Ute Römling Group

Research

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.

 

Candida parapsilosis

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.

 

Funding

Swedish Research Council - Natural Sciences and Engineering
Swedish Research Council – Swedish Research Links
European Commission

 

Recent Projects

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

Publications

Alterations of c-di-GMP turnover proteins modulate semi-constitutive rdar biofilm formation in commensal and uropathogenic Escherichia coli.
Cimdins A, Simm R, Li F, Lüthje P, Thorell K, Sjöling , et al
Microbiologyopen 2017 Oct;6(5):

Stand-Alone EAL Domain Proteins Form a Distinct Subclass of EAL Proteins Involved in Regulation of Cell Motility and Biofilm Formation in Enterobacteria.
El Mouali Y, Kim H, Ahmad I, Brauner A, Liu Y, Skurnik M, et al
J. Bacteriol. 2017 Sep;199(18):

"It's a gut feeling" - Escherichia coli biofilm formation in the gastrointestinal tract environment.
Rossi E, Cimdins A, Lüthje P, Brauner A, Sjöling , Landini P, et al
Crit. Rev. Microbiol. 2017 May;():1-30

Gre factors-mediated control of hilD transcription is essential for the invasion of epithelial cells by Salmonella enterica serovar Typhimurium.
Gaviria-Cantin T, El Mouali Y, Le Guyon S, Römling U, Balsalobre C
PLoS Pathog. 2017 Apr;13(4):e1006312

Detailed analysis of c-di-GMP mediated regulation of csgD expression in Salmonella typhimurium.
Ahmad I, Cimdins A, Beske T, Römling U
BMC Microbiol. 2017 Feb;17(1):27

Draft Genome Sequences of Semiconstitutive Red, Dry, and Rough Biofilm-Forming Commensal and Uropathogenic Escherichia coli Isolates.
Cimdins A, Lüthje P, Li F, Ahmad I, Brauner A, Römling U
Genome Announc 2017 Jan;5(4):

Nucleotide Second Messenger Signaling as a Target for the Control of Bacterial Biofilm Formation.
Martín-Rodríguez A, Römling U
Curr Top Med Chem 2017 Jan;():

Progress in Understanding the Molecular Basis Underlying Functional Diversification of Cyclic Dinucleotide Turnover Proteins.
Römling U, Liang Z, Dow J
J. Bacteriol. 2017 Mar;199(5):

BcsZ inhibits biofilm phenotypes and promotes virulence by blocking cellulose production in Salmonella enterica serovar Typhimurium.
Ahmad I, Rouf S, Sun L, Cimdins A, Shafeeq S, Le Guyon S, et al
Microb. Cell Fact. 2016 Oct;15(1):177

The Endurance of Microbiology: An Interview with Mike Jetten, Mark Martin, Ute Römling, and Victor Torres.
Jetten M, Martin M, Römling U, Torres V
Trends Microbiol. 2016 May;24(5):319-23

Amyloid formation: functional friend or fearful foe?
Bergman P, Roan N, Römling U, Bevins C, Münch J
J. Intern. Med. 2016 Aug;280(2):139-52

Protein homeostasis-more than resisting a hot bath.
Lee C, Wigren E, Lünsdorf H, Römling U
Curr. Opin. Microbiol. 2016 Apr;30():147-154



;():

Bacterial cellulose biosynthesis: diversity of operons, subunits, products, and functions.
Römling U, Galperin M
Trends Microbiol. 2015 Sep;23(9):545-57

Small molecules with big effects: Cyclic di-GMP-mediated stimulation of cellulose production by the amino acid ʟ-arginine.
Römling U
Sci Signal 2015 Jun;8(380):fs12

A novel protein quality control mechanism contributes to heat shock resistance of worldwide-distributed Pseudomonas aeruginosa clone C strains.
Lee C, Wigren E, Trček J, Peters V, Kim J, Hasni M, et al
Environ. Microbiol. 2015 Nov;17(11):4511-26

Dissecting the cyclic di-guanylate monophosphate signalling network regulating motility in Salmonella enterica serovar Typhimurium.
Le Guyon S, Simm R, Rehn M, Römling U
Environ. Microbiol. 2015 Apr;17(4):1310-20

Biofilm formation by enteric pathogens and its role in plant colonization and persistence.
Yaron S, Römling U
Microb Biotechnol 2014 Nov;7(6):496-516

Modulation of biofilm-formation in Salmonella enterica serovar Typhimurium by the periplasmic DsbA/DsbB oxidoreductase system requires the GGDEF-EAL domain protein STM3615.
Anwar N, Rouf S, Römling U, Rhen M
PLoS ONE 2014 ;9(8):e106095

GIL, a new c-di-GMP-binding protein domain involved in regulation of cellulose synthesis in enterobacteria.
Fang X, Ahmad I, Blanka A, Schottkowski M, Cimdins A, Galperin M, et al
Mol. Microbiol. 2014 Aug;93(3):439-52

Dissecting the cyclic di-guanylate monophosphate signalling network regulating motility in Salmonella enterica serovar Typhimurium.
Le Guyon S, Simm R, Rehn M, Römling U
Environ. Microbiol. 2015 Apr;17(4):1310-20

Microbial biofilm formation: a need to act.
Römling U, Kjelleberg S, Normark S, Nyman L, Uhlin B, Åkerlund B
J. Intern. Med. 2014 Aug;276(2):98-110

Draft Genome Sequence of Pseudomonas aeruginosa SG17M, an Environmental Isolate Belonging to Clone C, Prevalent in Patients and Aquatic Habitats.
Lee C, Peters V, Melefors O, Römling U
Genome Announc 2014 Mar;2(2):

Characterization of biofilm formation and the role of BCR1 in clinical isolates of Candida parapsilosis.
Pannanusorn S, Ramírez-Zavala B, Lünsdorf H, Agerberth B, Morschhäuser J, Römling U
Eukaryotic Cell 2014 Apr;13(4):438-51

Finally! The structural secrets of a HD-GYP phosphodiesterase revealed.
Wigren E, Liang Z, Römling U
Mol. Microbiol. 2014 Jan;91(1):1-5

The EAL-like protein STM1697 regulates virulence phenotypes, motility and biofilm formation in Salmonella typhimurium.
Ahmad I, Wigren E, Le Guyon S, Vekkeli S, Blanka A, El Mouali Y, et al
Mol. Microbiol. 2013 Dec;90(6):1216-32

Control of pathogen growth and biofilm formation using a urinary catheter that releases antimicrobial nitrogen oxides.
Kishikawa H, Ebberyd A, Römling U, Brauner A, Lüthje P, Lundberg J, et al
Free Radic. Biol. Med. 2013 Dec;65():1257-64

Microbiology: bacterial communities as capitalist economies.
Römling U
Nature 2013 May;497(7449):321-2

Prevalence of biofilm formation in clinical isolates of Candida species causing bloodstream infection.
Pannanusorn S, Fernandez V, Römling U
Mycoses 2013 May;56(3):264-72

Cyclic di-GMP: the first 25 years of a universal bacterial second messenger.
Römling U, Galperin M, Gomelsky M
Microbiol. Mol. Biol. Rev. 2013 Mar;77(1):1-52

Biofilm infections, their resilience to therapy and innovative treatment strategies.
Römling U, Balsalobre C
J. Intern. Med. 2012 Dec;272(6):541-61

Cyclic di-GMP, an established secondary messenger still speeding up.
Römling U
Environ. Microbiol. 2012 Aug;14(8):1817-29

Cyclic di-GMP, an established secondary messenger still speeding up.
Römling U
Environ. Microbiol. 2012 Aug;14(8):1817-29

Hfq and Hfq-dependent small RNAs are major contributors to multicellular development in Salmonella enterica serovar Typhimurium.
Monteiro C, Papenfort K, Hentrich K, Ahmad I, Le Guyon S, Reimann R, et al
RNA Biol 2012 Apr;9(4):489-502

Complex c-di-GMP signaling networks mediate transition between virulence properties and biofilm formation in Salmonella enterica serovar Typhimurium.
Ahmad I, Lamprokostopoulou A, Le Guyon S, Streck E, Barthel M, Peters V, et al
PLoS ONE 2011 ;6(12):e28351

Regulation of biofilm components in Salmonella enterica serovar Typhimurium by lytic transglycosylases involved in cell wall turnover.
Monteiro C, Fang X, Ahmad I, Gomelsky M, Römling U
J. Bacteriol. 2011 Dec;193(23):6443-51

Pyrosequencing of a hypervariable region in the internal transcribed spacer 2 to identify clinical yeast isolates.
Pannanusorn S, Elings M, Römling U, Fernandez V
Mycoses 2012 Mar;55(2):172-80

Opposing contributions of polynucleotide phosphorylase and the membrane protein NlpI to biofilm formation by Salmonella enterica serovar Typhimurium.
Rouf S, Ahmad I, Anwar N, Vodnala S, Kader A, Römling U, et al
J. Bacteriol. 2011 Jan;193(2):580-2

Virulence characteristics of translocating Escherichia coli and the interleukin-8 response to infection.
Ramos N, Lamprokostopoulou A, Chapman T, Chin J, Römling U, Brauner A, et al
Microb. Pathog. 2011 Feb;50(2):81-6

A 96-well-plate-based optical method for the quantitative and qualitative evaluation of Pseudomonas aeruginosa biofilm formation and its application to susceptibility testing.
Müsken M, Di Fiore S, Römling U, Häussler S
Nat Protoc 2010 Aug;5(8):1460-9

Uropathogenic Escherichia coli modulates immune responses and its curli fimbriae interact with the antimicrobial peptide LL-37.
Kai-Larsen Y, Lüthje P, Chromek M, Peters V, Wang X, Holm A, et al
PLoS Pathog. 2010 Jul;6(7):e1001010

Unphosphorylated CsgD controls biofilm formation in Salmonella enterica serovar Typhimurium.
Zakikhany K, Harrington C, Nimtz M, Hinton J, Römling U
Mol. Microbiol. 2010 Aug;77(3):771-86

Two antisense RNAs target the transcriptional regulator CsgD to inhibit curli synthesis.
Holmqvist E, Reimegård J, Sterk M, Grantcharova N, Römling U, Wagner E
EMBO J. 2010 Jun;29(11):1840-50

Human cathelicidin peptide LL37 inhibits both attachment capability and biofilm formation of Staphylococcus epidermidis.
Hell E, Giske C, Nelson A, Römling U, Marchini G
Lett. Appl. Microbiol. 2010 Feb;50(2):211-5

Earlier Publications

Publications 2003-2009 (pdf)

Publications 1989-2001 (pdf file) (Pdf file, 78 Kb)

 

Awards

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.

Review Articles

Review Articles (pdf file) (Pdf file, 43 Kb)

Book Contributions

Book Contributions (pdf file) (Pdf file, 43 Kb)

Collaborations

Ongoing Collaborations
Within the Karolinska Institutet

  • Birgitta Agerberth
  • Annelie Brauner
  • Ylva Lindquist
  • Mikael Rhen
  • Gunter Schneider

Within Sweden

  • Sun Nyunt Wai, University of Umeå
  • Gerhard Wagner, Uppsala University

International

  • 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

 

Group Members

Professor

Ute Römling

Phone: +46-(0)8-524 873 19
Organizational unit: Ute Römling group
E-mail: Ute.Romling@ki.se

Ute Römling Curriculum Vitae (pdf)

Linnea GustafssonAssociated
Shady KamalPhD student, Graduate Student
Fengyang LiGraduate Student
Ute RömlingProfessor
Sulman ShafeeqPostdoc
Stefanie SperleinAssociated

Alumni

Ute Römling Group alumni

News

Srisuda Pannanusorn successfully defended her thesis on the 6th of September, 2013.

Srisuda Pannanusorn discusses her thesisSrisuda has worked on the characterization of biofilm formation in Candida spp bloodstream isolates collected during one year in Sweden. In addition, Srisuda has characterized the biofilm formation in clinical isolates of Candida parapsilosis and investigated the role of the biofilm regulator Bcr1 in these isolates. The opponent  was Geraldine Butler from the University College Dublin, Ireland and the examination committee consisted of Jan Sjölin, Uppsala University; Erja Chryssanthou, Karolinska Institutet and Volkan Özenci, Karolinska Institutet.

You can find the thesis of Srisuda Pannanusorn in the Open Archive of the Karolinska Institutet’s library here:

Srisuda Pannanusorn thesis