The unexpected finding that little bits of genes called superantigen pathogenicity islands (SaPIs) can commandeer invading bacteriophage, or “phage,” proteins and use them to escape staphylococcal genomes, repackage themselves into compact particles and flee the infected host bacterium has been reported by an international team of researchers led by José R. Penadés from the Centro de Investigatiòn y Tecnologia Animal in Segorbe, Castellón, Spain.
“Once a bacterium has been infected by a phage, a so-called ‘helper’ phage in this case, it’s not long for the world; it will not be replicating again, ever. Thus the SaPI is trying to abandon ship,” says Ray Schuch, a phage scientist at ContraFect Biotechnology in Yonkers, New York, adding that the mechanism described in this elegant research helps explain how SaPIs sense phage infection and mobilize.
The commandeered phage proteins are said to “moonlight” because they work for both the virus and the SaPI
Penadés and his team call the co-opted proteins “moonlighters” because they do different jobs for invading phages than for the SaPIs. The ability of SaPIs to escape their host with co-opted phage proteins is “a remarkable evolutionary adaption,” say the scientists. Once out, SaPIs find new bacteria to infect, thereby turning otherwise mild-mannered microbes into toxic-shock- causing killers.
SaPIs are discrete units embedded on specific chromosomal sites and appear to detach and replicate only in the presence of phages. “After replication,” says Richard P. Novick from New York University School of Medicine in New York City, who was involved in these studies, “they’re encapsidated at high efficiency into highly mobile phage-like infectious particles.
Normally, staphylococcal pathogenicity islands are held in place by a repressor protein known as Stl which keeps the superantigen-encoding genes tethered to the bacterial genome. Previous research done by Penadés and Novick proved the importance of Stl by showing that mutational inactivation of the stl gene causes the SaPI to free itself from the bacterial chromosome and replicate in the absence of inducing phages.
Infection with one type of phage can mobilize a number of different SaPIs
Infection of a SaPI-containing Staphylococcus aureus by helper phage 80a mobilizes at least five different SaPIs, each using a different Stl protein. This got Maria Ángeles Tormo-Más, the current study’s lead investigator, wondering how one phage can have such broad specificity. To find out, Tormo-Más tested S. aureus pathogenicity islands, SaPI1, SaPIbov1 and SaPIbov2 and discovered that each uses a different 80a protein for its own derepression.
Toxin genes stay tethered to bacterial chromosomes when invaded by SaPI-resistant mutant phages
Some phages are immune to protein high-jacking by SaPIs. Reasoning that these mutants would readily lyse pathogenicity-island-carrying S. aureus and form visible plaques in culture, Tormo-Más began studying SaPI-resistant 80a phages in SaPIbov1-containing strains of S. aureus. “The pathogenicity islands stayed tethered to their chromosomes and this was consistent with failure to relieve Stl-mediated repression,” says Penadés. Further investigation revealed that the changes enabling ready killing of S. aureus by SaPIbov-1-resistant phage mutants were carried on a single phage gene called dut. The dut gene also encodes an enzyme that encourages SaPIbov-1 replication, which is a completely different function, thus showing that it is a true “moonlighting” protein, explains Penadés.
SaPI-carrying S. aureus are ubiquitous in nature encouraging the widespread transfer of deadly staphylococcal toxins
SaPIbov1 is promiscuous, readily spreading among a variety of staphylococci including S. xylosus, S. chromogenes, S. epidermidis, and S. intermedius. Both SaPI1 and SaPIbov1 have also been found in Listeria monocytogenes, a completely other type of bacterium.
“The staphylococcal phages that induce SaPI transfer to L. monocytogenes don’t form plaques ; thus, silently spreading toxicity islands may represent a new and important mechanism of horizontal gene transfer among bacteria,” says Novick who also notes that by impairing phage reproduction, SaPIs are a fitness asset to the host. In other words, bacteria carrying these toxin genes are more likely to survive than their more benign counterparts.
These researchers consider it very worrisome that SaPIs are highly mobile and the only known repository of several superantigen genes, including tst, seb and sec and therefore play a major role in the dissemination of genes that negatively impact human health. There is also scientific concern that the widespread agricultural use of anti-aureus phages will accelerate the spread of staphylococcal toxins to other bacteria.
For details of this research see:
Tormo-Más MA, Mir I., Shrestha A. Tallent SM, et al: Moonlighting bacteriophage proteins derepress staphylococcal pathogenicity islands in Nature (2010); 465, pp. 779-782.
Chen, John and Novick, Richard P: Phage-Mediated Intergeneric Transfer of Toxin Genes in Science (2009); 323, pp. 139-141.
Ubeda C, Barry P, Penadés JR, Novick RP: A pathogenicity island replicon in Staphylococcus aureus replicates as an unstable plasmid in PNAS (2007); 104, pp. 14182-14188.
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