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Exoproteomic profiling uncovers critical determinants for virulence of livestock-associated and human-originated Staphylococcus aureus ST398 strains.

ABSTRACT: Staphylococcus aureus: with the sequence type (ST) 398 was previously associated with livestock carriage. However, in recent years livestock-independent S. aureus ST398 has emerged, representing a potential health risk for humans especially in nosocomial settings. Judged by whole-genome sequencing analyses, the livestock- and human originated strains belong to two different S. aureus ST398 clades but, to date, it was not known to what extent these clades differ in terms of actual virulence. Therefore, the objective of this study was to profile the exoproteomes of 30 representative S. aureus ST398 strains by mass spectrometry, to assess clade-specific differences in virulence factor secretion, and to correlate the identified proteins and their relative abundance to the strains' actual virulence. Although the human-originated strains are more heterogeneous at the genome level, our observations show that they are more homogeneous in terms of virulence factor production than the livestock-associated strains. To assess differences in virulence, infection models based on larvae of the wax moth Galleria mellonella and the human HeLa cell line were applied. Correlation of the exoproteome data to larval killing and toxicity toward HeLa cells uncovered critical roles of the staphylococcal Sbi, SpA, SCIN and CHIPS proteins in virulence. These findings were validated by showing that sbi or spa mutant bacteria are attenuated in G. mellonella and that the purified SCIN and CHIPS proteins are toxic for HeLa cells. Altogether, we show that exoproteome profiling allows the identification of critical determinants for virulence of livestock-associated and human-originated S. aureus ST398 strains.

SUBMITTER: Zhao X

PROVIDER: S-EPMC7550020 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An increasing number of severe infections caused by Staphylococcus aureus ST398 strains has been observed. However, it has not been elucidated whether all ST398 strains are equally virulent. We collected 13 strains from China and Canada to test in a Caenorhabditis elegans infection model and compared their whole genome sequences (WGS) to explore potential insights into their virulence. All isolates belonged to ST398-methicillin-susceptible S. aureus (MSSA) with variant spa types (t034, t571, t1451, t1250). Pulsed field gel electrophoresis (PFGE) and WGS analyses showed that the 13 isolates clustered into 3 genomic types (Types A-C). WGS and prophage phylogenetic analyses also revealed that the strains could be divided into 3 phage groups (Groups 1-3), which correlated with high-, moderate-, and low-nematocidal activities, with mean killing rates of 94, 67, and 40%, respectively. Group 1 carried ?Sa3-Group 1 (?Sa3-G1), Group 2 carried ?Sa3-G2, and Group 3 lacked ?Sa3. Interestingly, strain GD1706 (that genetically clustered within Type C) and strain GD487 (within Type B) both carried ?Sa3-G1 like phages and killed 92% of the nematodes, similar to the Type A strains carrying ?Sa3-G1. This study demonstrated that different ST398 sub-lineages possess variable virulence capacities, depending on the presence or absence, as well as the structure of the prophage ?Sa3 that carries virulence factors. IMPORTANCE:Since first being reported in the early 2000s, Staphylococcus aureus ST398 has not only become recognized as a frequent colonizing strain in economically important livestock animals, but has also proven to be a concern for infection in humans and, in particular, has been linked to higher rates of severe invasive human infections. We collected ST398 strains from China and Canada to test in a worm (Caenorhabditis elegans) infection model and compared their whole genome sequences to gain insight into pathogenesis. We have shown that different ST398 sub-strains differ in their virulence potential based on the presence or absence and structure of prophage ?Sa3, which carries important virulence factors. Our observations suggest that ST398 strains are relatively heterogeneous from a clinical perspective, and more studies are needed to differentiate between virulent and non-virulent ST398 strains to determine the true global spread of relevant sub-strains.

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Exoproteomic profiling uncovers critical determinants for virulence of livestock-associated and human-originated Staphylococcus aureus ST398 strains.

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