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Cellular and molecular determinants of bacterial burden in leprosy granulomas revealed by single-cell multimodal omics.
Mi, Zihao; Wang, Zhenzhen; Wang, Yi; Xue, Xiaotong; Liao, Xiaojie; Wang, Chuan; Sun, Lele; Lin, Yingjie; Wang, Jianwen; Guo, Dianhao; Liu, Tingting; Liu, Jianjun; Modlin, Robert L; Liu, Hong; Zhang, Furen.
Afiliação
  • Mi Z; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Wang Z; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Wang Y; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Xue X; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Liao X; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Wang C; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Sun L; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Lin Y; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Wang J; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Guo D; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Liu T; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China.
  • Liu J; Laboratory of Human Genomics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), Singapore, Republic of Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
  • Modlin RL; Division of Dermatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: RModlin@mednet.ucla.edu.
  • Liu H; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China. Electronic address: hongyue2519@hotmail.com.
  • Zhang F; Hospital for Skin Diseases, Shandong First Medical University, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Shandong, China. Electronic address: zhangfuren@hotmail.com.
EBioMedicine ; 108: 105342, 2024 Sep 24.
Article em En | MEDLINE | ID: mdl-39321499
ABSTRACT

BACKGROUND:

Which cell populations that determine the fate of bacteria in infectious granulomas remain unclear. Leprosy, a granulomatous disease with a strong genetic predisposition, caused by Mycobacterium leprae infection, exhibits distinct sub-types with varying bacterial load and is considered an outstanding disease model for studying host-pathogen interactions.

METHODS:

We performed single-cell RNA and immune repertoire sequencing on 11 healthy controls and 20 patients with leprosy, and integrated single-cell data with genome-wide genetic data on leprosy. Multiplex immunohistochemistry, and in vitro and in vivo infection experiments were conducted to confirm the multimodal omics findings.

FINDINGS:

Lepromatous leprosy (L-LEP) granulomas with high bacterial burden were characterised by exhausted CD8+ T cells, and high RGS1 expression in CD8+ T cells was associated with L-LEP. By contrast, tuberculoid leprosy (T-LEP) granulomas with low bacterial burden displayed enrichment in resident memory IFNG+ CD8+ T cells (CD8+ Trm) with high GNLY expression. This enrichment was potentially attributable to the communication between IL1B macrophages and CD8+ Trm via CXCL10-CXCR3 signalling. Additionally, IL1B macrophages in L-LEP exhibited anti-inflammatory phenotype, with high APOE expression contributing to high bacterial burden. Conversely, IL1B macrophages in T-LEP were distinguished by interferon-γ induced GBP family genes.

INTERPRETATION:

The state of IL1B macrophages and functional CD8+ T cells, as well as the relationship between them, is crucial for controlling bacterial persistence within granulomas. These insights may indicate potential targets for host-directed immunotherapy in granulomatous diseases caused by mycobacteria and other intracellular bacteria.

FUNDING:

The Key research and development program of Shandong Province (2021LCZX07), Natural Science Foundation of Shandong Province (ZR2023MH046), Youth Science Foundation Cultivation Funding Plan of Shandong First Medical University (Shandong Academy of Medical Sciences) (202201-123), National Natural Science Foundation of China (82471800, 82230107, 82273545, 82304039), the China Postdoctoral Science Foundation (2023M742162), Shandong Province Taishan Scholar Project (tspd20230608), Joint Innovation Team for Clinical & Basic Research (202410), Central guidance for local scientific and technological development projects of Shandong Province (YDZX2023058).
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: EBioMedicine Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Holanda
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: EBioMedicine Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Holanda