International Course on Nucleotide Second Messenger Signaling with a Focus on Cyclic Di-GMP Signaling

Jointly Organized by:

COMSTECH Secretariat, Islamabad
International Center for Chemical and Biological Sciences (ICCBS)
Karolinska Institutet, Stockholm, Sweden
Sindh Innovation Research, and Education Network (SIREN)

Dates: 22 May – 2 June, 2023

Introduction to Course

Nucleotide based second messengers are signaling molecules throughout the tree of life. In bacteria, cyclic di-GMP and other cyclic di-nucleotides such as cyclic di-AMP are major second messengers involved in the regulation of fundamental physiological and metabolic processes. Surprisingly, cyclic di-GMP ubiquitously regulates the life style switch between sessility (biofilm formation) and motility, and in the context of pathogens, the life style switch between chronic and acute virulence. The second messenger cyclic di-AMP is involved in the regulation of potassium and osmo homeostasis equally as in cell wall synthesis and rearrangement. Furthermore, other nucleotide second messengers including cyclic AMP-GMP are involved in microbial innate and adaptive immune response. Nucleotide-based second messenger signaling extends into the eukaryotic world with a major role in innate immune defense. Thus, nucleotide-based second messengers ubiquitously fulfill those and other important physiological, metabolic, morphological and behavioral functions in all organisms.


Prof. Dr. Ute Römling, PhD

Professor of Medical Microbial Physiology                        

Department of Microbiology, Tumor and Cell Biology Karolinska Institutet, Stockholm, Sweden

Prof. Ute Römling is Professor of Medical Microbial Physiology at the Karolinska Institutet in Stockholm, Sweden. Her research focuses on the molecular mechanisms of biofilm formation mainly in Enterobacteria such as Salmonella typhimurium and persistence mechanisms of Pseudomonas aeruginosa pandemic clone C. Prof. Romling has 134 publications of original work; 48 peer-reviewed reviews; 2 peer reviewed protocols; 10 popular-scientific publications; 15 book chapters and 1 book editorial. In addition, she has received research grants from the Swedish Research Council, ALF Foundation, European Commission and the German Research Foundation. In 2000, she received the Young Investigator Award for Research in Clinical Microbiology and Infectious Diseases 2000 of the ESCMID (European Society of Clinical Microbiology and Infectious Diseases). In 2013, she organized a Nobel Conference on Biofilm formation in Stockholm. Furthermore, Prof. Romling has been an Associate faculty at the International Center for Chemical Biology and Sciences, University of Karachi, Pakistan since 2016. Furthermore, she is a member of The European Academy of Microbiology since 2017 and Member USERN since 2020.

Further Information:

Dr. Irfan Ahmad

Irfan Ahmad is a researcher in the field of Molecular Biology, specializing in c-di-GMP signalling, antimicrobial drug resistance and host-pathogen interactions. Currently serving as Associate Professor and coordinator of the network on adaptive antimicrobial drug resistance at the Department of Molecular Biology, Umeå University in Sweden. His current research project focuses on identifying novel regulators of host-pathogen interactions in Acinetobacter baumannii, a high-priority nosocomial pathogen. Dr. Ahmad has made a notable discovery in this field by identifying the molecular mechanism by which Acinetobacter baumannii establishes infection through initial contact with host epithelial cells.

With a Ph.D. in Microbiology from the Karolinska Institute in Stockholm, Sweden, Dr. Ahmad’s doctoral research explored the regulatory network of c-di-GMP signaling involved in biofilm formation, motility, and host-pathogen interactions in Salmonella typhimurium. Dr. Ahmad’s technical expertise spans various areas, including development of cellular assays for assessing microbial behaviour, gene expression analysis, molecular cloning, and protein-protein interaction assays. He has also conducted animal models of bacterial infections and developed in vivo antimicrobial susceptibility assays.

In addition to his research and teaching contributions, Dr. Ahmad has secured several research grants including grants from The Swedish research council, The Kempe foundation, Sweden, The Swedish foundation for international cooperation in research and higher education (STINT)  and Higher Education Commission, Pakistan.

Participation: Physcial participation is only open for residents of Karachi and Islamabad, Pakistan.

Virtual participation is open to all interested individuals of OIC member states and others.

Registration link:

Registration outcome will be shared through email, therefore, pl. give your valid email address.

Participants will receive E-certificates.

Contact persons:

Lecture schedule

Monday, 22nd of May
Time: 10:00
Essential elements of microbial life
Ute Römling, Karolinska Institutet/Adjunct Faculty University of Karachi
This lecture will introduce essential components of that are required for microbial life.

Time Online 15:00
Recognition of homologous sequences by BLAST
Michael Galperin, National Institutes of Health, Bethesda, USA
This lecture will introduce into the bioinformatic approaches to identify and assess homologous proteins with a focus on cyclic di-GMP signaling

Tuesday 23rd of May

Time: 9:00
Second messenger signaling: general introduction
Ute Römling
This lecture will introduce into the basic components of second messenger signaling and major second messenger signaling pathways in microorganisms.

Time: 10:30
Second messenger signaling cyclic di-GMP, part 1 cyclic di-GMP turnover proteins
Ute Römling
This lecture will give an introduction into the proteins required to synthesize and hydrolize the second messenger cyclic di-GMP

Wednesday 24th of May
Time: 9:30
Second messenger signaling cyclic di-GMP part 2, cyclic di-GMP binding proteins
Ute Römling
This lecture will give an introduction into components that bind the second messenger cyclic di-GMP

Thursday 25th of May
Time: 9:30
Cyclic di-GMP signaling in Acinetobacter
Irfan Ahmad, University of Umeå, Sweden
This lecture will describe cyclic di-GMP signaling in Acinetobacter

Friday 26th of May
Time: 9:30
Regulation of biofilm formation by cyclic di-GMP signaling
Ute Römling
This lecture will describe regulation of biofilm formation by cyclic di-GMP signaling.

Monday 29th of May
Time: 10:00
Regulation of motility and virulence by cyclic di-GMP signaling
Ute Römling
This lecture will describe regulation of motility and virulence by cyclic di-GMP signaling.

Tuesday 30th of May
Time; 10:00
Nucleotide second messenger signaling – alternative (cyclic di-)nucleotide second messengers
Ute Römling
This lecture will introduce bacterial nucleotide second messengers other than cyclic di-GMP

Wednesday 31st of May
Time: 10:00
Cyclic di-nucleotide signaling in higher organisms
Ute Römling
This lecture will give an overview over the discovery and role of cyclic di-nucleotide signaling in metazoans

Thursday 1st of June
Time: 10:00
Second messenger signaling cyclic di-AMP – Streptococcus
Roger Simm, University of Oslo, Norway
This lecture will introduce cyclic di-AMP signaling with a focus on Streptococcus

Friday 2nd of June
No lectures – Examination

Suggested reading

Overview cyclic di-GMP signaling

  • Römling U, Galperin MY, Gomelsky M. Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev. 2013 Mar;77(1):1-52. doi: 10.1128/MMBR.00043-12. PMID: 23471616; PMCID: PMC3591986.

Discovery of cyclic di-GMP and some of its major functions

  • Römling U, Galperin MY. Discovery of the Second Messenger Cyclic di-GMP. Methods Mol Biol. 2017;1657:1-8. doi: 10.1007/978-1-4939-7240-1_1. PMID: 28889281; PMCID: PMC5931213.
  • Simm R, Morr M, Kader A, Nimtz M, Römling U. GGDEF and EAL domains inversely regulate cyclic di-GMP levels and transition from sessility to motility. Mol Microbiol. 2004 Aug;53(4):1123-34. doi: 10.1111/j.1365-2958.2004.04206.x. PMID: 15306016.
  • Amikam D, Steinberger O, Shkolnik T, Ben-Ishai Z. The novel cyclic dinucleotide 3′-5′ cyclic diguanylic acid binds to p21ras and enhances DNA synthesis but not cell replication in the Molt 4 cell line. Biochem J. 1995 Nov 1;311 ( Pt 3)(Pt 3):921-7. doi: 10.1042/bj3110921. PMID: 7487952; PMCID: PMC1136090.
  • Steinberger O, Lapidot Z, Ben-Ishai Z, Amikam D. Elevated expression of the CD4 receptor and cell cycle arrest are induced in Jurkat cells by treatment with the novel cyclic dinucleotide 3′,5′-cyclic diguanylic acid. FEBS Lett. 1999 Feb 5;444(1):125-9. doi: 10.1016/s0014-5793(99)00036-8. PMID: 10037160.
  • Tal R, Wong HC, Calhoon R, Gelfand D, Fear AL, Volman G, Mayer R, Ross P, Amikam D, Weinhouse H, Cohen A, Sapir S, Ohana P, Benziman M. Three cdg operons control cellular turnover of cyclic di-GMP in Acetobacter xylinum: genetic organization and occurrence of conserved domains in isoenzymes. J Bacteriol. 1998 Sep;180(17):4416-25. doi: 10.1128/JB.180.17.4416-4425.1998. PMID: 9721278; PMCID: PMC107450.
  • Ross P, Weinhouse H, Aloni Y, Michaeli D, Weinberger-Ohana P, Mayer R, Braun S, de Vroom E, van der Marel GA, van Boom JH, Benziman M. Regulation of cellulose synthesis in Acetobacter xylinum by cyclic diguanylic acid. Nature. 1987 Jan 15-21;325(6101):279-81. doi: 10.1038/325279a0. PMID: 18990795.

Alternative (cyclic) nucleotide signaling systems

  • Rousset F, Sorek R. The evolutionary success of regulated cell death in bacterial immunity. Curr Opin Microbiol. 2023 Apr 6;74:102312. doi: 10.1016/j.mib.2023.102312. Epub ahead of print. PMID: 37030143.
  • Bernheim A, Sorek R. The pan-immune system of bacteria: antiviral defence as a community resource. Nat Rev Microbiol. 2020 Feb;18(2):113-119. doi: 10.1038/s41579-019-0278-2. Epub 2019 Nov 6. PMID: 31695182.

Nucleotide signaling in metazoans

  • Patel, D.J., Yu, Y. & Xie, W. (2023) CGAMP-activated cgas-sting signaling: Its bacterial origins and evolutionary adaptation by metazoans. Nat Struct Mol Biol, 30,  245-260
  • Wein T, Sorek R. Bacterial origins of human cell-autonomous innate immune mechanisms. Nat Rev Immunol. 2022 Oct;22(10):629-638. doi: 10.1038/s41577-022-00705-4. Epub 2022 Apr 8. PMID: 35396464.

Overview cyclic di-AMP signaling

  • Corrigan RM, Gründling A. Cyclic di-AMP: another second messenger enters the fray. Nat Rev Microbiol. 2013 Aug;11(8):513-24. doi: 10.1038/nrmicro3069. Epub 2013 Jul 1. PMID: 23812326.
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