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The Role of TSC1 in the Macrophages Against Vibrio vulnificus Infection
Xian-Hui Huang1,2,3, Yao Ma1,2,4, Han Lou5
1Department of Microbiology and Immunology, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China.
Abstract:
Vibrio vulnificus (V. vulnificus) is an estuarine bacterium that is capable of causing rapidly fatal infection in humans. Proper polarization and bactericidal activity of macrophages play essential roles in defending against invading pathogens. How macrophages limit V. vulnificus infection remains not well understood. Here we report that tuberous sclerosis complex 1 (TSC1) is crucial for the regulation of V. vulnificus-induced macrophage polarization, bacterial clearance, and cell death. Mice with myeloid-specific deletion of TSC1 exhibit a significant reduction of survival time after V. vulnificus infection. V. vulnificus infection induces both M1 and M2 polarization. However, TSC1 deficient macrophages show enhanced M1 response to V. vulnificus infection. Interestedly, the absence of TSC1 in myeloid cells results in impaired bacterial clearance both in vivo and in vitro after V. vulnificus infection. Inhibition of the mammalian target of rapamycin (mTOR) activity significantly reverses V. vulnificus-induced hypersensitive M1 response and resistant bactericidal activity both in wild-type and TSC1-deficient macrophages. Moreover, V. vulnificus infection causes cell death of macrophages, possibly contributes to defective of bacterial clearance, which also exhibits in a mTORC1-dependent manner. These findings highlight an essential role for the TSC1-mTOR signaling in the regulation of innate immunity against V. vulnificus infection.
Insights
Tuberous sclerosis complex 1 (TSC1) is vital for macrophage response to Vibrio vulnificus (V. vulnificus) infection. Loss of TSC1 impairs bacterial clearance and survival, highlighting the TSC1-mTOR pathway
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Vibrio vulnificus (V. vulnificus) causes severe human infections.
- Macrophages are key in fighting pathogens, but their role in V. vulnificus infection is unclear.
- Tuberous sclerosis complex 1 (TSC1) is a protein complex involved in cell growth and metabolism.
Purpose of the Study:
- To investigate the role of TSC1 in macrophage response to V. vulnificus infection.
- To elucidate the mechanisms by which TSC1 regulates macrophage polarization, bacterial clearance, and cell death.
- To determine the involvement of the TSC1-mammalian target of rapamycin (mTOR) signaling pathway.
Main Methods:
- Utilized mouse models with myeloid-specific deletion of TSC1.
- Performed in vivo and in vitro experiments to assess bacterial clearance.
- Analyzed macrophage polarization (M1/M2) and cell death.
- Investigated the effect of mTOR inhibition on macrophage responses.
Main Results:
- Myeloid-specific deletion of TSC1 reduced survival in mice infected with V. vulnificus.
- TSC1 deficiency led to enhanced M1 macrophage polarization but impaired bacterial clearance.
- Inhibition of mTOR reversed V. vulnificus-induced hypersensitive M1 response and improved bactericidal activity.
- Macrophage cell death during infection was dependent on mTORC1 signaling.
Conclusions:
- TSC1 is critical for regulating macrophage polarization and bacterial clearance against V. vulnificus.
- The TSC1-mTOR signaling pathway plays a crucial role in innate immunity against V. vulnificus.
- Targeting the TSC1-mTOR pathway may offer therapeutic strategies for V. vulnificus infections.
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