Phosphate shortages could explain how Pseudomonas aeruginosa shifts from being a mere colonizer of the human gastrointestinal (GI) tract into a lethal agent, says John Alverdy, a surgeon at the University of Chicago School of Medicine in Chicago, Ill. Although P. aeruginosa sometimes remains benign when it colonizes GI tracts, stresses such as surgery or illness often trigger virulence, potentially leading to inflammatory responses, sepsis, and death. However, adding phosphate can reverse that shift and protects animals against death from such infections, he and his collaborators report.

Invasive medical procedures such as radiation therapy, chemotherapy, transplants, and surgery "stir up Pseudomonas in the gut," Alverdy says. To better understand this phenomenon, he and his collaborators introduced a benign strain of P. aeruginosa into the GI tracts of some mice but not others, and then surgically removed parts of their livers, an invasive procedure from which they ordinarily recover. However, following surgery, the mice carrying that supposedly avirulent strain of bacteria developed severe complications, Alverdy says. "In response to the surgical stress, the bacterium switched its phenotype and somehow killed the mice." Noting that phosphate levels drop drastically following major surgery, he decided to test whether phosphate affected the P. aeruginosa strain that the mice carried.

As part of their broader analysis, Alverdy and his collaborators switched host species, in part to simplify some of their manipulations, but also to determine whether the host contributes to this change in microbial virulence. Thus, he and his team began studying the impact of P. aeruginosa on the worm Caenorhabditis elegans, which were fed diets containing the poorly virulent PAO1 strain of P. aeruginosa. The bacteria were grown in either highor low-phosphate medium.

Worms that fed on P. aeruginosa from low-phosphate medium died after developing large red spots in the digestive tube, a novel syndrome that the researchers call "red death." Adding phosphate or iron suppressed the red death. Meanwhile, those worms that were fed high-phosphate-grown P. aeruginosa thrived.

Alverdy and his collaborators next identified three virulence systems that appear to be activated in the Pseudomonas strain that grew on a low-phosphate medium and that caused red lesions in the worms. "A low-virulence strain of Pseudomonas can be turned into a potent killer simply by lowering phosphate," he says. This shift from low to high virulence depends not only on phosphate depletion but also on iron signaling and quorum sensing. Details appear in the April 14, 2009, Proceedings of the National Academy of Sciences.

When the PAO1 strain is grown in media depleted of phosphate, the cells produce higher levels of the PA-I lectin and pyocyanin, form biofilms, and boost expression of PstS, a gene encoding a phosphate acquisition protein, as well as other genes whose products contribute to virulence. The PA-I lectin, for example, disrupts the epithelial barrier within the GI tract of mice, allowing exotoxin A to disseminate and cause sepsis. Biofilms interfere with antibiotics and host immune responses, while pyocyanin kills neutrophils. These findings "highlight the importance of the nutritional environment in regulating virulence in Pseudomonas," says Matt Parsek, a microbiologist at the University of Washington, Seattle. "It's narrowminded not to consider nutritional needs of bacterium," yet few experiments consider how the host's diet might affect microbial virulence factors. It is too early to say whether these findings will lead to a new therapeutic approach, he adds.

Nevertheless, Alverdy is already testing compounds that might prevent Pseudomonas from expressing virulence in the GI tracts of patients. One approach is to use polyethylene glycol polymers for delivering phosphate to the lower GI tract, as a way of overcoming its absorption in the upper GI and rapid loss in urine. His idea is that recovering surgical patients will drink this or some other phosphate-containing concoction to prevent bacteria from becoming virulent, and thus avoid a need for systemic antibiotics.

Carol Potera
Carol Potera is a freelance writer in Great Falls, Mont.

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