RESUMEN
The establishment of a virus infection is the result of the pathogen's ability to replicate in a hostile environment generated by the host's immune system. Here, we found that ISG15 restricts Dengue and Zika viruses' replication through the stabilization of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signaling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2's stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing host's IFN-I mediated response and promoting virus replication.
Asunto(s)
Dengue , Interferón Tipo I , Infección por el Virus Zika , Virus Zika , Humanos , Interferón Tipo I/metabolismo , Infección por el Virus Zika/genética , Replicación Viral , Dengue/genética , Ubiquitinas/metabolismo , Citocinas/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Factor de Transcripción STAT2/genética , Factor de Transcripción STAT2/metabolismoRESUMEN
IFN-stimulated gene 15 (ISG15) deficiency in humans leads to severe IFNopathies and mycobacterial disease, the latter being previously attributed to its extracellular cytokine-like activity. In this study, we demonstrate a novel role for secreted ISG15 as an IL-10 inducer, unique to primary human monocytes. A balanced ISG15-induced monocyte/IL-10 versus lymphoid/IFN-γ expression, correlating with p38 MAPK and PI3K signaling, was found using targeted in vitro and ex vivo systems analysis of human transcriptomic datasets. The specificity and MAPK/PI3K-dependence of ISG15-induced monocyte IL-10 production was confirmed in vitro using CRISPR/Cas9 knockout and pharmacological inhibitors. Moreover, this ISG15/IL-10 axis was amplified in leprosy but disrupted in human active tuberculosis (TB) patients. Importantly, ISG15 strongly correlated with inflammation and disease severity during active TB, suggesting its potential use as a biomarker, awaiting clinical validation. In conclusion, this study identifies a novel anti-inflammatory ISG15/IL-10 myeloid axis that is disrupted in active TB.
Asunto(s)
Citocinas/inmunología , Interleucina-10/inmunología , Leucocitos Mononucleares/inmunología , Tuberculosis/inmunología , Ubiquitinas/inmunología , HumanosRESUMEN
ISG15 is a ubiquitin-like type I IFN-stimulated protein of 15 kDa and is one of the most prominently expressed proteins in viral infections. ISG15 is widely known to be involved in a process called ISGylation, where it binds to over 150 targets from a variety of classes of proteins including central immune signaling pathways such as those mediated by NFκB, JNK, and IRF-3. However, ISG15 also exists in a free form that can act intra- or extracellularly. In vitro and in vivo evidences suggest that free ISG15 play different roles in several cellular processes, from cancer and defense against viral infections to activation of immune cells such as lymphocytes, monocytes, and NK cells. This review discusses the roles of free intracellular and secreted ISG15 approaching questions yet to be answered about the mechanism of action of this protein.
Asunto(s)
Infecciones Bacterianas/inmunología , Citocinas/inmunología , Interferón gamma/inmunología , Transducción de Señal/inmunología , Ubiquitinas/inmunología , Virosis/inmunología , Infecciones Bacterianas/genética , Infecciones Bacterianas/microbiología , Citocinas/genética , Regulación de la Expresión Génica , Humanos , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/inmunología , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Interferón gamma/genética , Monocitos/inmunología , Monocitos/microbiología , Monocitos/virología , Neutrófilos/inmunología , Neutrófilos/microbiología , Neutrófilos/virología , Linfocitos T/inmunología , Linfocitos T/microbiología , Linfocitos T/virología , Ubiquitinas/genética , Virosis/genética , Virosis/virología , eIF-2 Quinasa/genética , eIF-2 Quinasa/inmunologíaRESUMEN
BACKGROUND: Triatoma sordida, a vector of Trypanosoma cruzi, is native of Brazil, Bolivia, Paraguay, Argentina, and Uruguay, and occurs primarily in peridomiciles. Currently, it is the species most frequently captured by the Chagas Disease Control Program in Brazil. For this reason, population genetic studies attract great interest, as they can provide further information about the dispersal and household invasion processes of this species. In the absence of suitable markers, the objective of this study was to test the cross amplification of microsatellite primers. FINDINGS: 23 primers were tested for microsatellite loci already described for other species of the genus Triatoma sp. Forty four specimens of T. sordida captured in the north of Minas Gerais were used to validate the use of standardized loci for population genetic analyses. It was possible to amplify 10 of the 23 loci tested for T. sordida. CONCLUSIONS: This is the first study that provides 10 microsatellite markers for population analysis of this triatomine species. Cross-amplification of primers can be used among other phylogenetically related species whose loci are already available for study.