Project Details
Projekt
A role for the ESX-4 Type VII secretion system in interbacterial competition in the opportunistic pathogen Mycobacterium abscessus?
Applicant
Dr. Nicole Mietrach
Subject Area
Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
Term
from 2022 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 496149397
The Type VII secretion system (T7SS) was discovered ~20 years ago in Mycobacterium tuberculosis and was linked to pathogenicity of the bacterium. In following years, it was shown that not only Actinobacteria like Mycobacterium abscessus, Mycobacterium smegmatis, Thermomonospora curvata but also Firmicutes such as Streptococcus intermedius, Staphylococcus aureus, Bacillus subtilis encode this system. The two systems are distantly related and now called T7SSa and T7SSb, respectively. The T7SSb in S. aureus and S. intermedius was shown to be involved in bacterial competition. These bacteria encode anti-bacterial toxins with adjacent immunity genes for self-protection, which are secreted by the T7SSb. A bioinformatic study showed that Listeria monocytogenes strains collectively encode ~50 different T7SSb toxin/immunity genes, suggesting an important role for the T7SSb in bacterial antagonism. By contrast, the T7SSa has not been associated with bacterial competition. The T7SSa is heavily studied in pathogenic mycobacteria, which can encode up to five of these systems, designated ESX-1 to ESX-5. At least three of these are major players in virulence, including roles in phagosomal escape and ion acquisition. M. abscessus is a fast-growing non-tuberculous mycobacterium that is an opportunistic pathogen. The bacterium is being increasingly detected in infections of vulnerable patients with respiratory pathologies, particularly with cystic fibrosis. M. abscessus is highly competitive and rapidly becomes a dominant pathogen within its niche, overcoming well-established bacteria. Little is known about the mechanisms that M. abscessus uses for competitive colonisation. It encodes two T7SSa; ESX-3 and ESX-4. At present there is limited knowledge about the role of either of these systems in M. abscessus. It has been reported that ESX-3 modulates host inflammatory response during infection, while a single study on ESX-4 has shown that it is required for survival/replication in the host. My preliminary genomic analysis of the T7SSa systems of M. abscessus identified a large family of proteins containing a T7SS-targeting domain combined with a toxin domain, and a potential immunity protein encoded adjacently. These proteins appear to be genetically linked to ESX-4. Across M. abscessus sequenced genomes I have identified >40 different toxins, of which each strain encodes between 7 to 10. I propose that M. abscessus uses its ESX-4 T7SSa for antibacterial warfare. To test my hypothesis, I will characterize potential toxin/immunity proteins and detect their secretion via the T7SSa. In addition, I will analyse the contribution of these toxins, along with ESX-3 and ESX-4 to virulence and intraspecies competition. This study may ultimately identify the T7SSa as an apparatus for bacterial competition, assigning an unexpected role to the Mycobacterial ESX-systems.
DFG Programme
WBP Fellowship
International Connection
United Kingdom
