Researchers in the US have developed a new type of treatment that could herald a new approach to fighting infectious diseases that stimulates the immune system to protect the body against a range of bacteria instead of relying on antibiotics to attack them directly, which can lead to the emergence of resistant strains of pathogens.

The team, comprising scientists from government, academia and private industry, wrote a paper about their study that was published in the May issue of the open access journal PLoS Pathogens, available online.

Dr Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health, said in a statement that:

“A therapeutic that protects against a wide array of bacterial pathogens would have enormous medical and public health implications for naturally occurring infections and potential agents of bioterrorism.”

Dr Catharine Bosio, and her colleagues at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, led the study.

Bosio and colleagues developed a new treatment that protected mice from infection with the bacterium Francisella tularensis that causes the highly infectious rodent disease tularemia (rabbit fever), which can also pass to humans.

In a further set of experiments with human immune cells, they showed that the treatment was also able to confer protection against bacteria that cause plague, melioidosis and brucellosis. These bacteria occur naturally, can be highly virulent, and are considered possible agents of bioterrorism.

The novel approach works by stimulating the host immune system to destroy the bacteria. In contrast, treatments based on antibiotics rely on the drugs to destroy the pathogens, which often develop resistance to the medications.

The researchers suggest their new approach has the potential to enhance the action of antibiotics as well as provide an alternative to them.

For the study, Bosio and colleagues isolated membrane protein fractions (MPFs) from a weakened strain of F. tularensis and combined them with CLDC (cationic liposome DNA complexes) and tested them in vitro (using mouse and human cell cultures) and in vivo (using live mice).

CLDC is used as an adjuvant with vaccines to activate the innate immune response by mimicking natural infection; but as in this study, more and more researchers are also investigating its potential use in immunotherapy.

In vitro, the CLDC+MPF combination stimulated the natural antibacterial reactions ROS (reactive oxygen species) and RNS (reactive nitrogen species) in mouse cells and ROS in human cells. ROS and RNS target and kill invading bacteria (macrophages) and stop them replicating and spreading to other cells.

In vivo, 60 per cent of mice injected with CLDC+MPF three days before lethal intranasal pulmonary infection with virulent F. tularensis survived. As with the in vitro experiments, the researchers showed this was due to the presence of RNS and ROS.

No mice survived when given either CLDC or MPF alone, showing that it was the combination that conferred protection.

And finally, the researchers showed that the combination also protected human immune cells from bacteria that cause plague, melioidosis and brucellosis (Yersinia pestis, Burkholderia pseudomallei and Brucella abortus).

Mostly seen in the tropics, melioidosis spreads to humans and animals through contaminated soil and water, and while brucellosis mostly affects animals, it can also infect humans who come in contact with infected animals or animal products, such as contaminated milk.

The researchers concluded that:

“Thus, CLDC+MPF represents a novel prophylaxis to protect against multiple, highly virulent pathogens.”

Bosio said giving the treatment to the mice three days before infection appeared to be crucial: it gave enough time to stimulate the immune system. When they gave the protection less than three days in advance, it failed, she said.

“We are continuing to improve the versatility of this treatment as an antibacterial therapeutic with respect to timing of delivery and efficacy,” she told the press.

“Meanwhile, CLDC plus membrane protein fractions is proving to be an excellent tool to determine how to safely and successfully stimulate the body’s own antibacterial army to protect itself against highly infectious invaders,” she added.

Bosio and colleagues are now moving on to study exactly how MPFs work with CLDC to produce RNS and ROS in mouse and human cells.

“Effective, Broad Spectrum Control of Virulent Bacterial Infections Using Cationic DNA Liposome Complexes Combined with Bacterial Antigens.”
Robin Ireland, Norma Olivares-Zavaleta, Jonathan M Warawa, Frank C Gherardini, Clayton Jarrett, B Joseph Hinnebusch, John T. Belisle, Jeffery Fairman, Catharine M. Bosio.
PLoS Pathog 6(5): e1000921, May 2010.

Source: NIH News.

Written by: Catharine Paddock, PhD