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Identification of Virulence Markers of Mycobacterium abscessus for Intracellular Replication in Phagocytes
Published on: September 27, 2018
Heterologous expression of the M. abscessus CBASS system confers phage TM4 resistance in M. smegmatis
Chun-Liang Wang1, Ao-Fei Duan1, Da-Min Pan1
1NHC Key Laboratory of Systems Biology of Pathogens, State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology and Center for Tuberculosis Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 102629, China.
Abstract:
Phage therapy for multidrug-resistant Mycobacterium abscessus is constrained by the narrow lytic spectrum of phages due to unknown antiphage mechanisms. Bacteria deploy various defense strategies to prevent phage infection, but few have been comprehensively characterized in mycobacteria. Mycobacteriophage TM4 successfully delivers DNA into M. abscessus but fails to establish infection. Bioinformatic analyses predicted three candidate phage defense systems and multiple individual putative defense proteins in M. abscessus. Among them, Mab_2091, Mab_2092, and Mab_2093, designated CmaABC, are components of a cyclic oligonucleotide-based antiphage signaling system (CBASS) preventing TM4 infection. However, the inability of TM4 to form plaques even in CBASS-deficient M. abscessus implies the involvement of additional resistance mechanisms. Our findings underscore the challenges faced by mycobacteriophages in infecting M. abscessus, and highlight the complex interactions between this pathogen and its viral adversaries.
Insights
Mycobacterium abscessus employs cyclic oligonucleotide-based antiphage signaling system (CBASS) defenses against phage TM4 infection. Additional resistance mechanisms also impede phage therapy, highlighting challenges in treating this multidrug-resistant pathogen.
Area of Science:
- Microbiology
- Bacteriology
- Virology
Background:
- Phage therapy faces limitations in treating multidrug-resistant Mycobacterium abscessus due to narrow phage lytic spectra.
- Bacterial antiphage mechanisms are diverse, but poorly understood in mycobacteria.
Purpose of the Study:
- To investigate the antiphage mechanisms employed by Mycobacterium abscessus against mycobacteriophage TM4.
- To identify specific defense systems hindering phage infection and therapy.
Main Methods:
- Bioinformatic analysis to predict potential phage defense systems in M. abscessus.
- Experimental validation of identified defense systems, including CBASS components (CmaABC).
Main Results:
- Identified Mab_2091, Mab_2092, and Mab_2093 (CmaABC) as components of a cyclic oligonucleotide-based antiphage signaling system (CBASS) that prevents TM4 infection.
- Demonstrated that TM4 fails to infect M. abscessus even after CBASS deficiency, indicating additional resistance mechanisms.
Conclusions:
- CBASS is a key antiphage system in M. abscessus.
- Multiple, yet uncharacterized, resistance mechanisms contribute to TM4 infection failure.
- Complex host-phage interactions present significant hurdles for developing effective phage therapy against M. abscessus.
