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PreprintCC BY-NC-NDbioRxiv

Shared and distinct immunometabolic states link to divergent pathology in cutaneous mycobacterial infections

  • H. Guo
  • R. Zeng
  • Q. Wei
  • J. Xiong
  • H. Jiang
  • Y. Shi
  • W. Zhang
  • C. Pan
  • C. Cheng
  • H. Wang1
  • Y. Wang1
  1. 1Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences
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Abstract

Cutaneous mycobacterial infections provide a common tissue setting in which related intracellular pathogens elicit distinct pathological responses, but the innate immune basis of this divergence remains incompletely understood. Here, we combined single-cell profiling from 33 individuals with histological and functional analyses, examining healthy skin and lesions from multibacillary leprosy (MB), paucibacillary leprosy (PB), cutaneous tuberculosis (CTB) and Mycobacterium marinum infection (Mari). All infections showed lower mononuclear phagocyte and higher natural killer (NK) cell proportions within the CD45 compartment, alongside shared and infection-associated dendritic cell, macrophage and NK cell programs. CTB and Mari displayed broader macrophage antimicrobial signatures, whereas MB showed lipid-associated programs and attenuated interferon-associated effector expression across multiple macrophage subsets. Reduced expression of fructose-1,6-bisphosphatase 1 (FBP1) was associated with the absence of Langhans giant cells in MB, and pharmacological FBP1 inhibition nearly abolished fusion of macrophages. Compared with NK cells from Mari, MB NK cells showed reduced central carbon and oxidative metabolism signatures alongside increased lipid-associated programs. Functional experiments showed that inhibition of glucose utilization, disruption of mitochondrial function, or co-culture with foamy macrophages abundant in MB lesions reduced NK cell IFN-{gamma} production. These findings identify shared and distinct innate immune programs and suggest that their interplay with local metabolic environments shapes divergent pathology across cutaneous mycobacterial infections.

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Cite

BibTeXRIS
BibTeX
@misc{guo2026shared,
  title = {{Shared and distinct immunometabolic states link to divergent pathology in cutaneous mycobacterial infections}},
  author = {H. Guo and R. Zeng and Q. Wei and J. Xiong and H. Jiang and Y. Shi and W. Zhang and C. Pan and C. Cheng and H. Wang and Y. Wang},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.19.760140},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.19.760140v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Shared and distinct immunometabolic states link to divergent pathology in cutaneous mycobacterial infections
AU  - H. Guo
AU  - R. Zeng
AU  - Q. Wei
AU  - J. Xiong
AU  - H. Jiang
AU  - Y. Shi
AU  - W. Zhang
AU  - C. Pan
AU  - C. Cheng
AU  - H. Wang
AU  - Y. Wang
PY  - 2026
DA  - 2026/10/19
PB  - bioRxiv
DO  - 10.64898/2026.10.19.760140
UR  - https://www.biorxiv.org/content/10.64898/2026.10.19.760140v1
AB  - Cutaneous mycobacterial infections provide a common tissue setting in which related intracellular pathogens elicit distinct pathological responses, but the innate immune basis of this divergence remains incompletely understood. Here, we combined single-cell profiling from 33 individuals with histological and functional analyses, examining healthy skin and lesions from multibacillary leprosy (MB), paucibacillary leprosy (PB), cutaneous tuberculosis (CTB) and Mycobacterium marinum infection (Mari). All infections showed lower mononuclear phagocyte and higher natural killer (NK) cell proportions within the CD45 compartment, alongside shared and infection-associated dendritic cell, macrophage and NK cell programs. CTB and Mari displayed broader macrophage antimicrobial signatures, whereas MB showed lipid-associated programs and attenuated interferon-associated effector expression across multiple macrophage subsets. Reduced expression of fructose-1,6-bisphosphatase 1 (FBP1) was associated with the absence of Langhans giant cells in MB, and pharmacological FBP1 inhibition nearly abolished fusion of macrophages. Compared with NK cells from Mari, MB NK cells showed reduced central carbon and oxidative metabolism signatures alongside increased lipid-associated programs. Functional experiments showed that inhibition of glucose utilization, disruption of mitochondrial function, or co-culture with foamy macrophages abundant in MB lesions reduced NK cell IFN-{gamma} production. These findings identify shared and distinct innate immune programs and suggest that their interplay with local metabolic environments shapes divergent pathology across cutaneous mycobacterial infections.
ER  -