Refine
Year of publication
- 2020 (3) (remove)
Document Type
- Article (2)
- Doctoral Thesis (1)
Language
- English (3) (remove)
Has Fulltext
- yes (3)
Is part of the Bibliography
- no (3)
Keywords
- Staphylococcus aureus (3) (remove)
Institute
Publisher
- MDPI (2)
Staphylococcus aureussuperantigens (SAgs) are among the most potent T cell mitogensknown.They stimulate large fractions of T cells by cross-linking their T cell receptor withmajor histocompatibility complex class-II molecules on antigen presenting cells, resulting in Tcell proliferation and massive cytokine release. To date, 26 different SAgs have been described in thespeciesS. aureus; they comprise the toxic shock syndrome toxin (TSST-1), as well as 25 staphylococcalenterotoxins (SEs) or enterotoxin-like proteins (SEls). SAgs can cause staphylococcal food poisoningand toxic shock syndrome and contribute to the clinical symptoms of staphylococcal infection. Inaddition, there is growing evidence that SAgs are involved in allergic diseases. This review providesan overview on recent epidemiological data on the involvement ofS. aureusSAgs and anti-SAg-IgEin allergy, demonstrating that being sensitized to SEs—in contrast to inhalant allergens—is associatedwith a severe disease course in patients with chronic airway inflammation. The mechanisms by whichSAgs trigger or amplify allergic immune responses, however, are not yet fully understood. Here, wediscuss known and hypothetical pathways by which SAgs can drive an atopic disease
Lipoproteins of Staphylococcus aureus represent a major class of surface proteins, which are anchored to the outer leaflet of the cell membrane. Although they play a key role in the immune response and virulence, the majority of lipoproteins in this organism is still of unknown function. The aim of our study was to investigate the function of so far poorly or uncharacterized lipoproteins in S. aureus strain Newman. To this end, an integrated bioinformatical approach was applied to define the pan-lipoproteome of 123 completely sequenced S. aureus strains. In total, this analysis predicted 192 different potential lipoproteins, with a core lipoproteome of 39 and a variable lipoproteome of 153 lipoproteins. Out of those 192 lipoproteins, 141 are so far functionally uncharacterized. Primarily focusing on members of the core-lipoproteome with unknown or poorly characterized function, 24 lipoproteins or co-encoded neighbor proteins were selected for further characterization. Of those 24 proteins, 20 S. aureus markerless deletion mutants were constructed (S. aureus delta l01 - delta l20) and screened for an altered growth behavior under various conditions. Here, three mutants showed a temperature-sensitive phenotype, two mutants formed aggregates in the TSB of the manufacturer Merck (TSBMerck), and four mutants showed reduced growth under osmotic stress with 8% NaCl. An altered aggregation behavior was observed for four mutants in the presence of Triton X-100 and for eleven mutants in the presence of SDS. Furthermore, ten mutants revealed an impaired biofilm formation capacity as well as reduced hemolytic activity. Interestingly, S. aureus deletion mutants delta l14 (delta NWMN_1435) and delta l16 (delta NWMN_0646) showed an altered phenotype under nearly all tested growth and stress conditions. Most strikingly, both deletion mutants demonstrated dramatic defects in cell morphology and cell division during the transient growth phase in TSBMerck and were therefore selected for further detailed characterization. Electron microscopy imaging of the two mutants revealed an irregular cell shape, increased cell size, multiple displaced division septa, and incomplete separation of daughter cells resulting in the formation of cell aggregates in TSBMerck. Complementarily, microarray-based transcriptome analysis and whole-genome sequencing of S. aureus delta l14 and delta l16 suppressor mutants strongly point to a functional association of both lipoproteins with cell envelope- or cell division-related processes. Specifically, multiple hints suggest a functional connection of both lipoproteins with lipo- or wall teichoic acids. Of note, the phenotypes of S. aureus delta l14 and delta l16 are conditional and appear under some, but not all growth conditions. Thus, it is conceivable that the function of L14 and L16 is modulated by metabolic processes, or that the proteins might be part of a “backup system” becoming important only under certain conditions. Collectively, we propose that L14 and L16 fulfill a basic role in cell envelope- or cell division-related processes under specific growth conditions. Particularly, the activity of L14 and L16 might be necessary for the function or localization of lipo- or wall teichoic acids, and thus, might be linked to the regulation of autolysins. In conclusion, this study reveals important insights into the function of two so far uncharacterized but highly conserved lipoproteins in S. aureus.
Staphylococcus aureus(S. aureus) is a pathobiont of humans as well as a multitude of animalspecies. The high prevalence of multi-resistant and more virulent strains ofS. aureusnecessitatesthe development of new prevention and treatment strategies forS. aureusinfection. Major advancestowards understanding the pathogenesis ofS. aureusdiseases have been made using conventionalmouse models, i.e., by infecting naïve laboratory mice with human-adaptedS. aureusstrains. However,the failure to transfer certain results obtained in these murine systems to humans highlights thelimitations of such models. Indeed, numerousS. aureusvaccine candidates showed promising resultsin conventional mouse models but failed to offer protection in human clinical trials. These limitationsarise not only from the widely discussed physiological differences between mice and humans, but alsofrom the lack of attention that is paid to the specific interactions ofS. aureuswith its respectivehost. For instance, animal-derivedS. aureuslineages show a high degree of host tropism and carry arepertoire of host-specific virulence and immune evasion factors. Mouse-adaptedS. aureusstrains,humanized mice, and microbiome-optimized mice are promising approaches to overcome theselimitations and could improve transferability of animal experiments to human trials in the future.