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Evolution of hypervirulence during bloodstream adaptation of CA-MRSA strain USA300

ABSTRACT: The epidemic community-acquired methicillin-resistant S. aureus (CA-MRSA) clone USA300 has recently become a leading cause of hospital-associated bloodstream infections (BSI). Leveraging this recent introduction into hospitals and the limited genetic variation across the USA300 strains, we combined microbial comparative genomics with phenotypic analyses to discover adaptive mutations. USA300 isolates from BSI were found to have independently evolved single nucleotide variants in the transcriptional regulator sarZ. sarZ inactivation lead to altered expression of virulence factors, resulting in increased lethality in a murine model of BSI. Thus, USA300 strains can optimize their fitness in hospitals through evolution of higher virulence.

ORGANISM(S): Staphylococcus aureus

PROVIDER: GSE185544 | GEO | 2022/10/08

REPOSITORIES: GEO

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Gene expression analysis of Staphyloccoccus aureus USA300 vs USA300 agr knockout.

Project description:The study aims to compare gene expression patterns of Staphyloccoccus aureus USA300 wild type (reference) vs USA300 agr knockout(query). The agr quorum sensing system is an important regulator of density dependent gene expression. To determine the role of agr in USA300 virulence a agr mutant was constructed and differential gene expression compared to the parental wildtype.

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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is the causative agent of serious hospital- and community-associated infections. Due to the global rise in community-associated MRSA, the respective lineages are increasingly introduced into hospitals. This raises the question whether and, if so, how they adapt to this new environment. The present study was aimed at investigating how MRSA isolates of the USA300 lineage, infamous for causing infections in the general population, have adapted to the hospital environment. To this end, a collection of community- and hospital-associated USA300 isolates was compared by RNA-sequencing. Here we report that merely 460 genes were differentially expressed between these two epidemiologically distinct groups, including genes for virulence factors, oxidative stress responses and the purine, pyrimidine and fatty acid biosynthetic pathways. Differentially regulated virulence factors included leukotoxins and phenol-soluble modulins, implicated in staphylococcal escape from immune cells. We therefore investigated the ability of the studied isolates to survive internalization by human neutrophils. This showed that the community-associated isolates have the highest neutrophil-killing activity, while the hospital-associated isolates are better adapted to intra-neutrophil survival. Importantly, the latter trait protects internalized staphylococci against a challenge with antibiotics. We therefore conclude that prolonged intra-neutrophil survival serves as a relatively simple early adaptation of S. aureus USA300 to the hospital environment where antibiotic pressure is high.

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Project description:The success of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) as pathogens is due to a combination of antibiotic resistance with high virulence. However, evolution of the exceptional virulence potential of CA-MRSA is not understood. Our previous study indicated that differential gene expression contributes substantially to this process. Thus, we here investigated the role of the pivotal virulence gene regulatory system agr in the most prevalent CA-MRSA strain USA300. Using a mouse subcutaneous infection model, we show that agr is essential for the development of CA-MRSA skin infections, the most frequent manifestation of disease caused by CA-MRSA. Furthermore, genome-wide analysis of gene expression revealed significant differences in agr-dependent virulence gene regulation between CA-MRSA, HA-MRSA, and laboratory strains. Our findings demonstrate that agr functionality is critical for CA-MRSA disease and indicate that an adaptation of the agr regulon to optimize expression of a broad set of virulence determinants may have contributed to the evolution of exceptionally pronounced virulence of CA-MRSA strains. Keywords: wild type vs mutant

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Role of the accessory gene regulator agr in community-associated MRSA pathogenesis

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Gene expression analysis of Staphyloccoccus aureus USA300 vs USA300 sae knockout

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Genetic Variation in Spatio-Temporal Confined USA300 Community-Associated MRSA Isolates: A Shift from Clonal Dispersion to Genetic Evolution?

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Analysis of gene expression of the lungs of mice challenged intratracheally with methicillin-resistant Staphylococcus aureus（MRSA） USA300 clone

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