University of Utah researchers have discovered a novel mechanism that infectious bacteria use to rapidly adapt to environmental stress, which could help explain why certain types of common infections such as sepsis can be so persistent.
The mechanism, described in the journal Nucleic Acids Research, alters the precision with which the bacteria make the proteins that carry out most of the work in cells. These changes may improve the bacteria’s chance for survival.
“Understanding how pathogens survive stressful situations can reveal new targets for development of anti-microbial drugs and vaccines,” said the study’s senior author, Professor Matthew Mulvey.
Adapt or die
Bacteria infecting a host are exposed to stresses such as acidity or antibiotics. If even one of the bacteria’s key pathways for survival is crippled, the entire population could die off.
However, bacteria can adapt, an ability that relies on a slight twist to basic principles of biology.
Traditionally, each gene is thought to carry instructions for making a single kind of protein. A molecule called transfer RNA (tRNA) then uses these instructions to oversee protein production in the cell. In times of stress, though, random changes to the tNRA-mediated process can be an especially quick way to alter a cell’s array of proteins. This can generate useful new proteins that help the organism to thrive.
“There is a growing appreciation that a little bit of noise in the system can be good,” Prof Mulvey said.
Shifting expectations
A graduate student in the lab happened to stumbled onto a bacterial enzyme, MiaA, which turned out to be both sensitive to environmental stress and key to regulating protein expression. In one experiment, he created a version of an especially pathogenic bacteria that lacked the gene that encodes MiaA.
“Every kind of stress we exposed the MiaA-deficient strain to seemed to cause problems,” said the study’s co-first author Matthew Blango, PhD, who is now a junior research group leader at the Leibniz Institute for Natural Product Research and Infection Biology in Jena, Germany. “So, we really thought that this protein might be playing an important role in gene regulation.”
Bacteria lacking MiaA did not thrive and did not cause urinary tract infections or sepsis in mice. This same effect also occurred with bacteria manipulated into expressing too much MiaA. “There appears to be a Goldilocks zone, where just the right amount of MiaA allows the optimal stress response,” Dr Blango said.
Seeing how badly things went when MiaA levels were out of balance, Brittany Fleming, PhD, the study’s co-first author, investigated further. She discovered that knocking out MiaA caused random ‘frameshifting’ – an error where tRNA delivers three-letter genetic codes to be translated into proteins that are off by one letter. For example, a genetic code of “CAT CAT GTA” might read as “ATC ATG TA…” when frameshifted. In the bacteria, the result of such a shift was impaired production of important proteins and production of unexpected proteins.
Another co-first author, graduate student Alexis Rousek, showed that changing levels of MiaA could alter the availability of key metabolites that feed into other important stress response pathways within the bacteria. These findings implicate MiaA as a key player within a web of pathways that can impact pathogen stress resistance
Prof Mulvey says his lab’s next step is learning how environmental stress alters MiaA levels within bacteria.
The implications for this research may extend beyond infection control. Humans express a version of MiaA that is linked to certain cancers and metabolic diseases. “What we learned about how MiaA works is likely to be relevant to research on cancer and other non-infectious human diseases,” Mulvey said.
Source: University of Utah
