학술논문

Allele-dependent interaction of LRRK2 and NOD2 in leprosy.
Document Type
Article
Source
PLoS Pathogens. 3/27/2023, Vol. 18 Issue 3, p1-32. 32p.
Subject
*DARDARIN
*LEPROSY
*CROHN'S disease
*WHOLE genome sequencing
*PARKINSON'S disease
*FAMILY farms
*IMMUNOPRECIPITATION
Language
ISSN
1553-7366
Abstract
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. Author summary: Children younger than 5-years old are rarely affected by leprosy, a chronic infectious disease of the skin and peripheral nerves caused by Mycobacterium leprae. Here, we report a case of a family with three generation of leprosy cases including a rare pair of identical twins of less than two years of age. To investigate if genetic factors in the twins may explain the early disease onset, we conducted a whole genome sequence analysis of family members. We found three amino acid changes in LRRK2 and NOD2 as candidate susceptibility variants for early onset leprosy. In follow-up functional assays, we demonstrated that LRRK2 and NOD2 proteins physically interact in macrophages and that this interaction was strongly impacted by the NOD2 variant. Furthermore, we showed a joint effect of LRRK2 and NOD2 variants that results in a reduced antimycobacterial response in these cells. Interestingly, the variants in LRRK2 and NOD2 found in the twins had previously been identified as genetic modulators for risk of Parkinson's and Crohn's diseases with the two LRRK2 variants showing antagonistic pleiotropy. This suggests pleiotropic effects of the NOD2 and LRRK2 variants across neurodegenerative, inflammatory and infectious diseases. [ABSTRACT FROM AUTHOR]