02241nas a2200421   4500000000100000008004100001260003700042653001300079653001300092653002200105653001500127653001700142653001700159100002100176700001000197700001700207700001000224700001300234700001500247700002000262700001200282700001400294700001100308700001200319700001200331700001600343700001200359700001400371700001200385700001300397700001200410245006200422856010400484300000900588490000700597520120100604022001401805       2023                            d  bPublic Library of Science (PLoS)10aVirology10aGenetics10aMolecular Biology10aImmunology10aMicrobiology10aParasitology1 aDallmann-Sauer M1 aXu YZ1 ada Costa ALF1 aTao S1 aGomes TA1 aPrata RBDS1 aCorrea-Macedo W1 aManry J1 aAlcaïs A1 aAbel L1 aCobat A1 aFava VM1 aPinheiro RO1 aLara FA1 aProbst CM1 aMira MT1 aSchurr E1 aHawn TR00aAllele-dependent interaction of LRRK2 and NOD2 in leprosy  uhttps://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011260&type=printable  a1-320 v193 a<p>Leprosy, caused by Mycobacterium leprae, rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified three amino acid mutations previously associated with Crohn’s disease and Parkinson’s disease as candidate variants for early onset leprosy: LRRK2 N551K, R1398H and NOD2 R702W. In genome-edited macrophages, we demonstrated that cells expressing the LRRK2 mutations displayed reduced apoptosis activity following mycobacterial challenge independently of NOD2. However, employing co-immunoprecipitation and confocal microscopy we showed that LRRK2 and NOD2 proteins interacted in RAW cells and monocyte-derived macrophages, and that this interaction was substantially reduced for the NOD2 R702W mutation. Moreover, we observed a joint effect of LRRK2 and NOD2 variants on Bacillus Calmette-Guérin (BCG)-induced respiratory burst, NF-κB activation and cytokine/chemokine secretion with a strong impact for the genotypes found in the twins consistent with a role of the identified mutations in the development of early onset leprosy.</p>
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