STING-Dependent 2'-5' Oligoadenylate Synthetase-Like Production Is Required for Intracellular Mycobacterium leprae...

Area of Science:

• Immunology
• Microbiology
• Genetics

Background:

• Cytosolic nucleic acid detection triggers type I interferon (IFN) responses, vital for combating intracellular pathogens.
• Leprosy, caused by Mycobacterium leprae, involves complex host-pathogen interactions within immune cells.

Purpose of the Study:

• To investigate the host gene expression profile in Mycobacterium leprae-infected human cells.
• To identify key host factors, particularly within the type I IFN pathway, that influence M. leprae infection.

Main Methods:

• Global gene expression profiling of M. leprae-infected primary human Schwann cells.
• Validation of gene expression in various human cell types and patient samples.
• OASL knockdown experiments to assess its role in M. leprae viability and host immune responses.
• Investigation of the signaling pathways (e.g., STING) involved in M. leprae-induced OASL expression.

Main Results:

• 2'-5' oligoadenylate synthetase-like (OASL) showed the highest upregulation in M. leprae-infected Schwann cells and was confirmed in macrophages, monocytes, and patient lesions.
• OASL knockdown led to reduced M. leprae viability, increased antimicrobial peptide expression, and enhanced autophagy.
• MCP-1/CCL2 release was downregulated upon OASL knockdown.
• M. leprae-induced OASL expression depends on cytosolic DNA sensing via stimulator of IFN genes (STING) signaling.
• Exogenous M. leprae DNA promoted BCG survival, suppressed antimicrobial peptides, and increased MCP-1/CCL2.

Conclusions:

• OASL plays a pro-mycobacterial role in M. leprae infection by modulating the host immune response.
• OASL directs the host immune environment to favor M. leprae survival.
• Targeting OASL may represent a novel therapeutic strategy for leprosy.