Scripps Research Institute scientists have found that bicarbonate, a major component of blood, plays a key role in signalling bacteria to become virulent.
The scientists identified bicarbonate, a chemical found in all body fluids and organs that plays a major role in maintaining pH balance in cells, as providing the signal for Bacillus anthracis to unleash virulence factors.
Focussing their study on Bacillus anthracis, the bacterium that causes anthrax, the scientists found that the absence of the bicarbonate transporter in the bloodstream ceased the bacterium's ability to become virulent.
This is the first study to confirm that it is indeed bicarbonate, rather than carbon dioxide, that signals the gram-positive B. anthracis to become virulent.
The research holds significance because other pathogenic bacteria such as Streptococcus pyogenes, Escherichia coli, Borrelia burgdorferi, and Vibrio cholera have bicarbonate transport pathways similar to B. anthracis and thus are likely to have similar virulence triggering mechanisms.
Gram-positive bacteria are the major culprits driving the increase of community and hospital acquired bacterial infections. These bacteria are often resistant to multiple antibiotics, making the problem a growing public health concern and the need for new antibacterial treatment more urgent.
Now, the scientists could harness the knowledge about bicarbonate transporter pathway, which may in turn act as a potential new target for drug intervention.
"We have identified an essential component for the induction of virulence gene expression in response to host bicarbonate levels and have used this finding to learn more about the extracellular and intracellular signals controlling virulence," said Scripps Research Associate Professor Marta Perego, Ph.D.
She added: "It was observed that the best medium for toxin production was one that people believed mimicked conditions found in the blood of a human or animal host, where anthrax bacteria would find both carbon dioxide and bicarbonate. But we've never known which of these two molecules was the more important for bacterial pathogenesis, and whether this belief was correct. Now, we know that it is bicarbonate and that the growth in the presence of bicarbonate really mimics the host growth conditions."
In the current study, the researchers identified a previously unknown ATP-binding cassette transporter (ABC-transporter)-which is identified by the gene number BAS2714-12-that was shown to be essential to transporting bicarbonate.
As a group, ABC-transporters use the energy of ATP hydrolysis to transport various substrates across cellular membranes.
In this case, when the genes that code for the BAS2714-12 ABC transporter were deleted, the rate of bicarbonate uptake inside the cell greatly decreased, induction of toxin gene expression did not occur, and virulence in an animal model of infection was abolished.
Elimination of carbon dioxide production within the bacterial cell had no effect on toxin production, suggesting that CO2 activity is not essential to virulence factor induction and that bicarbonate, not CO2, is the signal essential for virulence induction.
"In light of these findings, investigation of bicarbonate regulation and transport should be of much greater significance to a large number of pathogenic organisms," said Perego.
The study was published in the latest edition of the journal PLoS Pathogens.