Publikation 1
Willenborg J, Goethe R. (2016). Metabolic traits of pathogenic streptococci. FEBS Lett 590, 3905–3919.
Konzept: Willenborg
Diskussion, Beratung: Willenborg, Goethe Manuskript: Willenborg, Goethe Korrespondenz: Willenborg, Goethe
Publikation 2
Koczula A, Willenborg J*, Bertram R, Takamatsu D, Valentin-Weigand P, Goethe R.
(2014). Establishment of a Cre recombinase based mutagenesis protocol for markerless gene deletion in Streptococcus suis. J Microbiol Methods 107C:80-83.
*corresponding author
Konzept, Versuchsplanung: Willenborg, Goethe Experimentelle Durchführung: Koczula, Willenborg
Diskussion, Beratung: Willenborg, Bertram, Takamatsu, Valentin-Weigand, Goethe
Manuskript: Koczula, Willenborg, Goethe Korrespondenz: Willenborg
Publikation 3
Willenborg J, Huber C, Koczula A, Lange B, Eisenreich W, Valentin-Weigand P, Goethe R. (2015). Characterization of the pivotal carbon metabolism of
Darstellung über den eigenen Anteil an den Publikationen
67
Streptococcus suis serotype 2 under ex vivo and chemically defined in vitro conditions by isotopologue profiling. J Biol Chem 290(9):5840-54.
Konzept, Versuchsplanung: Willenborg, Eisenreich, Valentin-Weigand, Goethe Experimentelle Durchführung: Willenborg, Huber, Koczula, Lange
Diskussion, Beratung: Willenborg, Eisenreich, Valentin-Weigand, Goethe Manuskript: Willenborg, Huber, Eisenreich, Valentin-Weigand,
Goethe Korrespondenz: Willenborg
Publikation 4
Koczula A, Jarek M, Visscher C, Valentin-Weigand P, Goethe, Willenborg J. (2017).
Transcriptomic analysis reveals selective metabolic adaptation of Streptococcus suis to porcine blood and cerebrospinal fluid. Pathogens 6(1), pii: E7.
Konzept, Versuchsplanung: Goethe, Willenborg
Experimentelle Durchführung: Koczula, Jarek, Visscher, Willenborg
Diskussion, Beratung: Koczula, Jarek, Visscher, Valentin-Weigand, Goethe, Willenborg
Manuskript: Koczula, Valentin-Weigand, Goethe, Willenborg Korrespondenz: Willenborg
Publikation 5
Willenborg J, Fulde M, de Greeff A, Rohde M, Smith HE, Valentin-Weigand P, Goethe R. (2011). Role of glucose and CcpA in capsule expression and virulence of Streptococcus suis. Microbiology 157(Pt 6):1823-33.
Konzept, Versuchsplanung: Willenborg, Fulde, Goethe
Experimentelle Durchführung: Willenborg, Fulde, de Greeff, Rohde
Darstellung über den eigenen Anteil an den Publikationen
68
Diskussion, Beratung: Willenborg, Fulde, Smith, Valentin-Weigand, Goethe
Manuskript: Willenborg, Goethe Korrespondenz: Goethe
Publikation 6
Willenborg J, de Greeff A, Jarek M, Valentin-Weigand P, Goethe R. (2014). The CcpA regulon of Streptococcus suis reveals novel insights into the regulation of the streptococcal central carbon metabolism by binding of CcpA to two distinct binding motifs. Mol Microbiol 92(1):61-83.
Konzept, Versuchsplanung: Willenborg, Goethe
Experimentelle Durchführung: Willenborg, de Greeff, Jarek
Diskussion, Beratung: Willenborg, Valentin-Weigand, Goethe Manuskript: Willenborg, Goethe
Korrespondenz: Goethe
Publikation 7
Fulde M*, Willenborg J*, de Greeff A, Benga L, Smith HE, Valentin-Weigand P, Goethe R. (2011). ArgR is an essential local transcriptional regulator of the arcABC operon in Streptococcus suis and is crucial for biological fitness in an acidic environment. Microbiology 157(Pt 2):572-82. *contributed equally
Konzept, Versuchsplanung: Fulde, Willenborg, Goethe
Experimentelle Durchführung: Fulde, Willenborg, de Greeff, Benga
Diskussion, Beratung: Fulde, Willenborg, Smith, Valentin-Weigand, Goethe
Manuskript: Fulde, Willenborg, Goethe Korrespondenz: Goethe
Darstellung über den eigenen Anteil an den Publikationen
69 Publikation 8
Fulde M*, Willenborg J*, Huber C, Hitzmann A, Willms D, Seitz M, Eisenreich W, Valentin-Weigand P, Goethe R. (2014). The arginine-ornithine antiporter ArcD contributes to biological fitness of Streptococcus suis. Front Cell Infect Microbiol 12;
4:107. *contributed equally
Konzept, Versuchsplanung: Fulde, Willenborg, Valentin-Weigand, Goethe Experimentelle Durchführung: Fulde, Willenborg, Huber, Hitzmann, Willms,
Seitz
Diskussion, Beratung: Fulde, Willenborg, Eisenreich, Valentin-Weigand, Goethe
Manuskript: Fulde, Willenborg, Valentin-Weigand, Goethe Korrespondenz: Valentin-Weigand
Publikation 9
Willenborg J*, Koczula A*, Fulde M, de Greeff A, Beineke A, Eisenreich W, Huber C, Seitz M, Valentin-Weigand P, Goethe R. (2016). FlpS, the FNR-Like Protein of Streptococcus suis Is an Essential, Oxygen-Sensing Activator of the Arginine Deiminase System. Pathogens 5(3), pii: E51. *contributed equally
Konzept, Versuchsplanung: Willenborg, Fulde, Valentin-Weigand, Goethe Experimentelle Durchführung: Willenborg, Koczula, Fulde, de Greeff,
Beineke, Huber, Seitz
Diskussion, Beratung: Willenborg, Fulde, Eisenreich, Valentin-Weigand, Goethe
Manuskript: Willenborg, Valentin-Weigand, Goethe
Korrespondenz: Goethe
Danksagung
70 11. Danksagung
Mein ganz besonderer Dank gilt Herrn Prof. Dr. Ralph Goethe, der meine Habilitation unterstützt und mein wissenschaftliches Denken nachhaltig geprägt hat.
Sein Enthusiasmus und sein kritischer Verstand waren jederzeit ein positiver Antrieb unserer gemeinsamen Wissenschaft. Vor allem möchte ich mich dafür bedanken, dass er mir fortlaufend mit Rat und Tat zur Seite stand.
Einen großen Dank möchte ich Herrn Prof. Dr. Peter Valentin-Weigand aussprechen. Er hat mir im Laufe der Jahre am Institut für Mikrobiologie stets die Möglichkeit gegeben, eigenständige Forschungsbereiche zu erschließen, in der universitären Lehre mitzuwirken und mich persönlich weiterzuentwickeln. Für diese Unterstützung bin ich ihm sehr dankbar.
Ein besonderer Dank geht an die beteiligten Doktorandinnen und M.Sc.-Studentinnen, die durch ihren Einsatz einen großen Beitrag zu dieser Habilitationsschrift geleistet haben. Vielen Dank an Dr. Anna Koczula, Dr. Daniela Willms, Louise Prüfer und Kira van Vorst.
Bedanken möchte ich zudem bei allen Kooperationspartnern, die durch ihre konstruktive Zusammenarbeit wesentlich zum Gelingen dieser Arbeit beigetragen haben: Dr. Hilde E. Smith und Dr. Astrid de Greef (beide: Central Veterinary Institute of Wageningen, Lelystad, Niederlande); Birgit Lange, Dr. Claudia Huber, Prof. Dr.
Wolfgang Eisenreich (alle: Lehrstuhl für Biochemie, Technische Universität München); PD Dr. Ralph Bertram (Research Department of the Paracelsus Medical University in Nuremberg); Michael Jarek (Helmholtz Centre for Infection Research, Braunschweig); Jun.-Prof. Dr. Christian Visscher (Institut für Tierernährung, TiHo);
Prof. Dr. Andreas Beineke (Institut für Pathologie, TiHo); Dr. Daisuke Takamatsu (National Agriculture and Food Research Organization, Tsukuba, Japan); Prof. Dr.
Manfred Rohde (Helmholtz Centre for Infection Research, Braunschweig); Prof. Dr.
Karl-Heinz Waldmann, Dr. Alexandra von Altrock und Klaus Schlotter (alle: Klinik für kleine Klauentiere, TiHo); Prof. Dr. Ralph Brehm (Anatomisches Institut, TiHo).
Der Deutschen Forschungsgemeinschaft (DFG) möchte ich für die finanzielle Unterstützung im Rahmen des Schwerpunktprogrammes Host-adapted Metabolism of Bacterial Pathogens (SPP1316) danken.
Danksagung
71
Ein großes Dankeschön für einen nachhaltigen wissenschaftlichen Austausch richtet sich an folgende ehemalige Kolleginnen und Kollegen der Mikrobiologie der TiHo: Prof. Dr. Marcus Fulde, Dr. Andreas Nerlich, Prof. Dr. Christoph Baums, Dr.
Jochen Meens, Dr. Falk Büttner, Dr. Judith Rohde und Dr. Jutta Verspohl.
Mein herzlichster Dank geht an die ehemaligen Kolleginnen und Kollegen der Mikrobiologie der TiHo, die stets für eine hervorragende Arbeitsatmosphäre gesorgt und mich in unterschiedlichsten Anliegen unterstützt haben: Kristin Laarmann, Nina Janze, Dr. Jana Seele, Sabine Baumert, Dr. Elke Goethe, Antonio Eramo, Jörg Merkel, Dr. Jens Abel, Dr. Franziska Müller, Dr. Andreas Mietze, Silke Schiewe, Anja Schulze, Désirée Vötsch, Dr. Laurentiu Benga, Dr. Tina Basler, Dr. Nadine Büttner, Dr. Anna Seydel, Dr. Petra Grüning, Dr. Nicole de Buhr, Sabine Göbel, Dr. Christoph Kock, Ketema Merga Abdissa, Dennis Pägelow, Jörg Henstorf, Claudia Schrader, Werner Scharnhorst, Julian Sander, Dr. Ute Siesenop, Dr. Nantaporn Ruangkiattikul, Dr. Matthias Stehr, Dr. Inka Stolle, Dr. Yenehiwot Berhanu Weldearegay.
Bei meiner wunderbaren Familie möchte ich mich für ihre liebevolle Motivation und ihre großartige Unterstützung bedanken. Insbesondere du, Maren, hast mir in den letzten Wochen den Rücken freigehalten und mich ununterbrochen unterstützt.
Vielen Dank euch allen.
Anhang
72
12. Anhang (9 verwendete Publikationen)
12.1 Publikation 1
Metabolic traits of pathogenic streptococci
Willenborg J, Goethe R.
FEBS Lett. 2016 Jul 21; 590, 3905–3919.
doi:10.1002/1873-3468.12317.
https://www.ncbi.nlm.nih.gov/pubmed/27442496
Abstract
Invasive and noninvasive diseases caused by facultative pathogenic streptococci depend on their equipment with virulence factors and on their ability to sense and adapt to changing nutrients in different host environments. The knowledge of the principal metabolic mechanisms which allow these bacteria to recognize and utilize nutrients in host habitats is a prerequisite for our understanding of streptococcal pathogenicity and the development of novel control strategies. This review aims to summarize and compare the central carbohydrate metabolic and amino acid biosynthetic pathways of a selected group of streptococcal species, all belonging to the naso-oropharyngeal microbiome in humans and/or animals. We also discuss the urgent need of comprehensive metabolomics approaches for a better understanding of the streptococcal metabolism during host-pathogen interaction.
Anhang
12.2 Publikation 2
Establishment of a Cre recombinase based mutagenesis protocol for markerless gene deletion in Streptococcus suis
Koczula A, Willenborg J, Bertram R, Takamatsu D, Valentin-Weigand P, Goethe R.
J Microbiol Methods. 2014 Oct 1; 107C:80-83.
doi:10.1016/j.mimet.2014.09.007.
https://www.ncbi.nlm.nih.gov/pubmed/25281472
Abstract
The lack of knowledge about pathogenicity mechanisms of Streptococcus (S.) suis is, at least partially, attributed to limited methods for its genetic manipulation. Here, we established a Cre-lox based recombination system for markerless gene deletions in S. suis serotype 2 with high selective pressure and without undesired side effects.
Anhang
12.3 Publikation 3
Characterization of the pivotal carbon metabolism of Streptococcus suis serotype 2 under ex vivo and chemically defined in vitro conditions by isotopologue profiling.
Willenborg J, Huber C, Koczula A, Lange B, Eisenreich W, Valentin-Weigand P, Goethe R.
J Biol Chem. 2015 Feb 27; 290(9):5840-54.
doi:10.1074/jbc.M114.619163.
https://www.ncbi.nlm.nih.gov/pubmed/25575595
Abstract
Streptococcus (S.) suis is a neglected zoonotic pathogen that has to adapt to the nutritional requirements in the different host niches encountered during infection and establishment of invasive diseases. To dissect the central metabolic activity of S. suis under different conditions of nutrient availability, we performed labeling experiments starting from [13C]glucose specimens and analyzed the resulting isotopologue patterns in amino acids of S. suis grown under in vitro and ex vivo conditions. In combination with classical growth experiments, we found that S. suis is auxotrophic for Arg, Gln/Glu, His, Leu, and Trp in chemically defined medium. De novo biosynthesis was shown for Ala, Asp, Ser, and Thr at high rates and for Gly, Lys, Phe, Tyr, and Val at moderate or low rates, respectively. Glucose degradation occurred mainly by glycolysis and to a minor extent by the pentose phosphate pathway. Furthermore, the exclusive formation of oxaloacetate by phosphoenolpyruvate (PEP) carboxylation became evident from the patterns in de novo synthesized amino acids. Labeling experiments with S. suis grown ex vivo in blood or cerebrospinal fluid reflected the metabolic adaptation to these host niches with different nutrient availability; however, similar key metabolic activities were identified under these conditions. This points at the robustness of the core metabolic pathways in S. suis during the infection process. The crucial role of PEP carboxylation for growth of S. suis in the host was supported by experiments with a PEP carboxylase-deficient mutant strain in blood and cerebrospinal fluid.
Anhang
12.4 Publikation 4
Transcriptomic analysis reveals selective metabolic adaptation of Streptococcus suis to porcine blood and cerebrospinal fluid.
Koczula A, Jarek M, Visscher C, Valentin-Weigand P, Goethe, Willenborg J.
Pathogens. 2017 Feb 15;6(1). pii: E7.
doi:10.3390/pathogens6010007
https://www.ncbi.nlm.nih.gov/pubmed/28212285
Abstract
Streptococcus (S.) suis is a zoonotic pathogen that can cause severe pathologies such as septicemia and meningitis in its natural porcine host as well as in humans.
Establishment of disease requires not only virulence of the infecting strain but also an appropriate metabolic activity of the pathogen in its host environment. However, it is yet largely unknown how the streptococcal metabolism adapts to the different host niches encountered during infection. Our previous isotopologue profiling studies on S. suis grown in porcine blood and cerebrospinal fluid (CSF) revealed conserved activities of central carbon metabolism in both body fluids. On the other hand, they suggested differences in the de novo amino acid biosynthesis. This prompted us to further dissect S. suis adaptation to porcine blood and CSF by RNA deep sequencing (RNA-seq). In blood, the majority of differentially expressed genes were associated with transport of alternative carbohydrate sources and the carbohydrate metabolism (pentose phosphate pathway, glycogen metabolism). In CSF, predominantly genes involved in the biosynthesis of branched-chain and aromatic amino acids were differentially expressed. Especially, isoleucine biosynthesis seems to be of major importance for S. suis in CSF because several related biosynthetic genes were more highly expressed. In conclusion, our data revealed niche-specific metabolic gene activity which emphasizes a selective adaptation of S. suis to host environments.
Anhang
12.5 Publikation 5
Role of glucose and CcpA in capsule expression and virulence of Streptococcus suis.
Willenborg J, Fulde M, de Greeff A, Rohde M, Smith HE, Valentin-Weigand P, Goethe R.
Microbiology. 2011 Jun; 157(Pt 6):1823-33.
doi:10.1099/mic.0.046417-0.
https://www.ncbi.nlm.nih.gov/pubmed/21349980
Abstract
Streptococcus (S.) suis is one of the most important pathogens in pigs and is also an emerging zoonotic agent. After crossing the epithelial barrier, S. suis causes bacteraemia, resulting in meningitis, endocarditis and bronchopneumonia. Since the host environment seems to be an important regulatory component for virulence, we related expression of virulence determinants of S. suis to glucose availability during growth and to the sugar metabolism regulator catabolite control protein A (CcpA). We found that expression of the virulence-associated genes arcB, representing arcABC operon expression, cps2A, representing capsular locus expression, as well as sly, ofs, sao and epf, differed significantly between exponential and early stationary growth of a highly virulent serotype 2 strain. Deletion of ccpA altered the expression of the surface-associated virulence factors arcB, sao and eno, as well as the two currently proven virulence factors in pigs, ofs and cps2A, in early exponential growth.
Global expression analysis using a cDNA expression array revealed 259 differentially expressed genes in early exponential growth, of which 141 were more highly expressed in the CcpA mutant strain 10ΔccpA and 118 were expressed to a lower extent. Interestingly, among the latter genes, 18 could be related to capsule and cell wall synthesis. Correspondingly, electron microscopy characterization of strain 10ΔccpA revealed a markedly reduced thickness of the capsule. This phenotype correlated with enhanced binding to porcine plasma proteins and a reduced resistance to killing by porcine neutrophils. Taken together, our data demonstrate that CcpA has a significant effect on the capsule synthesis and virulence properties of S. suis.
Anhang
12.6 Publikation 6
The CcpA regulon of Streptococcus suis reveals novel insights into the regulation of the streptococcal central carbon metabolism by binding of CcpA to two distinct binding motifs.
Willenborg J, de Greeff A, Jarek M, Valentin-Weigand P, Goethe R.
Mol Microbiol. 2014 Apr; 92(1):61-83.
doi:10.1128/IAI.00080-14.
https://www.ncbi.nlm.nih.gov/pubmed/24673665
Abstract
Streptococcus suis (S. suis) is a neglected zoonotic streptococcus causing fatal diseases in humans and in pigs. The transcriptional regulator CcpA (catabolite control protein A) is involved in the metabolic adaptation to different carbohydrate sources and virulence of S. suis and other pathogenic streptococci. In this study, we determined the DNA binding characteristics of CcpA and identified the CcpA regulon during growth of S. suis. Electrophoretic mobility shift analyses showed promiscuous DNA binding of CcpA to cognate cre sites in vitro. In contrast, sequencing of immunoprecipitated chromatin revealed two specific consensus motifs, a pseudo-palindromic cre motif (WWGAAARCGYTTTCWW) and a novel cre2 motif (TTTTYHWDHHWWTTTY), within the regulatory elements of the genes directly controlled by CcpA. Via these elements CcpA regulates expression of genes involved in carbohydrate uptake and conversion, and in addition in important metabolic pathways of the central carbon metabolism, like glycolysis, mixed-acid fermentation, and the fragmentary TCA cycle. Furthermore, our analyses provide evidence that CcpA regulates the genes of the central carbon metabolism by binding either the pseudo-palindromic cre motif or the cre2 motif in a HPr(Ser)∼P independent conformation.
Anhang
12.7 Publikation 7
ArgR is an essential local transcriptional regulator of the arcABC operon in Streptococcus suis and is crucial for biological fitness in an acidic environment.
Fulde M*, Willenborg J*, de Greeff A, Benga L, Smith HE, Valentin-Weigand P, Goethe R. *contributed equally
Microbiology. 2011 Feb; 157(Pt 2):572-82.
doi:10.1099/mic.0.043067-0.
https://www.ncbi.nlm.nih.gov/pubmed/20947575
Abstract
Streptococcus suis is one of the most important pathogens in pigs and can also cause severe infections in humans. Despite its clinical relevance, very little is known about the factors that contribute to its virulence. Recently, we identified a new putative virulence factor in S. suis, the arginine deiminase system (ADS), an arginine catabolic enzyme system encoded by the arcABC operon, which enables S. suis to survive in an acidic environment. In this study, we focused on ArgR, an ADS-associated regulator belonging to the ArgR/AhrC arginine repressor family. Using an argR knockout strain we were able to show that ArgR is essential for arcABC operon expression and necessary for the biological fitness of S. suis. By cDNA expression microarray analyses and quantitative real-time RT-PCR we found that the arcABC operon is the only gene cluster regulated by ArgR, which is in contrast to the situation in many other bacteria. Reporter gene analysis with gfp under the control of the arcABC promoter demonstrated that ArgR is able to activate the arcABC promoter.
Electrophoretic mobility shift assays with fragments of the arcABC promoter and recombinant ArgR, and chromatin immunoprecipitation with antibodies directed against ArgR, revealed that ArgR interacts with the arcABC promoter in vitro and in vivo by binding to a region from −147 to −72 bp upstream of the transcriptional start point. Overall, our results show that in S. suis, ArgR is an essential, system-specific transcriptional regulator of the ADS that interacts directly with the arcABC promoter in vivo.
Anhang
12.8 Publikation 8
The arginine-ornithine antiporter ArcD contributes to biological fitness of Streptococcus suis.
Fulde M*, Willenborg J*, Huber C, Hitzmann A, Willms D, Seitz M, Eisenreich W, Valentin-Weigand P, Goethe R. *contributed equally
Front Cell Infect Microbiol. 2014 Aug 12; 4:107.
doi:10.3389/fcimb.2014.00107.
https://www.ncbi.nlm.nih.gov/pubmed/25161959
Abstract
The arginine-ornithine antiporter (ArcD) is part of the Arginine Deiminase System (ADS), a catabolic, energy-providing pathway found in a variety of different bacterial species, including the porcine zoonotic pathogen Streptococcus suis. The ADS has recently been shown to play a role in the pathogenicity of S. suis, in particular in its survival in host cells. The contribution of arginine and arginine transport mediated by ArcD, however, has yet to be clarified. In the present study, we showed by experiments using [U-13C6]arginine as a tracer molecule that S. suis is auxotrophic for arginine and that bacterial growth depends on the uptake of extracellular arginine.
To further study the role of ArcD in arginine metabolism, we generated an arcD-specific mutant strain and characterized its growth compared to the wild-type (WT) strain, a virulent serotype 2 strain. The mutant strain showed a markedly reduced growth in chemically defined media supplemented with arginine when compared to the WT strain, suggesting that ArcD promotes arginine uptake. To further evaluate the in vivo relevance of ArcD, we studied the intracellular bacterial survival of the arcD mutant strain in an epithelial cell culture infection model. The mutant strain was substantially attenuated, and its reduced intracellular survival rate correlated with a lower ability to neutralize the acidified environment. Based on these results, we propose that ArcD, by its function as an arginine-ornithine antiporter, is important for supplying arginine as substrate of the ADS and, thereby, contributes to biological fitness and virulence of S. suis in the host.
Anhang
12.9 Publikation 9
FlpS, the FNR-Like Protein of Streptococcus suis Is an Essential, Oxygen-Sensing Activator of the Arginine Deiminase System.
Willenborg J*, Koczula A*, Fulde M, de Greeff A, Beineke A, Eisenreich W, Huber C, Seitz M, Valentin-Weigand P, Goethe R. *contributed equally
Pathogens. 2016 Jul 21; 5(3). pii: E51.
doi:10.3390/pathogens5030051.
https://www.ncbi.nlm.nih.gov/pubmed/27455333
Abstract
Streptococcus (S.) suis is a zoonotic pathogen causing septicemia and meningitis in pigs and humans. During infection S. suis must metabolically adapt to extremely diverse environments of the host. CcpA and the FNR family of bacterial transcriptional regulators are important for metabolic gene regulation in various bacteria. The role of CcpA in S. suis is well defined, but the function of the FNR-like protein of S. suis, FlpS, is yet unknown. Transcriptome analyses of wild-type S. suis and a flpS mutant strain suggested that FlpS is involved in the regulation of the central carbon, arginine degradation and nucleotide metabolism. However, isotopologue profiling revealed no substantial changes in the core carbon and amino acid de novo biosynthesis. FlpS was essential for the induction of the arcABC operon of the arginine degrading pathway under aerobic and anaerobic conditions. The arcABC-inducing activity of FlpS could be associated with the level of free oxygen in the culture medium. FlpS was necessary for arcABC-dependent intracellular bacterial
Streptococcus (S.) suis is a zoonotic pathogen causing septicemia and meningitis in pigs and humans. During infection S. suis must metabolically adapt to extremely diverse environments of the host. CcpA and the FNR family of bacterial transcriptional regulators are important for metabolic gene regulation in various bacteria. The role of CcpA in S. suis is well defined, but the function of the FNR-like protein of S. suis, FlpS, is yet unknown. Transcriptome analyses of wild-type S. suis and a flpS mutant strain suggested that FlpS is involved in the regulation of the central carbon, arginine degradation and nucleotide metabolism. However, isotopologue profiling revealed no substantial changes in the core carbon and amino acid de novo biosynthesis. FlpS was essential for the induction of the arcABC operon of the arginine degrading pathway under aerobic and anaerobic conditions. The arcABC-inducing activity of FlpS could be associated with the level of free oxygen in the culture medium. FlpS was necessary for arcABC-dependent intracellular bacterial