18 research outputs found
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old
Influence of vitamin A on the immune response of Schistosoma mansoni-infected rats.
Nutritional (vitamin A levels, weights), parasitological (adult worm burden, count of eggs in liver, stool examination) and immunological (IgE serum levels, anti-Schistosoma mansoni antibodies, lymphocyte stimulation by concanavalin A and S. mansoni antigenic extract) parameters were studied in three groups of rats, a non-infected and normally fed control group, a S. mansoni-infected but normally fed group, and a S. mansoni-infected group with experimentally induced vitamin A deficiency. The number of worms was found significantly higher in the third (53 +/- 19) than in the second group (2 +/- 2) (p less than 0.001). There were many eggs in the liver surrounded by granulomatous reactions in the third group (399 +/- 73 epg liver). All stool examinations were negative. IgE levels and anti-S. mansoni antibody titres were significantly lower (p less than 0.001) in the third than in the second group. The concanavalin A lymphocyte stimulation indexes did not differ significantly between groups 2 and 3; the S. mansoni lymphocyte stimulation index was only significantly positive in group 3 (p less than 0.001). These results indicate a decrease in the humoral immune response without alteration of cellular immune response in vitamin A-deficient rats infected with S. mansoni.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe