Ute Römling Group
Ute Römling Group researches in Multicellular behavior in Enterobacteriaceae, Cyclic di-GMP signaling, Pseudomonas aeruginosa clone C – a world wide prevalent clone and Candida parapsilosis.
Research
Multicellular behavior in Enterobacteriaceae
Multicellular behavior (biofilm formation) is found in almost all prokaryotes. This ancient life style, which has shaped the history of the earth is today generally considered a survival and stress resistance 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 investigate 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.
Cyclic di-GMP signaling
Cyclic di-GMP and other cyclic dinucleotides are ubiquitous second messengers in Bacteria. Cyclic di-GMP, the first cyclic di-nucleotide to be discovered was first identified in Bacteria in 1987 by the group of Moshe Benziman. My group rediscovered cyclic di-GMP in 2004 as a ubiquitous regulator of motility/sessility life style transition. Cyclic di-GMP signaling has since been shown to be involved in a broad range of phenotypes in all bacterial branches of the phylogenetic tree. Furthermore, a variety of novel cyclic di-nucleotides have been discovered since then. Importantly, a cyclic di-nucleotide pathway with 2’-3’-cyclic GMP-AMP has been detected at the heart of innate immunity signaling in eukaryotes.
Major findings: We have (re)discovered cyclic di-GMP as a ubiquitous second messenger in bacteria, and have defined its ubiquitous role in the sessility/motility life style transition. We experimental characterized PilZ as the first cyclic di-GMP receptor. We have also shown that a virulence/benign biofilm life style transition is regulated by cyclic di-GMP in S. typhimurium. Recently, we have identified a cyclic GMP-AMP signaling system in the animal commensal strain Escherichia coli ECOR31.
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.
Major findings: Discovery of world-wide prevalent Pseudomonas aeruginosa clone C and identification of the transmissible locus of protein quality control (TLPQC) as harboring stress resistance components of P. aeruginosa clone C.
Candida parapsilosis
C. parapsilosis is a nosocomial pathogen where biofilm formation is considered to be a major virulence factor. We have recently shown that clinical isolates of C. parapsilosis produce a wide variety of biofilm phenotypes. In particular, certain clinical isolates have the capability to form high differentiated biofilms under certain growth conditions. We are currently investigating 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.
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. The membrane bound BcsG is an alkaline phosphatase superfamily member stabilizing the cellulose synthase and decorating the 1,4 beta-glucan chain with phosphoethanolamine.
Key publications: Zogaj et al, Mol Microbiol, 2001; Fang et al, Mol Microbiol, 2014; Ahmad et al, Microb Cell Factories, 2016; Sun et al, J Mol Biol, 2018
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 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.; Li et al, mBio, 2019.
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. We have developed the concept of c-di-GMP ubiquitously regulating sessility/motility life style transition. Since then, phenotypes mostly related to biofilm formation, motility, the cell cycle, virulence and antimicrobial tolerance, but also a broad variety of other phenotypes have been 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
Pseudomonas aeruginosa clone C
P. aeruginosa clone C is a clone, a cluster of closely related strains spead world-wide and present in patients and aquatic habitats. We have recently identified the P. aeruginosa clone C specific genomic island PACGI-1 with the transmissible locus of protein quality control (TLPQC) mainly dedicated to protein homeostasis and other stress resistant proteins. On this island, we have genetically and biochemically characterized several stress related proteins, a small heat shock protein with holding chaperone activity, a novel stand-alone disaggregase and a membrane-bound FtsH protease to be involved in heat resistance and protein homeostasis.
Key publications: Römling et al, J Infect Dis, 1994; Römling et al, Appl Environ Microbiol, 1994; Römling et al, Environ Microbiol, 2005; Lee et al, Environ Microbil, 2015; Lee et al, PNAS, 2018; Kamal et al, Frontiers Microbiol, 2019.
Candida parapsilosis biofilm formation
We discovered a high spider-like biofilm forming phenotype of C. parapsilosis consisting of hyphae and pseudohyphae.. We could also show that C. parapsilosis forms hyphae under certain environmental conditions independently in parallel with the group of Eleftherios Mylonakis.
Key publications: Pannanusorn et al, Eukaryot Cell, 2014; Shafeeq et al, FEMS Yeast Res, 2019.
Alumni
Funding
- Swedish Research Council - Natural Sciences and Engineering
- Swedish Research Council – Swedish Research Links
- European Commission
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.
Collaborations
Ongoing Collaborations
Within the Karolinska Institutet:
- Roman Zubarev
- 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
News
Cover publication in the Journal of Internal Medicine October 2018. View the Journal of Internal Medicine here
Defended thesis
Congratulations! Happy Fengyang Li after his public PhD defense (May 22, 2020).
Publications
Draft Genome Sequence of the Urinary Catheter Isolate Enterobacter ludwigii CEB04 with High Biofilm Forming Capacity.
Shafeeq S, Wang X, Lünsdorf H, Brauner A, Römling U
Microorganisms 2020 Apr;8(4):
2-Methylcitrate cycle: a well-regulated controller of Bacillus sporulation.
Zheng C, Yu Z, Du C, Gong Y, Yin W, Li X, et al
Environ. Microbiol. 2020 Mar;22(3):1125-1140
ClpG Provides Increased Heat Resistance by Acting as Superior Disaggregase.
Katikaridis P, Meins L, Kamal SM, Römling U, Mogk A
Biomolecules 2019 12;9(12):
Impact of manganese on biofilm formation and cell morphology of Candida parapsilosis clinical isolates with different biofilm forming abilities.
Shafeeq S, Pannanusorn S, Elsharabasy Y, Ramírez-Zavala B, Morschhäuser J, Römling U
FEMS Yeast Res. 2019 09;19(6):
Two FtsH Proteases Contribute to Fitness and Adaptation of Pseudomonas aeruginosa Clone C Strains.
Kamal SM, Rybtke ML, Nimtz M, Sperlein S, Giske C, Trček J, et al
Front Microbiol 2019 ;10():1372
High frequency of double crossover recombination facilitates genome engineering in Pseudomonas aeruginosa PA14 and clone C strains.
Lee C, Kamal SM, Römling U
Microbiology (Reading, Engl.) 2019 07;165(7):757-760
A unique methylation pattern by a type I HsdM methyltransferase prepares for DpnI rare cutting sites in the Pseudomonas aeruginosa PAO1 genome.
Fischer S, Römling U, Tümmler B
FEMS Microbiol. Lett. 2019 03;366(5):
DncV Synthesizes Cyclic GMP-AMP and Regulates Biofilm Formation and Motility in Escherichia coli ECOR31.
Li F, Cimdins A, Rohde M, Jänsch L, Kaever V, Nimtz M, et al
mBio 2019 03;10(2):
Innate Immune Mechanisms with a Focus on Small-Molecule Microbe-Host Cross Talk.
Römling U
J Innate Immun 2019 ;11(3):191-192
Multilocus sequence typing of Shewanella algae isolates identifies disease-causing Shewanella chilikensis strain 6I4.
Martín-Rodríguez AJ, Suárez-Mesa A, Artiles-Campelo F, Römling U, Hernández M
FEMS Microbiol. Ecol. 2019 01;95(1):
JAGN1 is required for fungal killing in neutrophil extracellular traps: Implications for severe congenital neutropenia.
Khandagale A, Lazzaretto B, Carlsson G, Sundin M, Shafeeq S, Römling U, et al
J. Leukoc. Biol. 2018 12;104(6):1199-1213
Structural and Functional Characterization of the BcsG Subunit of the Cellulose Synthase in Salmonella typhimurium.
Sun L, Vella P, Schnell R, Polyakova A, Bourenkov G, Li F, et al
J. Mol. Biol. 2018 09;430(18 Pt B):3170-3189
Biofilm formation - what we can learn from recent developments.
Bjarnsholt T, Buhlin K, Dufrêne YF, Gomelsky M, Moroni A, Ramstedt M, et al
J. Intern. Med. 2018 10;284(4):332-345
The cellulose synthase BcsA plays a role in interactions of Salmonella typhimurium with Acanthamoeba castellanii genotype T4.
Gill MA, Rafique MW, Manan T, Slaeem S, Römling U, Matin A, et al
Parasitol. Res. 2018 Jul;117(7):2283-2289
Stand-alone ClpG disaggregase confers superior heat tolerance to bacteria.
Lee C, Franke KB, Kamal SM, Kim H, Lünsdorf H, Jäger J, et al
Proc. Natl. Acad. Sci. U.S.A. 2018 01;115(2):E273-E282
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 Å, et al
Microbiologyopen 2017 10;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 09;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 Å, Landini P, et al
Crit. Rev. Microbiol. 2018 Feb;44(1):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 AJ, 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 ZX, Dow JM
J. Bacteriol. 2017 03;199(5):
BcsZ inhibits biofilm phenotypes and promotes virulence by blocking cellulose production in Salmonella enterica serovar Typhimurium.
Ahmad I, Rouf SF, 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 MSM, Martin MO, Römling U, Torres VJ
Trends Microbiol. 2016 May;24(5):319-323
Amyloid formation: functional friend or fearful foe?
Bergman P, Roan NR, Römling U, Bevins CL, 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 MY
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 MS, 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 SF, 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 MY, 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 BE, 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 ZX, 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 JO, et al
Free Radic. Biol. Med. 2013 Dec;65():1257-1264
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 MY, 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
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 MA, 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 SF, Ahmad I, Anwar N, Vodnala SK, 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 NL, Lamprokostopoulou A, Chapman TA, Chin JC, 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 CR, Nimtz M, Hinton JC, 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 EG
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 CG, Nelson A, Römling U, Marchini G
Lett. Appl. Microbiol. 2010 Feb;50(2):211-5