Signalling pathways controlling bacterial adaptation

The conversion of environmental signals into cellular responses is a critically important process that occurs in all organisms. The ability to process information depends, in general, on complex signal transduction and regulatory networks that control genes required to cope with certain environmental conditions. Bacteria exhibit a bewildering range of strategies that allow them to exploit their surrounding to the maximum and to colonize environmental niches, which are inaccessible for most other organisms. A detailed understanding of bacterial signalling processes is required to control bacterial spread in medicine, health care, and to utilize the beneficial behaviours of bacteria in biotechnology and industry.

The focus of this thesis is the BarA-UvrY-Csr signalling system, which is widely distributed among bacteria. In the present work the system was predominantly studied in the model organism Escherichia coli and in part in Salmonella enterica serovar Typhimurium. A transposon-based search identified YhdA (CsrD) as a new component of the system (Paper I). YhdA was found to regulate the expression of the two small noncoding RNAs (sRNAs) CsrB and CsrC, which antagonize the action of the global carbon storage regulator protein CsrA. YhdA contains so called GGDEF and EAL domains, which have been associated with the turnover of c-di-GMP, a second messenger molecule that triggers the transition from a sessile to a motile life style, an integrative part of biofilm formation. YhdA neither synthesizes c-di-GMP nor breaks it down. However, it seems to play an indirect role in the regulation of c-di-GMP metabolism as it controls the activity of CsrA through the Csr sRNAs (Paper II, III). CsrA, in turn, was discovered to control the expression of several GGDEF and/or EAL proteins in E. coli as well as in Salmonella and thereby to globally adjust the levels of the c-di-GMP second messenger.

Previous studies have demonstrated that CsrA controls motility and biofilm formation by directly regulating the master regulator of flagella synthesis and the production of the biofilm matrix component PGA. Thus, by combining these direct regulatory pathways with the control of c-di-GMP levels, CsrA plays a central role in switching between motility and biofilm behaviour. The Csr system is predominantly controlled by the BarA-UvrY two-component system, which activates the expression of the Csr sRNAs in response to extracellular signals. We found that the membrane anchored histidine kinase BarA is inactivated at a pH below 5 (Paper IV). On the other hand, expression of the Csr sRNAs was strongly induced in nutrient poor media, suggesting that the Csr system is controlled by the nutrient availability in the environment (Paper V). The ability to respond to external pH and the availability of nutrients might be important for the bacteria to switch between environmental growth and survival in the host.

List of scientific papers

I. Jonas K, Tomenius H, Römling U, Georgellis D, Melefors O (2006). Identification of YhdA as a regulator of the Escherichia coli carbon storage regulation system. FEMS Microbiol Lett. 264(2): 232-7
https://pubmed.ncbi.nlm.nih.gov/17064377

II. Jonas K, Edwards AN, Simm R, Romeo T, Römling U, Melefors O (2008). The RNA binding protein CsrA controls cyclic di-GMP metabolism by directly regulating the expression of GGDEF proteins. Mol Microbiol. 70(1): 236-57. Epub 2008 Aug 18
https://pubmed.ncbi.nlm.nih.gov/18713317

III. Jonas K, Edwards AN, Ahmad I, Lamprokostopoulou A, Romeo T, Römling U, Melefors Ö (2009). Coordinated control of EAL domain proteins with functions in motility, invasion and biofilm formation mediated by the Salmonella Typhimurium post-transcriptional regulator CsrA. [Submitted]

IV. Mondragón V, Franco B, Jonas K, Suzuki K, Romeo T, Melefors O, Georgellis D (2006). pH-dependent activation of the BarA-UvrY two-component system in Escherichia coli. J Bacteriol. 188(23): 8303-6. Epub 2006 Sep 15
https://pubmed.ncbi.nlm.nih.gov/16980446

V. Jonas K, Melefors Ö (2009). The Escherichia coli CsrB and CsrC small RNAs are strongly induced during growth in nutrient poor medium. [Submitted]