Ute Römling Group
Multicellular behavior in Enterobacteriaceae
Multicellular behavior (biofilm formation) is found in almost all prokaryotes. It is generally considered a survival mechanism, which is induced upon nutrient starvation. In the clinical setting, bacteria, which build up biofilms, cause persistent infections and colonize indwelling devices. Members of the Enterobacteriaceae, among them Salmonella typhimurium, Escherichia coli and others, cause a high percentage of nosocomial and community acquired infections whereby some are biofilm-related infections. In addition, transmission, colonization and persistence of the organisms include a biofilm component.
Our model system is the rdar morphotype, a bacterial colony morphology biofilm behavior characterized by the expression of amyloid curli fimbriae and the exopolysaccharide cellulose. This morphotype is commonly expressed by S. typhimurium and Escherichia coli.
We are interested the regulatory network leading to rdar morphotype expression through the transcriptional regulator CsgD in Enterobacteriaceae. Our research focuses on cyclic di-GMP, a novel secondary messenger in Bacteria, which regulates rdar morphotype expression on several levels. In addition, we characterize extracellular matrix components of biofilms and investigate their role in bacteria-host interactions.
Major findings: We have identified the orphan transcriptional regulator CsgD as a major activator of the rdar colony morphology biofilm and the exopolysaccharide cellulose as an extracellular matrix component of the rdar biofilm. In addition, we have (re)discovered cyclic di-GMP as a ubiquitous second messenger in bacteria, which regulates the sessility/motility life style transition. We have also shown that a virulence/benign biofilm life style transition is regulated by cyclic di-GMP in S. typhimurium.
Pseudomonas aeruginosa clone C – a world wide prevalent clone
The population structure of Pseudomonas aeruginosa is endemic with the occasional emergence of highly successful clones. We have identified the P. aeruginosa clone C strain cluster, which has been found to be prevalent in acute and chronic infections in patients world-wide as well as in the aquatic habitat.
Successful spread of P. aeruginosa clone C members might be a population-wide phenomenon where specific features on the core genome provide an advantage. As an alternative, individual strains of the clonal population harbor distinct genetic elements, which provide an advantage. A combination of these two components is also possible.
We investigate the molecular mechanism of persistence, transmission and infection of highly successful P. aeruginosa clone C members. In this context, we have recently identified the P. aeruginosa clone C specific genomic island PACGI-1 partially dedicated to protein homeostasis. On this island, we have characterized a small heat shock protein with holding chaperone activity to be involved in heat resistance and protein homeostasis.
C. parapsilosis is a nosocomial pathogen where biofilm formation is considered to be a major virulence factor. We have recently shown that C. parapsilosis can form differentiated biofilms under certain growth conditions. We currently investigate the molecular basis of C. parapsilosis biofilm formation.
We offer Master thesis project work to highly interested and qualified applicants. Please ask for possibilities for a project for post-graduate and post-doctoral studies.
Swedish Research Council - Natural Sciences and Engineering
Swedish Research Council – Swedish Research Links
Multicellular morphotype and biofilm behavior in Salmonella typhimurium
Multicellular rdar behavior in bacteria has impact for the survival of cells in the natural environments, but is also causing disease in medical settings.
Extracellular matrix components
The multicellular rdar morphotype in Salmonella typhimurium is characterized by the expression of an extracellular matrix composed of among other components, thin aggregative fimbriae and the exopolysaccharide cellulose.
Recently, we have shown that the cellulase BcsZ is required for downregulation of cellulose in the rdar biofilm as well as for the efficient expression of virulence phenotypes.
Key publications: Zogaj et al, Mol Microbiol, 2001; Ahmad et al, Microb Cell Factories, 2016
Regulation of the rdar morphotype
The multicellular morphotype is controlled by the expression of the transcriptional regulator CsgD a major regulator of multicellular behavior in S. Typhimurium. CsgD expression is highly regulated by a variety of environmental conditions and global regulatory proteins. Expression of the multicellular rdar morphotype is directed by a complex regulatory network that is only partially explored.
Most importantly, the novel secondary messenger cyclic di-GMP affects CsgD expression. At least eight di-guanylate cyclases and phosphodiesterases are regulating CsgD expression. In addition, CsgD regulates the di-guanylate cyclase AdrA, which is required for the activation of cellulose
Figure 3: Cyclic di-GMP signaling network leading to rdar morphotype and CsgD expression (from Simm et al., Future Microbiol, 2014)
biosynthesis. Currently, we are investigating the molecular mechanisms leading to csgD expression including by c-di-GMP signaling.
Key publications: Römling et al, Mol Microbiol, 1998; Römling et al, J Bacteriol, 1998; Römling et al, Mol Microbiol, 2000; Gerstel and Römling, Environ Microbiol, 2001; Gerstel et al, Mol Microbiol, 2003
Cyclic di-GMP signaling
Cyclic di-GMP is a novel secondary signaling molecule in Bacteria. It was originally discovered by the group around Moshe Benziman as an allosteric activator of cellulose synthase in Gluconacetobacter xylinus 20 years ago.
In 2004, our group and, independently, the group of Urs Jenal and Andrew Camilli, demonstrated that cyclic di-GMP is a novel secondary messenger in Bacteria. Since then, phenotypes mostly related to biofilm formation and motiliy, but also other phenotypes such as virulence are discovered to be cyclic di-GMP dependent in many bacteria.
Key publications: Römling et al, Mol Microbiol, 2000; Simm et al, Mol Microbiol, 2004; Kader et al, Mol Microbiol, 2006; Simm et al, J Bacteriol, 2007; Rouf et al, PloS One, 2013.
Role of biofilm formation in bacterial-host interaction
The rdar morphotype is expressed by pathogenic S. Typhimurium isolates. We could recently show that cyclic di-GMP is a potent inhibitor of virulence phenotypes in Salmonella typhimurium mediated by complex mechanisms among them upregulation of the exopolysaccharide cellulose. Cellulose production is downregulated by the cellulase BcsZ, which is required for efficient expression of virulence.
In addition, rdar biofilm formation by commensal E. coli isolates also regulates bacterial-host interactions.
Key publications: Wang et al, CMLS, 2006; Lamprokostopoulou et al, Environ Microbiol, 2010; Ahmad et al, PloS One, 2013; Ahmad et al, Microb Cell Factories, 2016
ESCMID (European Society of Clinical Microbiology and Infectious Diseases)
Young Investigator Award for Research in Clinical Microbiology and Infectious Diseases 2000
Sir Hans Krebs-Preis 1997 der Gesellschaft der Freunde der Medizinischen Hochschule e.V.
Within the Karolinska Institutet
- Birgitta Agerberth
- Annelie Brauner
- Ylva Lindquist
- Mikael Rhen
- Gunter Schneider
- Sun Nyunt Wai, University of Umeå
- Gerhard Wagner, Uppsala University
- Bernd Bukau and Axel Mogk, University of Heidelberg, ZMBH Department, Germany
- Iqbal Choudhary, University of Karachi, Pakistan
- Michael Galperin, National Institute of Health, Bethesda, USA
- Mark Gomelsky, University of Wyoming, USA
- Zhao-Xun Liang, Nanyang Technological University, Singapore
- Heinrich Lünsdorf, Helmholtz Center of Infection Biology, Braunschweig, Germany
- Joachim Morschhäuser, University of Würzburg, Germany
- Manfred Nimtz and Lothar Jänsch, Helmholtz Center of Infection Biology, Braunschweig, Germany
|Shady Kamal||Doktorand, Forskarstuderande|
|Fengyang Li||Doktorand, Forskarstuderande|
Cover publication in the Journal of Internal Medicine October 2018