glicólise , Mitocôndrias/patologia , Replicação Viral , Infecção por Zika virus/complicações , Zika virus/fisiologia , Animais , Chlorocebus aethiops , Suplementos Nutricionais , Feminino , Humanos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Via de Pentose Fosfato , Ácido Pirúvico/administração & dosagem , Células Vero , Infecção por Zika virus/patologia , Infecção por Zika virus/virologiaRESUMO
Despite useful in vivo activity, no therapeutic against dengue virus (DENV) has demonstrated efficacy in clinical trials. Herein, we explored dosing and virological endpoints to guide the design of human trials of VIS513, a pan-serotype anti-DENV IgG1 antibody, in non-human primates (NHPs). Dosing VIS513 pre- or post-peak viremia in NHPs neutralized infectious DENV although RNAemia remained detectable post-treatment; differential interaction of human IgGs with macaque Fc-gamma receptors may delay clearance of neutralized DENV. Our findings suggest useful antiviral utility of VIS513 and highlight an important consideration when evaluating virological endpoints of trials for anti-DENV biologics.