publications of the junior research group infection biology of
Salmonella (IBIS)
http://hdl.handle.net/10033/620650
2024-03-28T10:14:01ZExpression of the MexXY aminoglycoside efflux pump and presence of an aminoglycoside modifying enzyme in clinical isolates are highly correlated.
http://hdl.handle.net/10033/622532
Expression of the MexXY aminoglycoside efflux pump and presence of an aminoglycoside modifying enzyme in clinical isolates are highly correlated.
Seupt, Alexander; Schniederjans, Monika; Tomasch, Jürgen; Häussler, Susanne
The impact of MexXY efflux pump expression on aminoglycoside resistance in clinical Pseudomonas aeruginosa isolates has been debated. In this study, we found that in general, elevated mexXY gene expression levels in clinical P. aeruginosa isolates confer to slight increases in aminoglycoside MIC levels, however those levels rarely lead to clinically relevant resistance phenotypes. The main driver of resistance in the clinical isolates studied here was the acquisition of aminoglycoside modifying enzymes (AMEs). Nevertheless, acquisition of an AME was strongly associated with mexY overexpression. In line with this observation, we demonstrate that the introduction of a gentamicin acetyl-transferase confers to full gentamicin resistance levels in a P. aeruginosa type strain only if the MexXY efflux pump was active. We discuss that increased mexXY activity in clinical AME harboring P. aeruginosa isolates might affect ion fluxes at the bacterial cell membrane and thus might play a role in the establishment of enhanced fitness that extends beyond aminoglycoside resistance.
2020-10-12T00:00:00ZRegulation of Flagellum Biosynthesis in Response to Cell Envelope Stress in Serovar Typhimurium.
http://hdl.handle.net/10033/621383
Regulation of Flagellum Biosynthesis in Response to Cell Envelope Stress in Serovar Typhimurium.
Spöring, Imke; Felgner, Sebastian; Preuße, Matthias; Eckweiler, Denitsa; Rohde, M; Häussler, Susanne; Weiss, Siegfried; Erhardt, Marc
Flagellum-driven motility of serovar Typhimurium facilitates host colonization. However, the large extracellular flagellum is also a prime target for the immune system. As consequence, expression of flagella is bistable within a population of , resulting in flagellated and nonflagellated subpopulations. This allows the bacteria to maximize fitness in hostile environments. The degenerate EAL domain protein RflP (formerly YdiV) is responsible for the bistable expression of flagella by directing the flagellar master regulatory complex FlhDC with respect to proteolytic degradation. Information concerning the environmental cues controlling expression of and thus about the bistable flagellar biosynthesis remains ambiguous. Here, we demonstrated that RflP responds to cell envelope stress and alterations of outer membrane integrity. Lipopolysaccharide (LPS) truncation mutants of Typhimurium exhibited increasing motility defects due to downregulation of flagellar gene expression. Transposon mutagenesis and genetic profiling revealed that σ (RpoE) and Rcs phosphorelay-dependent cell envelope stress response systems sense modifications of the lipopolysaccaride, low pH, and activity of the complement system. This subsequently results in activation of RflP expression and degradation of FlhDC via ClpXP. We speculate that the presence of diverse hostile environments inside the host might result in cell envelope damage and would thus trigger the repression of resource-costly and immunogenic flagellum biosynthesis via activation of the cell envelope stress response. Pathogenic bacteria such as Typhimurium sense and adapt to a multitude of changing and stressful environments during host infection. At the initial stage of gastrointestinal colonization, uses flagellum-mediated motility to reach preferred sites of infection. However, the flagellum also constitutes a prime target for the host's immune response. Accordingly, the pathogen needs to determine the spatiotemporal stage of infection and control flagellar biosynthesis in a robust manner. We found that uses signals from cell envelope stress-sensing systems to turn off production of flagella. We speculate that downregulation of flagellum synthesis after cell envelope damage in hostile environments aids survival of during late stages of infection and provides a means to escape recognition by the immune system.
2018-05-01T00:00:00ZOptimizing Salmonella enterica serovar Typhimurium for bacteria-mediated tumor therapy.
http://hdl.handle.net/10033/621281
Optimizing Salmonella enterica serovar Typhimurium for bacteria-mediated tumor therapy.
Felgner, Sebastian; Kocijancic, Dino; Frahm, Michael; Curtiss, Roy; Erhardt, Marc; Weiss, Siegfried
Bacteria-mediated tumor therapy using Salmonella enterica serovar Typhimurium is a therapeutic option with great potential. Numerous studies explored the potential of Salmonella Typhimurium for therapeutic applications, however reconciling safety with vectorial efficacy remains a major issue. Recently we have described a conditionally attenuated Salmonella vector that is based on genetic lipopolysaccharide modification. This vector combines strong attenuation with appropriate anti-tumor properties by targeting various cancerous tissues in vivo. Therefore, it was promoted as an anti-tumor agent. In this addendum, we summarize these findings and demonstrate additional optimization steps that may further improve the therapeutic efficacy of our vector strain.
2016-01-01T00:00:00ZA brewing understanding of the regulation of Bax function by Bcl-xL and Bcl-2.
http://hdl.handle.net/10033/621163
A brewing understanding of the regulation of Bax function by Bcl-xL and Bcl-2.
Renault, Thibaud T; Dejean, Laurent M; Manon, Stéphen
Bcl-2 family members form a network of protein-protein interactions that regulate apoptosis through permeabilization of the mitochondrial outer membrane. Deciphering this intricate network requires streamlined experimental models, including the heterologous expression in yeast. This approach had previously enabled researchers to identify domains and residues that underlie the conformational changes driving the translocation, the insertion and the oligomerization of the pro-apoptotic protein Bax at the level of the mitochondrial outer membrane. Recent studies that combine experiments in yeast and in mammalian cells have shown the unexpected effect of the anti-apoptotic protein Bcl-xL on the priming of Bax. As demonstrated with the BH3-mimetic molecule ABT-737, this property of Bcl-xL, and of Bcl-2, is crucial to elaborate about how apoptosis could be reactivated in tumoral cells.
2017-01-01T00:00:00Z