@phdthesis{Groma2021,
  author    = {Groma, Michaela},
  title     = {Identification of a novel LysR-type transcriptional regulator in \(Staphylococcus\) \(aureus\)},
  doi       = {10.25972/OPUS-24675},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246757},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Staphylococcus aureus is a facultative pathogen which causes a variety of infections. The treatment of staphylococcal infections is complicated because the bacteria is resistant to multiple common antibiotics. S. aureus is also known to express a variety of virulence factors which modulate the host's immune response in order to colonize and invade certain host cells, leading to the host cell's death. Among the virulence factors is a LysR-type transcriptional regulator (lttr) which is required for efficient colonization of secondary organs. In a recent report, which used transposon screening on S. aureus-infected mice, it was found that the amount of a novel lttr852 mutant bacteria recovered from the kidneys was significantly lower compared to the wildtype strains. This doctoral thesis therefore focused on phenotypical and molecular characterization of lttr852. An assessment of the S. aureus biofilm formation and the hemolysis revealed that lttr852 was not involved in the regulation of these virulence processes. RNA-sequencing for potential target genes of lttr852 identified differentially expressed genes that are involved in branched chain amino-acid biosynthesis, methionine sulfoxide reductase and copper transport, as well as a reduced transcription of genes encoding urease and of components of pyrimidine nucleotides. Promoter fusion with GFP reporters as as well as OmniLog were used to identify conditions under which the lttr852 was active. The promoter studies showed that glucose and high temperatures diminish the lttr852 promoter activity in a time-dependent manner, while micro-aerobic conditions enhanced the promoter activity. Copper was found to be a limiting factor. In addition, the impact on promoter activity of the lttr852 was tested in the presence of various regulators, but no central link to the genes involved in virulence was identified. The present work, thus, showed that lttr852, a new member of the class of LysR-type transcriptional regulators in S. aureus, has an important role in the rapid adaptation of S. aureus to the changing microenvironment of the host.},
  language  = {en}
}
@article{GromaHorstDasetal.2020,
  author    = {Groma, Michaela and Horst, Sarah A. and Das, Sudip and Huettel, Bruno and Klepsch, Maximilian and Rudel, Thomas and Medina, Eva and Fraunholz, Martin},
  title     = {Identification of a Novel LysR-Type Transcriptional Regulator in Staphylococcus aureus That Is Crucial for Secondary Tissue Colonization during Metastatic Bloodstream Infection},
  series = {mbio},
  volume    = {11},
  journal   = {mbio},
  number    = {4},
  doi       = {10.1128/mBio.01646-20},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230473},
  year      = {2020},
  abstract  = {Staphylococcus aureus is a common cause of bacteremia that can lead to severe complications once the bacteria exit the bloodstream and establish infection in secondary organs. Despite its clinical relevance, little is known about the bacterial factors facilitating the development of these metastatic infections. Here, we used an S. aureus transposon mutant library coupled to transposon insertion sequencing (Tn-Seq) to identify genes that are critical for efficient bacterial colonization of secondary organs in a murine model of metastatic bloodstream infection. Our transposon screen identified a LysR-type transcriptional regulator (LTTR), which was required for efficient colonization of secondary organs such as the kidneys in infected mice. The critical role of LTTR in secondary organ colonization was confirmed using an isogenic mutant deficient in the expression of LTTR. To identify the set of genes controlled by LTTR, we used an S. aureus strain carrying the LTTR gene in an inducible expression plasmid. Gene expression analysis upon induction of LTTR showed increased transcription of genes involved in branched-chain amino acid biosynthesis, a methionine sulfoxide reductase, and a copper transporter as well as decreased transcription of genes coding for urease and components of pyrimidine nucleotides. Furthermore, we show that transcription of LTTR is repressed by glucose, is induced under microaerobic conditions, and required trace amounts of copper ions. Our data thus pinpoints LTTR as an important element that enables a rapid adaptation of S. aureus to the changing host microenvironment. IMPORTANCE Staphylococcus aureus is an important pathogen that can disseminate via the bloodstream and establish metastatic infections in distant organs. To achieve a better understanding of the bacterial factors facilitating the development of these metastatic infections, we used in this study a Staphylococcus aureus transposon mutant library in a murine model of intravenous infection, where bacteria first colonize the liver as the primary infection site and subsequently progress to secondary sites such as the kidney and bones. We identified a novel LysR-type transcriptional regulator (LTTR), which was specifically required by S. aureus for efficient colonization of secondary organs. We also determined the transcriptional activation as well as the regulon of LTTR, which suggests that this regulator is involved in the metabolic adaptation of S. aureus to the host microenvironment found in secondary infection sites.},
  language  = {en}
}
@article{EisenreichRudelHeesemannetal.2019,
  author    = {Eisenreich, Wolfgang and Rudel, Thomas and Heesemann, J{\"u}rgen and Goebel, Werner},
  title     = {How viral and intracellular bacterial pathogens reprogram the metabolism of host cells to allow their intracellular replication},
  series = {Frontiers in Cellular and Infection Microbiology},
  volume    = {9},
  journal   = {Frontiers in Cellular and Infection Microbiology},
  issn      = {2235-2988},
  doi       = {10.3389/fcimb.2019.00042},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197188},
  year      = {2019},
  abstract  = {Viruses and intracellular bacterial pathogens (IBPs) have in common the need of suitable host cells for efficient replication and proliferation during infection. In human infections, the cell types which both groups of pathogens are using as hosts are indeed quite similar and include phagocytic immune cells, especially monocytes/macrophages (MOs/MPs) and dendritic cells (DCs), as well as nonprofessional phagocytes, like epithelial cells, fibroblasts and endothelial cells. These terminally differentiated cells are normally in a metabolically quiescent state when they are encountered by these pathogens during infection. This metabolic state of the host cells does not meet the extensive need for nutrients required for efficient intracellular replication of viruses and especially IBPs which, in contrast to the viral pathogens, have to perform their own specific intracellular metabolism to survive and efficiently replicate in their host cell niches. For this goal, viruses and IBPs have to reprogram the host cell metabolism in a pathogen-specific manner to increase the supply of nutrients, energy, and metabolites which have to be provided to the pathogen to allow its replication. In viral infections, this appears to be often achieved by the interaction of specific viral factors with central metabolic regulators, including oncogenes and tumor suppressors, or by the introduction of virus-specific oncogenes. Less is so far known on the mechanisms leading to metabolic reprogramming of the host cell by IBPs. However, the still scant data suggest that similar mechanisms may also determine the reprogramming of the host cell metabolism in IBP infections. In this review, we summarize and compare the present knowledge on this important, yet still poorly understood aspect of pathogenesis of human viral and especially IBP infections.},
  language  = {en}
}