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Microbiology

Jekyll or hide?

Many bacteria can adopt different lifestyles: in a free-living state, they are virulent and cause disease; in a surface-attached community, they are less virulent but may go unnoticed. How is this ‘decision’ made?

In the November issue of Developmental Cell, Goodman and colleagues1 report the identification of a regulatory system in the bacterium Pseudomonas aeruginosa that determines whether it causes disease or lies low and simply persists. This bacterium is of interest to the medical community because of its ability to infect people whose immune system is damaged, who have sustained serious burns or an eye injury, or who suffer from cystic fibrosis. Goodman et al. found that inactivating a so-called two-component regulatory system in P. aeruginosa results in a strain with a markedly decreased ability to cause disease, but an increased ability to form surface-attached, persistent communities known as biofilms (Fig. 1).

Figure 1: Persistence versus infection.
figure1

Goodman et al.1 have discovered a regulatory system in the bacterium Pseudomonas aeruginosa that might enable it to choose between two lifestyles in a mammalian host: growing as a surface-attached, persistent community (a biofilm), or causing a short-term infection. a, An electron micrograph of a P. aeruginosa biofilm on a suture. Individual cells can be seen, surrounded by a sugar-rich matrix. (Courtesy Jon Budzik and the Ripple EM facility, Dartmouth College, New Hampshire.) b, An inflamed eye — the effect of an acute P. aeruginosa infection of the cornea. (Courtesy Patrick Saine and Michael E. Zegans, Dartmouth Medical School, New Hampshire.)

Although there are many variations on bacterial two-component regulatory systems, their basic job is to constantly sample the external environment and transmit this information to the bacterial interior. This allows the organism to adapt to an ever-changing environment. Goodman et al.1 discovered a new protein component of a new such regulatory system, a component that they call RetS.

They also found that a RetS-deficient P. aeruginosa strain was better than a wild-type strain at forming a biofilm on both an abiotic surface, namely glass, and a biotic surface, cultured hamster cells. The RetS-deficient bacteria were, however, less able to damage the hamster cells they colonized, and to cause disease in a mouse model of pneumonia. Outside the lab, the ability of P. aeruginosa to form biofilms is best known with respect to abiotic surfaces such as catheters, but it might also be able to produce biofilms on tissues within a host, in diseases such as otitis media (earache) and cystic fibrosis2. It seems, then, that Goodman et al. might have identified a control element that allows this bacterium to switch between a virulent, disease-causing state and a biofilm state in a mammalian host. The biofilm state, although less virulent, might allow the microbe to persist for longer.

To understand better how the protein might control this pathogenesis/persistence switch, the investigators used DNA microarrays to identify all the genes in the organism that are regulated by RetS. They found that, in the RetS-deficient strain, the expression of genes required to make a ‘type III secretion system’ — necessary for P. aeruginosa to cause a short-term infection — was reduced by as much as 25 times. The expression of other genes associated with virulence was also reduced; these genes include those that produce surface appendages called pili, as well as those that encode toxins such as LipA and ToxA.

These data imply that RetS is normally required for the full expression of the factors required to produce an acute infection, and are consistent with the decreased ability of RetS-deficient P. aeruginosa to cause disease. In contrast, P. aeruginosa genes that are involved in the formation of the sugar-rich matrix that encloses a biofilm — the psl and pel genes3,4,5,6 — were markedly upregulated in the mutant bacteria. This suggests that RetS usually turns off the genes needed to make a biofilm.

We make choices every day on the basis of the information at hand. Bacteria must do so too, and the outcomes of their decisions can have life-or-death consequences, both to the bacteria and to the host. For bacteria, these choices — such as whether or not to form a persistent biofilm — are based in large part on local environmental cues, and are effected through altered gene expression. For instance, P. aeruginosa decides to form biofilms on abiotic surfaces, such as catheters or contact lenses, only when an energy source (such as sugars) and other nutrients (such as iron) are readily available7,8. Otherwise, it remains free-living. Goodman and colleagues' findings suggest that P. aeruginosa also has a decision to make when in the context of a mammalian host: does it cause a short-term infection or does it persist in a biofilm state? An acute infection provides a means of bacterial propagation, whereas in a biofilm the organism is lying low and is thus less likely to be recognized and attacked by the immune system.

The very existence of a regulatory system that mediates this decision suggests that the choice is a crucial one for microbes, and one that they must constantly re-evaluate. Studies of Bordetella bronchiseptica — an organism related to the microbe that causes whooping cough — provided one of the first molecular illustrations of this decision9. Thus, B. bronchiseptica forms biofilms best when the genes required for acute infection are turned off. However, expression of a toxin required for acute infection can block biofilm formation, hinting that the functions required to cause disease and those required to make a biofilm might actually be incompatible. Similarly, my own group has found that expression of the type III secretion system, required for acute infection in P. aeruginosa, also inhibits biofilm formation10.

We would do well to continue learning about how bacteria can switch from disease to persistence and back again. A better understanding of this decision could lead to new strategies for dealing with bacterial infections.

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O'Toole, G. Jekyll or hide?. Nature 432, 680–681 (2004). https://doi.org/10.1038/432680a

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