NDLI: Deciphering the molecular and cellular atlas of immune cells in septic patients with different bacterial infections

Content Provider	Springer Nature : BioMed Central
Author	Sun, Ping Cui, Mintian Jing, Jiongjie Kong, Fanyu Wang, Shixi Tang, Lunxian Leng, Junling Chen, Kun
Abstract	Background Sepsis is a life-threatening organ dysfunction caused by abnormal immune responses to various, predominantly bacterial, infections. Different bacterial infections lead to substantial variation in disease manifestation and therapeutic strategies. However, the underlying cellular heterogeneity and mechanisms involved remain poorly understood. Methods Multiple bulk transcriptome datasets from septic patients with 12 types of bacterial infections were integrated to identify signature genes for each infection. Signature genes were mapped onto an integrated large single-cell RNA (scRNA) dataset from septic patients, to identify subsets of cells associated with different sepsis types, and multiple omics datasets were combined to reveal the underlying molecular mechanisms. In addition, an scRNA dataset and spatial transcriptome data were used to identify signaling pathways in sepsis-related cells. Finally, molecular screening, optimization, and de novo design were conducted to identify potential targeted drugs and compounds. Results We elucidated the cellular heterogeneity among septic patients with different bacterial infections. In Escherichia coli (E. coli) sepsis, 19 signature genes involved in epigenetic regulation and metabolism were identified, of which DRAM1 was demonstrated to promote autophagy and glycolysis in response to E. coli infection. DRAM1 upregulation was confirmed in an independent sepsis cohort. Further, we showed that DRAM1 could maintain survival of a pro-inflammatory monocyte subset, C10_ULK1, which induces systemic inflammation by interacting with other cell subsets via resistin and integrin signaling pathways in blood and kidney tissue, respectively. Finally, retapamulin was identified and optimized as a potential drug for treatment of E. coli sepsis targeting the signature gene, DRAM1, and inhibiting E. coli protein synthesis. Several other targeted drugs were also identified in other types of sepsis, including nystatin targeting C1QA in Neisseria sepsis and dalfopristin targeting CTSD in Streptococcus viridans sepsis. Conclusion Our study provides a comprehensive overview of the cellular heterogeneity and underlying mechanisms in septic patients with various bacterial infections, providing insights to inform development of stratified targeted therapies for sepsis.
Related Links	https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-023-04631-4.pdf
Ending Page	22
Page Count	22
Starting Page	1
File Format	HTM / HTML
ISSN	14795876
DOI	10.1186/s12967-023-04631-4
Journal	Journal of Translational Medicine
Issue Number	1
Volume Number	21
Language	English
Publisher	BioMed Central
Publisher Date	2023-11-02
Access Restriction	Open
Subject Keyword	Biomedicine Medicine Public Health Sepsis Various bacterial infections Multi-omics Cellular heterogeneity Stratified targeted therapies Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology Medicine
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	6.3/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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