New research in the online open access journal BMC Genomics shows how S.aureus makes itself at home in human lung cells for up to two weeks.

A team of 12 researchers from University Hospital of Geneva, Switzerland and the Institute of Food Research, Norwich, UK set out to uncover what S. aureus (6850) did inside human lung epithelial cells (A549) using an in vitro model. They found that shortly after S. aureus entered the lung cells, the bacteria" gene expression profile dramatically changed: gene expression for bacterial metabolic functions and transport shut down, putting the bacteria in a dormant state. Simultaneously, production of toxins potentially lethal for the epithelial cells becomes strictly controlled to limit cellular damage. Mechanisms that helped the bacteria to survive and/or multiply, including metabolic and energy production functions, then resumed. Although most of the bacteria had died by about four days as a result of antibiotic treatment, the team still found viable bacteria in their model system two weeks after infection.

The findings may help in understanding persistent infections, and in designing new antibacterial drugs. S. aureus has not traditionally been considered an intracellular pathogen, but the molecular details that govern its extended persistence remain largely unknown. The bacteria can generate relapsing infections even years after the first episode was apparently cured.

"S. aureus intracellular survival appears related to its capability to adopt a discrete behaviour instead of actively duplicating," says Patrice Francois, a Geneva-based member of the research team. "S. aureus then benefits from natural or programmed cell death to re-emerge and trigger another episode of infection, leading to chronicity."

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To narrow this field, investigators conducted a second group of screening procedures. Using a variety of genome-scale approaches, they sought to determine if genes for any of the five kinases were unusually abundant in cancer cells. They found extra copies of IKBKE, but not of the other genes -- and correspondingly high levels of the IKBKE protein. This pointed to IKBKE's role as a breast cancer oncogene.

In the third part of the study, the investigators explored whether breast cancer cells depend on IKBKE for survival. In an earlier study, they had used a technique called RNA interference -- whose discovery was recognized with the Nobel Prize in Medicine and Physiology last year -- which uses bits of genetic material to systematically stile certain genes. With a high-throughput version of this technique, they found that when IKBKE was switched off, the cancer cells tended to stop proliferating and died.

"This triple screening approach enabled us to study what happened to cells when IKBKE was turned on and when it was shut off, and to take a global look at the genetic alterations within breast cancer cell lines and tumors," Hahn says. "Integrating these techniques allowed us to identify a new breast cancer oncogene and show that it plays a crucial role in the formation and survival of tumors."

The discovery that mutated IKBKE helps sustain a sizable percentage of breast cancers may spur the development of new treatments for the disease, Hahn remarks. Drugs able to target the oncogene and shut it down could offer an effective therapy for women whose tumor cells harbor the mutation.

The three-stage approach to finding breast cancer genes may be used in other forms of cancer as well, Hahn continues. "Our study provides a framework for integrated genomic methods of oncogene discovery."

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