Allele-dependent interaction of LRRK2 and NOD2 in leprosy
Copyright: © 2023 Dallmann-Sauer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
PLoS pathogens - 19(2023), 3 vom: 11. März, Seite e1011260 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dallmann-Sauer, Monica [VerfasserIn] |
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| Links: |
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| Themen: |
EC 2.7.11.1 |
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| Anmerkungen: |
Date Completed 10.04.2023 Date Revised 11.04.2023 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1371/journal.ppat.1011260 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM354773364 |
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| 100 | 1 | |a Dallmann-Sauer, Monica |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Allele-dependent interaction of LRRK2 and NOD2 in leprosy |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 11.04.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright: © 2023 Dallmann-Sauer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Nod2 Signaling Adaptor Protein |2 NLM | |
| 650 | 7 | |a NOD2 protein, human |2 NLM | |
| 650 | 7 | |a LRRK2 protein, human |2 NLM | |
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| 650 | 7 | |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 |2 NLM | |
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| 700 | 1 | |a Xu, Yong Zhong |e verfasserin |4 aut | |
| 700 | 1 | |a da Costa, Ana Lúcia França |e verfasserin |4 aut | |
| 700 | 1 | |a Tao, Shao |e verfasserin |4 aut | |
| 700 | 1 | |a Gomes, Tiago Araujo |e verfasserin |4 aut | |
| 700 | 1 | |a Prata, Rhana Berto da Silva |e verfasserin |4 aut | |
| 700 | 1 | |a Correa-Macedo, Wilian |e verfasserin |4 aut | |
| 700 | 1 | |a Manry, Jérémy |e verfasserin |4 aut | |
| 700 | 1 | |a Alcaïs, Alexandre |e verfasserin |4 aut | |
| 700 | 1 | |a Abel, Laurent |e verfasserin |4 aut | |
| 700 | 1 | |a Cobat, Aurélie |e verfasserin |4 aut | |
| 700 | 1 | |a Fava, Vinicius M |e verfasserin |4 aut | |
| 700 | 1 | |a Pinheiro, Roberta Olmo |e verfasserin |4 aut | |
| 700 | 1 | |a Lara, Flavio Alves |e verfasserin |4 aut | |
| 700 | 1 | |a Probst, Christian M |e verfasserin |4 aut | |
| 700 | 1 | |a Mira, Marcelo T |e verfasserin |4 aut | |
| 700 | 1 | |a Schurr, Erwin |e verfasserin |4 aut | |
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