UB research study reveals Zinc is able to modulate ‘Escherichia coli’ bacteria’s virulence

Zinc can modulate the virulence in Escherichia coli bacteria, a pathogen that causes urine infections in humans, according to the new study published in the journal Scientific Reports, led by the lecturer Carlos Balsalobre, from the Faculty of Biology of the UB. The new study reveals for the first time that Zinc can regulate the expression of bacterial virulence factors -in particular, alfa-hemolysin- an exotoxin produced by some Escherichia coli pathogenic strains.

Other participants in the study are the lecturer Annabel Valledor, from the mentioned Faculty, and the young researchers of the UB Elsa Velasco, Marianna Sanet, Jorgue Fernández-Vázquez, Daniel Jové and Estibaliz Glaría, apart from the experts Suning Wang and Thomas V. O’Halloran, from Northwestern University (United States).

About 150 million cases of urine infection are diagnosed each year worldwide, most of them result from bacteria. This pathology, which is usually recurrent, affects more women than men and can cause health complications if they are not treated on time. Between 70 % and 80 % of the infections result from pathogenic strains of the E. coli, a bacterial species with a wide range of bacterial factors that are involved in its virulence (such as the alfa-hemolysin, one of the most characterized bacterial toxins, with cytotoxic effects on the cells). In particular, alfa-hemolysin produces cytotoxic effects on the bladder epithelial cells during the infection process.

An essential metal in life which can be toxic in high concentrations

Zinc is an essential metal in cell physiology. Cellular respiration, DNA and RNA replication, intracellular signalling and protein synthesis are some of the basic processes in life in which Zinc is necessary. However, this element is toxic when in high concentrations, which is why the regulation of intracell zinc levels (homeostasis) is a precisely controlled machinery.

According to the lecturer Carlos Balsalobre, from the Department of Genetics, Microbiology and Statistics of the UB, “the concentration levels of zinc in the intestine, urine and in intracellular levels- areas this bacteria colonizes- can change in a wide range”.

“Regarding the intestine, which has high concentrations of zinc, the alfa-hemolysin stops its expression, and pathogenic E. coli does not usually generate infections. However, if the metal concentration lowers -for instance, in the urinary tract- this toxin expression increases. Also, during the infection process the bacteria gets into the cells, where zinc concentrations can be even lower”, adds Balsalobre.

Zinc and alfa-hemolysin: an open mechanism

Promoting in vitro bacterial growth with no zinc has been one of the most complex methodological challenges in this new study. Therefore, it was necessary to remove the with chelating elements and to add basic elements (except for zinc). Moreover, the collaboration with the team led by professor Thomas O’Halloran, from Northwestern University (United States) was determining to work with the purity of the Zur protein.

Zinc ads the Zur transcription factor (zinc uptake regulator) and favours its binding with DNA (in particular, in the gene promoting area it regulates). Elsa Velasco, first author of the study, notes that “as a result of this binding, the transcription stops and so does the gene expression. Therefore, when there is zinc, the Zur regulated genes are silenced. However, with a lack of zinc, the Zur factor cannot join the DNA and the regulated genes by this transcription factor do show expression”.

According to the new study, “some genes which are codified by hemolysin have a binding site for the Zur regulator in the promoting region”, says Velasco. “Therefore, the gene expression of this toxin is affected by the zinc levels”.

Between 40 % and 50 % of E.coli pathogenic strains are able to express alfa-hemolysin. However, not all genes that are related to hemolysin production are zinc-responsive. So far, two types of genes taking part in the alfa-hemolysin synthesis in pathogenic E.coli have been identified. The new study, now published, shows for the first time that these systems are regulated in different ways.

New strategies to fight multiresistant bacteria

Many bacteria are resistant to the drugs known so far. Some bacterial infections, which were overcome during years with pharmacological treatments, do not respond to antibiotics, not even the newest ones. Nowadays, bacterial resistance is one of the main threats for global health and it is a problem for patients suffering from recurrent urine infections.

Knowing in greater detail about regulation mechanisms in the virulence factors of the pathogenic E.coli will enable researchers discovering how these bacteria act during the infection process (that is, which elements and strategies are used to invade biological tissues). The new study, led by the UB, provides new tools to work on new therapeutic treatments, specifically designed to help treat some of the key phases of the bacterial infectious process.