RESUMO
Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.
Assuntos
COVID-19/imunologia , Citocinas/metabolismo , Inflamação/imunologia , Macrófagos/imunologia , SARS-CoV-2/fisiologia , Ubiquitinas/metabolismo , Diferenciação Celular , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Citocinas/genética , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Evasão da Resposta Imune , Imunidade Inata , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Células-Tronco Pluripotentes/citologia , Ubiquitinação , Ubiquitinas/genética , Zika virus/fisiologia , Infecção por Zika virus/imunologiaRESUMO
A prospective study of a dromedary camel herd during the 2013-14 calving season showed Middle East respiratory syndrome coronavirus infection of calves and adults. Virus was isolated from the nose and feces but more frequently from the nose. Preexisting neutralizing antibody did not appear to protect against infection.
Assuntos
Camelus/virologia , Infecções por Coronavirus/virologia , Coronavirus/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Animais , Infecções por Coronavirus/veterinária , Estudos Prospectivos , Infecções Respiratórias/veterinária , Infecções Respiratórias/virologia , Arábia SauditaRESUMO
We identified the near-full-genome sequence (29,908 nt, >99%) of Middle East respiratory syndrome coronavirus (MERS-CoV) from a nasal swab specimen from a dromedary camel in Egypt. We found that viruses genetically very similar to human MERS-CoV are infecting dromedaries beyond the Arabian Peninsula, where human MERS-CoV infections have not yet been detected.
