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Mycobacterium tuberculosis PE_PGRS19 Induces Pyroptosis through a Non-Classical Caspase-11/GSDMD Pathway in
Jianing Qian1, Youwei Hu1, Xiao Zhang1
1State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai 200438, China.
Abstract:
The PE/PPE protein family commonly exists in pathogenic species, such as Mycobacterium tuberculosis, suggesting a role in virulence and its maintenance. However, the exact role of most PE/PPE proteins in host-pathogen interactions remains unknown. Here, we constructed a recombinant Mycobacterium smegmatis expressing M. tuberculosis PE_PGRS19 (Ms_PE_PGRS19) and found that PE_PGRS19 overexpression resulted in accelerated bacterial growth in vitro, increased bacterial survival in macrophages, and enhanced cell damage capacity. Ms_PE_PGRS19 also induced the expression of pro-inflammatory cytokines, such as IL-6, TNF-α, IL-1β, and IL-18. Furthermore, we demonstrated that Ms_PE_PGRS19 induced cell pyroptosis by cleaving caspase-11 via a non-classical pathway rather than caspase-1 activation and further inducing the cleavage of gasdermin D, which led to the release of IL-1β and IL-18. To the best of our current knowledge, this is the first report of a PE/PPE family protein activating cell pyroptosis via a non-classical pathway, which expands the knowledge on PE/PPE protein functions, and these pathogenic factors involved in bacterial survival and spread could be potential drug targets for anti-tuberculosis therapy.
Insights
Mycobacterium tuberculosis PE_PGRS19 protein enhances bacterial growth and survival. It triggers pyroptosis, a cell death pathway, offering potential new drug targets for tuberculosis treatment.
Area of Science:
- Microbiology
- Immunology
- Molecular Biology
Background:
- PE/PPE proteins are common in pathogenic bacteria like Mycobacterium tuberculosis.
- Their precise roles in host-pathogen interactions are largely unknown.
- Understanding these proteins is crucial for developing anti-tuberculosis strategies.
Purpose of the Study:
- To investigate the function of Mycobacterium tuberculosis PE_PGRS19 protein.
- To elucidate its role in host-pathogen interactions and bacterial virulence.
- To explore its potential as a therapeutic target.
Main Methods:
- Constructed a recombinant Mycobacterium smegmatis strain overexpressing M. tuberculosis PE_PGRS19 (Ms_PE_PGRS19).
- Assessed bacterial growth, survival in macrophages, and cell damage capacity.
- Analyzed the induction of pro-inflammatory cytokines and pyroptosis pathway activation.
Main Results:
- Overexpression of Ms_PE_PGRS19 accelerated bacterial growth and enhanced survival in macrophages.
- Ms_PE_PGRS19 increased bacterial cell damage capacity and induced pro-inflammatory cytokines (IL-6, TNF-α, IL-1β, IL-18).
- Ms_PE_PGRS19 induced pyroptosis by cleaving caspase-11 and gasdermin D, releasing IL-1β and IL-18.
Conclusions:
- Ms_PE_PGRS19 promotes bacterial virulence and survival through pyroptosis induction.
- This study reveals a novel non-classical pathway for PE/PPE protein-mediated pyroptosis.
- PE_PGRS19 represents a potential drug target for combating tuberculosis.
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