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1.
J Infect Dis ; 220(11): 1797-1801, 2019 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-31352487

RESUMEN

Congenital Zika syndrome (CZS) is a cluster of malformation, and the mechanisms that lead it are still unclear. Using hypothesis-driven candidate genes and their function in viral infections, single-nucleotide polymorphisms (SNPs) were genotyped by quantitative polymerase chain reaction in a sample population from Sergipe State, Brazil. This study shows that rs3775291 SNP at Toll-like receptor 3, which triggers type I interferon antiviral responses in mothers infected by Zika virus during pregnancy, is associated with CZS occurrence (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.158-4.148). Moreover, rs1799964 SNP at tumor necrosis factor-α gene in CZS babies is associated with severe microcephaly (OR, 2.63; 95% CI, 1.13-6.21).


Asunto(s)
Genotipo , Microcefalia/genética , Receptor Toll-Like 3/genética , Factor de Necrosis Tumoral alfa/genética , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/genética , Adolescente , Adulto , Brasil , Femenino , Técnicas de Genotipaje , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto Joven
3.
Nat Commun ; 14(1): 6605, 2023 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-37884534

RESUMEN

Arthritogenic alphaviruses are positive-strand RNA viruses that cause debilitating musculoskeletal diseases affecting millions worldwide. A recent discovery identified the four-and-a-half-LIM domain protein 1 splice variant A (FHL1A) as a crucial host factor interacting with the hypervariable domain (HVD) of chikungunya virus (CHIKV) nonstructural protein 3 (nsP3). Here, we show that acute and chronic chikungunya disease in humans correlates with elevated levels of FHL1. We generated FHL1-/- mice, which when infected with CHIKV or o'nyong-nyong virus (ONNV) displayed reduced arthritis and myositis, fewer immune infiltrates, and reduced proinflammatory cytokine/chemokine outputs, compared to infected wild-type (WT) mice. Interestingly, disease signs were comparable in FHL1-/- and WT mice infected with arthritogenic alphaviruses Ross River virus (RRV) or Mayaro virus (MAYV). This aligns with pull-down assay data, which showed the ability of CHIKV and ONNV nsP3 to interact with FHL1, while RRV and MAYV nsP3s did not. We engineered a CHIKV mutant unable to bind FHL1 (CHIKV-ΔFHL1), which was avirulent in vivo. Following inoculation with CHIKV-ΔFHL1, mice were protected from disease upon challenge with CHIKV and ONNV, and viraemia was significantly reduced in RRV- and MAYV-challenged mice. Targeting FHL1-binding as an approach to vaccine design could lead to breakthroughs in mitigating alphaviral disease.


Asunto(s)
Artritis , Fiebre Chikungunya , Virus Chikungunya , Vacunas , Animales , Humanos , Ratones , Artritis/genética , Fiebre Chikungunya/prevención & control , Péptidos y Proteínas de Señalización Intracelular , Proteínas con Dominio LIM/genética , Proteínas Musculares/genética , Virus O'nyong-nyong
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