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del Toro Duany, Yoandris

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del Toro Duany

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Yoandris

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del Toro Duany, Yoandris

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2014 - 20152

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    Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling
    (2014) Rice, Gillian I; del Toro Duany, Yoandris; Jenkinson, Emma M; Forte, Gabriella MA; Anderson, Beverley H; Ariaudo, Giada; Bader-Meunier, Brigitte; Baildam, Eileen M; Battini, Roberta; Beresford, Michael W; Casarano, Manuela; Chouchane, Mondher; Cimaz, Rolando; Collins, Abigail E; Cordeiro, Nuno JV; Dale, Russell C; Davidson, Joyce E; De Waele, Liesbeth; Desguerre, Isabelle; Faivre, Laurence; Fazzi, Elisa; Isidor, Bertrand; Lagae, Lieven; Latchman, Andrew R; Lebon, Pierre; Li, Chumei; Livingston, John H; Lourenço, Charles M; Mancardi, Maria Margherita; Masurel-Paulet, Alice; McInnes, Iain B; Menezes, Manoj P; Mignot, Cyril; O’Sullivan, James; Orcesi, Simona; Picco, Paolo P; Riva, Enrica; Robinson, Robert A; Rodriguez, Diana; Salvatici, Elisabetta; Scott, Christiaan; Szybowska, Marta; Tolmie, John L; Vanderver, Adeline; Vanhulle, Catherine; Vieira, Jose Pedro; Webb, Kate; Whitney, Robyn N; Williams, Simon G; Wolfe, Lynne A; Zuberi, Sameer M; Hur, Sun; Crow, Yanick J
    The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, and of other patients with undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer a gain-of-function - so that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
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    Identification of a Natural Viral RNA Motif That Optimizes Sensing of Viral RNA by RIG-I
    (American Society of Microbiology, 2015) Xu, Jie; Mercado-López, Xiomara; Grier, Jennifer T.; Kim, Won-keun; Chun, Lauren F.; Irvine, Edward B.; del Toro Duany, Yoandris; Kell, Alison; Hur, Sun; Gale, Michael; Raj, Arjun; López, Carolina B.
    ABSTRACT Stimulation of the antiviral response depends on the sensing of viral pathogen-associated molecular patterns (PAMPs) by specialized cellular proteins. During infection with RNA viruses, 5′-di- or -triphosphates accompanying specific single or double-stranded RNA motifs trigger signaling of intracellular RIG-I-like receptors (RLRs) and initiate the antiviral response. Although these molecular signatures are present during the replication of many viruses, it is unknown whether they are sufficient for strong activation of RLRs during infection. Immunostimulatory defective viral genomes (iDVGs) from Sendai virus (SeV) are among the most potent natural viral triggers of antiviral immunity. Here we describe an RNA motif (DVG70-114) that is essential for the potent immunostimulatory activity of 5′-triphosphate-containing SeV iDVGs. DVG70-114 enhances viral sensing by the host cell independently of the long stretches of complementary RNA flanking the iDVGs, and it retains its stimulatory potential when transferred to otherwise inert viral RNA. In vitro analysis showed that DVG70-114 augments the binding of RIG-I to viral RNA and promotes enhanced RIG-I polymerization, thereby facilitating the onset of the antiviral response. Together, our results define a new natural viral PAMP enhancer motif that promotes viral recognition by RLRs and confers potent immunostimulatory activity to viral RNA.