In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 3 ( 2023-3-27), p. e1011260-
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011260
DOI:
10.1371/journal.ppat.1011260.g001
DOI:
10.1371/journal.ppat.1011260.g002
DOI:
10.1371/journal.ppat.1011260.g003
DOI:
10.1371/journal.ppat.1011260.g004
DOI:
10.1371/journal.ppat.1011260.g005
DOI:
10.1371/journal.ppat.1011260.s001
DOI:
10.1371/journal.ppat.1011260.s002
DOI:
10.1371/journal.ppat.1011260.s003
DOI:
10.1371/journal.ppat.1011260.s004
DOI:
10.1371/journal.ppat.1011260.s005
DOI:
10.1371/journal.ppat.1011260.s006
DOI:
10.1371/journal.ppat.1011260.s007
DOI:
10.1371/journal.ppat.1011260.s008
DOI:
10.1371/journal.ppat.1011260.s009
DOI:
10.1371/journal.ppat.1011260.s010
DOI:
10.1371/journal.ppat.1011260.s011
DOI:
10.1371/journal.ppat.1011260.s012
DOI:
10.1371/journal.ppat.1011260.s013
DOI:
10.1371/journal.ppat.1011260.s014
DOI:
10.1371/journal.ppat.1011260.s015
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2023
ZDB Id:
2205412-1
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