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1.
PLoS Pathog ; 13(3): e1006258, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28278235

RESUMO

Zika virus (ZIKV) is a mosquito borne flavivirus, which was a neglected tropical pathogen until it emerged and spread across the Pacific Area and the Americas, causing large human outbreaks associated with fetal abnormalities and neurological disease in adults. The factors that contributed to the emergence, spread and change in pathogenesis of ZIKV are not understood. We previously reported that ZIKV evades cellular antiviral responses by targeting STAT2 for degradation in human cells. In this study, we demonstrate that Stat2-/- mice are highly susceptible to ZIKV infection, recapitulate virus spread to the central nervous system (CNS), gonads and other visceral organs, and display neurological symptoms. Further, we exploit this model to compare ZIKV pathogenesis caused by a panel of ZIKV strains of a range of spatiotemporal history of isolation and representing African and Asian lineages. We observed that African ZIKV strains induce short episodes of severe neurological symptoms followed by lethality. In comparison, Asian strains manifest prolonged signs of neuronal malfunctions, occasionally causing death of the Stat2-/- mice. African ZIKV strains induced higher levels of inflammatory cytokines and markers associated with cellular infiltration in the infected brain in mice, which may explain exacerbated pathogenesis in comparison to those of the Asian lineage. Interestingly, viral RNA levels in different organs did not correlate with the pathogenicity of the different strains. Taken together, we have established a new murine model that supports ZIKV infection and demonstrate its utility in highlighting intrinsic differences in the inflammatory response induced by different ZIKV strains leading to severity of disease. This study paves the way for the future interrogation of strain-specific changes in the ZIKV genome and their contribution to viral pathogenesis.


Assuntos
Modelos Animais de Doenças , Infecção por Zika virus/imunologia , Zika virus/imunologia , Zika virus/patogenicidade , Animais , Inflamação/imunologia , Inflamação/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Filogenia , Reação em Cadeia da Polimerase em Tempo Real , Zika virus/genética
2.
Cell Host Microbe ; 19(6): 882-90, 2016 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-27212660

RESUMO

The ongoing epidemic of Zika virus (ZIKV) illustrates the importance of flaviviruses as emerging human pathogens. All vector-borne flaviviruses studied thus far have to overcome type I interferon (IFN) to replicate and cause disease in vertebrates. The mechanism(s) by which ZIKV antagonizes IFN signaling is unknown. Here, we report that the nonstructural protein NS5 of ZIKV and other flaviviruses examined could suppress IFN signaling, but through different mechanisms. ZIKV NS5 expression resulted in proteasomal degradation of the IFN-regulated transcriptional activator STAT2 from humans, but not mice, which may explain the requirement for IFN deficiency to observe ZIKV-induced disease in mice. The mechanism of ZIKV NS5 resembles dengue virus (DENV) NS5 and not its closer relative, Spondweni virus (SPOV). However, unlike DENV, ZIKV did not require the E3 ubiquitin ligase UBR4 to induce STAT2 degradation. Hence, flavivirus NS5 proteins exhibit a remarkable functional convergence in IFN antagonism, albeit by virus-specific mechanisms.


Assuntos
Interferon Tipo I/antagonistas & inibidores , Fator de Transcrição STAT2/metabolismo , Proteínas não Estruturais Virais/metabolismo , Infecção por Zika virus/metabolismo , Zika virus/metabolismo , Animais , Sequência de Bases , Proteínas de Ligação a Calmodulina/metabolismo , Chlorocebus aethiops , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Células HEK293/efeitos dos fármacos , Humanos , Interferon Tipo I/metabolismo , Camundongos , Filogenia , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo , Células Vero , Proteínas não Estruturais Virais/genética , Infecção por Zika virus/virologia
3.
J Virol ; 86(16): 8359-66, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22674996

RESUMO

PB1-F2 is a small, 87- to 90-amino-acid-long protein encoded by the +1 alternate open reading frame of the PB1 gene of most influenza A virus strains. It has been shown to contribute to viral pathogenicity in a host- and strain-dependent manner, and we have previously discovered that a serine at position 66 (66S) in the PB1-F2 protein increases virulence of the 1918 and H5N1 pandemic viruses. Recently, we have shown that PB1-F2 inhibits the induction of type I interferon (IFN) at the level of the MAVS adaptor protein. However, the molecular mechanism for the IFN antagonist function of PB1-F2 has remained unclear. In the present study, we demonstrated that the C-terminal portion of the PB1-F2 protein binds to MAVS in a region that contains the transmembrane domain. Strikingly, PB1-F2 66S was observed to bind to MAVS more efficiently than PB1-F2 66N. We also tested the effect of PB1-F2 on the IFN antagonist functions of the polymerase proteins PB1, PB2, and PA and observed enhanced IFN inhibition by the PB1 and PB2 proteins in combination with PB1-F2 but not by the PA protein. Using a flow cytometry-based assay, we demonstrate that the PB1-F2 protein inhibits MAVS-mediated IFN synthesis by decreasing the mitochondrial membrane potential (MMP). Interestingly, PB1-F2 66S affected the MMP more efficiently than wild-type PB1-F2. In summary, the results of our study identify the molecular mechanism by which the influenza virus PB1-F2 N66S protein increases virulence.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , Vírus da Influenza A Subtipo H1N1/patogenicidade , Interferon Tipo I/antagonistas & inibidores , Potencial da Membrana Mitocondrial , Proteínas Virais/metabolismo , Linhagem Celular , Humanos , Ligação Proteica , Mapeamento de Interação de Proteínas
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