[R03] Emerging Pathogen Stenotrophomonas maltophilia and its Antibacterial T2SS

Ente: National Institute of Allergy and Infectious Diseases

Scadenza: 2028-06-30

Importo max: 80.000 EUR

Paese: US

Descrizione

PROJECT SUMMARY / ABSTRACT Gram-negative Stenotrophomonas maltophilia (Sm) is an emerging human pathogen, causing, among other things, pneumonia and bacteremia. Sm especially afflicts persons with compromised defenses, e.g., cystic fibrosis patients. Sm infections are very often polymicrobial in nature, with the co-infecting bacteria including the Gram-negative pathogen Pseudomonas aeruginosa and the Gram-positive pathogen Staphylococcus aureus. Overall, Sm infections can be very difficult to treat due to the multi-drug resistance of Sm strains. Since Sm is often part of mixed infections, defining the interactions between Sm and other bacteria is likely important for understanding pathogenesis. We previously found that the Sm type IV protein secretion system (T4SS) confers a contact-dependent antibacterial activity against P. aeruginosa. Recently, others found that some strains of Sm encode a type VI protein secretion system (T6SS) that is also capable of killing other Gram-‘s. Though Sm can kill S. aureus upon co-incubation, neither the T4SS nor the T6SS has proven to be required for that effect, implying that Sm has yet additional means for antagonizing competitors, especially Gram+ ones. Interbacterial antagonism encompasses all major phyla, and over many years, its mechanisms have been revealed to include secreted metabolites, peptidic bacteriocins, and larger protein secretion systems, including not only the above- mentioned T6SS and T4SS but also forms of T3SS, T5SS, T7SS, and T9SS. Despite this, the Gram- type II protein secretion system (T2SS), though very well studied for other reasons, has been essentially ignored for its role in interbacterial competition. Thus, we tested the hypothesis that the Sm T2SS is important for Sm’s interactions with co-infecting S. aureus. We observed that cell-free, culture supernatant samples obtained from wild-type Sm majorly reduced S. aureus numbers. However, supernatant samples obtained from a Sm mutant specifically lacking the XpsF T2SS (but not the samples obtained from the mutant’s complemented derivative) were significantly impaired in the ability to decrease S. aureus numbers. Combined, these data indicated that Sm secretes through its Xps T2SS an anti-staphylococcal protein(s) that appears to be bactericidal in nature. Supporting these data, in silico analysis of the Sm genome revealed proteins with potential to be Xps T2SS- dependent mediators of interbacterial antagonism. Thus, this R03 proposal aims to identify and then begin to biochemically characterize the Sm T2SS secreted substrate(s) that mediates the observed bactericidal effect on S. aureus and perhaps other clinically relevant microbes. Overall, this work i) will advance our understanding of Sm pathogenesis, interbacterial antagonism, and the T2SS, and ii) have the potential to reveal new bactericidal mechanisms as well as secreted proteins that may be useful as new antimicrobial agents. Istituzione: NORTHWESTERN UNIVERSITY PI: NICHOLAS P CIANCIOTTO Progetto: 1R03AI195773-01A1

Settori: National Institute of Allergy and Infectious Diseases

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