An expensive deal

To maintain a costly ability, harmful gut bacteria use a clever toxin-antitoxin system

June 15, 2023

The production of virulence factors that allow harmful gut bacteria to attack their host cells is expensive and slows down reproduction. However, the microbes do not lose this ability when they temporarily do not need it. Max Planck researchers in Marburg have now shown how this happens.

Bacteria that infect human cells and cause disease use so-called virulence factors. These factors can be toxins or specific tools that enable the bacteria to attach to host cells and manipulate or even destroy them. Nothing comes for free, even for bacteria. Production and use of virulence factors requires energy, and bacteria that produce such factors pay for their abilities with slower growth. Such bacteria therefore run the risk of losing the relevant genes when they are not needed. Yet this does not seem to happen. How do bacteria manage to retain their ability to produce virulence factors - and thus to cause infection?

A team led by Andreas Diepold at the Max Planck Institute for Terrestrial Microbiology is studying the bacterium Yersinia enterocolitica. This gastrointestinal pathogen uses the type III secretion system (T3SS), a kind of nanoscale needle, as a virulence factor. By injecting proteins into host cells, it suppresses parts of the immune system. Saskia Schott, a master's student in Andreas Diepold's lab, has now shown how the bacterium ensures that its T3SS genes are maintained even without contact with host cells.

Toxin-antitoxin system

The researchers found a toxin-antitoxin system between the T3SS genes. Such systems are known to be a clever way of preventing the loss of gene segments: The toxin-antitoxin system genes encode a stable toxin and an antidote, the antitoxin, which is degraded more rapidly. If progeny lose these genes, the antitoxin the antitoxin is no longer produced and quickly degraded; the stable toxin remains, and these bacteria cannot reproduce. This ensures that all reproducing bacteria contain the toxin-antitoxin system, including the surrounding genes.

Due to the close proximity of the toxin-antitoxin system in Yersinia enterocolitica, it was suspected that the known growth inhibition in secreting bacteria might also be a consequence of toxin action resulting from transcription of the adjacent large T3SS gene complex. First author Saskia Schott explains, "At first, we thought that the growth inhibition occurred because the virulence system and toxin genes overlapped.” But that was not the case, the team discovered, also with the help of colleagues led by Elena Evguenieva-Hackenberg at the University of Giessen, Germany.

The slow growth is therefore entirely due to the cost of virulence factor production. And the toxin-antitoxin system - regardless of the direct overlap - ensures that the genes for the T3SS are maintained in the bacteria. "If we remove the toxin-antitoxin system from the bacteria, they quickly lose the T3SS and the ability to infect. This is especially true under conditions similar to those found in the human body.“

The findings show how precisely pathogenic bacteria regulate their virulence factors and the ability to produce them to maintain a balance between rapid replication and manipulation of the host organism. The researchers found it particularly interesting that some bacteria manage to remove the T3SS unharmed and then replicate more rapidly - whether this subpopulation plays a role in the infection process is still unclear.

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