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Freeze-Thaw Microfluidic System Produces "Themis" Nanocomplex for Cleaning Persisters-Infected Macrophages and
Mingyue Su1, Mengying Yin1, Yifu Zhou1
1School of stomatology, Lanzhou University, Lanzhou, 730000, China.
Abstract:
Macrophages are the primary effectors against potential pathogen infections. They can be "parasitized" by intracellular bacteria, serving as "accomplices", protecting intracellular bacteria and even switching them to persisters. Here, using a freeze-thaw strategy-based microfluidic chip, a "Themis" nanocomplex (TNC) is created. The TNC consists of Lactobacillus reuteri-derived membrane vesicles, heme, and vancomycin, which cleaned infected macrophages and enhanced uninfected macrophages. In infected macrophages, TNC releases heme that led to the reconstruction of the respiratory chain complexes of intracellular persisters, forcing them to regrow. The revived bacteria produces virulence factors that destroyed host macrophages (accomplices), thereby being externalized and becoming vulnerable to immune responses. In uninfected macrophages, TNC upregulates the TCA cycle and oxidative phosphorylation (OXPHOS), contributing to immunoenhancement. The combined effect of TNC of cleaning the accomplice (infected macrophages) and reinforcing uninfected macrophages provides a promising strategy for intracellular bacterial therapy.
Insights
A novel Themis nanocomplex (TNC) therapy revives dormant intracellular bacteria, causing them to destroy infected macrophages and enhancing immune cells. This dual action offers a promising strategy for treating bacterial infections.
Area of Science:
- Immunology
- Microbiology
- Biotechnology
Background:
- Macrophages are crucial immune cells that combat pathogens but can be compromised by intracellular bacteria.
- Intracellular bacteria can evade immune responses by residing within macrophages, becoming dormant or
- persisters
- and are difficult to eradicate with conventional antibiotics.
Purpose of the Study:
- To develop a novel therapeutic strategy targeting intracellular bacteria within macrophages.
- To investigate the efficacy of a newly created Themis nanocomplex (TNC) in combating intracellular bacterial infections and enhancing host immunity.
Main Methods:
- A microfluidic chip with a freeze-thaw strategy was utilized to create the TNC.
- The TNC, composed of Lactobacillus reuteri-derived membrane vesicles, heme, and vancomycin, was applied to infected and uninfected macrophages.
Main Results:
- In infected macrophages, TNC released heme, reconstructing bacterial respiratory chains and forcing dormant bacteria to regrow.
- Regrown bacteria produced virulence factors, leading to the destruction of infected host macrophages and externalization of bacteria for immune clearance.
- In uninfected macrophages, TNC enhanced the TCA cycle and oxidative phosphorylation (OXPHOS), boosting immune function.
Conclusions:
- The TNC effectively clears infected macrophages by reviving and enabling bacteria to destroy their host.
- The TNC simultaneously enhances uninfected macrophages, providing a dual therapeutic approach for intracellular bacterial infections.
- This strategy presents a promising new avenue for the treatment of challenging bacterial infections that reside within host cells.
