Abstract
Staphylococcus aureus is a major human pathogen, and a leading cause of soft tissue and blood stream infections. One of the causes of its success as a pathogen is the peculiar array of immune evasion factors through which the bacterium avoids host defenses, where the staphylococcal protein A (SpA) plays a major role thanks to its IgG binding activities. Moreover, SpA has recently been proposed as a promising vaccine antigen. In this study, we evaluated the expression of SpA in a collection of staphylococcal strains, about 7% of which did not express SpA (SpA- strains), despite the presence of the gene. By a comparative genomic analysis, we identified that a mutation in the spa 5′ UTR sequence affecting the RBS is responsible for the loss of SpA in a subset of SpA- strains. Using a high-throughput qRT-PCR approach on a selected panel of virulence-related genes, we identified that the SpA- phenotype is associated with lower spa transcript levels and increased expression and production of capsule as well as other changes in the transcription of several key virulence factors. Our data suggest that the SpA- phenotype has occurred in geographically distinct strains through different molecular mechanisms including both mutation, leading likely to translation alterations, and transcriptional deregulation. Furthermore, we provide evidence that SpA- strains are highly susceptible to phagocytic uptake mediated by anti-capsule antibodies. These data suggest that S. aureus may alter its virulence factor expression pattern as an adaptation to the host or environment. Vaccination strategies targeting both SpA and capsule could therefore result in broader coverage against staphylococcal isolates than SpA alone.
Highlights
Staphylococcus aureus is a Gram-positive bacterium that colonizes the human nares and skin (Kluytmans et al, 1997; Wertheim et al, 2005)
The collection included strains belonging to 33 different sequence types (ST) (Figure 1A), of which the largest portion was composed of ST5 (39 isolates) and ST8 (20 isolates), which are the most common types globally, FIGURE 1 | staphylococcal protein A (SpA) expression screening in a large panel of strains. (A) Lineages represented in the S. aureus collection
The SpA negative (SpA−) strains include members of clonal complex (CC) 5: Mu50 (Hiramatsu et al, 1997), four strains isolated in United States (MB01, MM1, MM2, and S27), two isolates from Italy (ITSA18 and ITSA19); and two laboratory strains belonging to CC25, Lowenstein (ATCC 49521) and Reynolds (Fournier et al, 1987)
Summary
Staphylococcus aureus is a Gram-positive bacterium that colonizes the human nares and skin (Kluytmans et al, 1997; Wertheim et al, 2005). Factors involved in colonization (cell wall-associated proteins with adhesive and tissue-binding functions) are preferentially expressed during the exponential phase of an in vitro growth curve, while proteins involved in dissemination and spreading of the infection (exoproteins, proteases, toxins, haemolysins) are more likely to be expressed in the stationary phase (Cheung et al, 2004) This expression profile is the result of a highly complex and interconnected regulation that enables the pathogen to respond to external stimuli and environmental changes (Wang and Muir, 2016; Haag and Bagnoli, 2017). Immunization of mice with this mutated protein protected from infection in a subsequent challenge with S. aureus USA300, determining an increase in the IgG titers of other staphylococcal antigens as compared with non-immunized control animals (Kim et al, 2010)
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