Laboratory researchers have developed a new way to cripple avirulent class of microbes that have become increasinglyresistant to antibiotics and continue to kill hundreds ofthousands of hospital patients every year.
The discovery, based on experiments with laboratory mice,provides immunization against the Pseudomonas aeruginosabacterium, suggesting a fresh alternative to antibiotics inthe fight against the microbes responsible for mosthospital-acquired pneumonia deaths. The bacteria kill halfthe hospital patients they infect.
The new finding led by scientists at the University ofCalifornia San Francisco and the Medical College ofWisconsin is reported in the April issue of Nature Medicine.A commentary on the research and its significance appears inthe same issue.
Nationally, more than two billion dollars a year are spentcombating hospital pneumonia, a condition most oftencontracted by patients already under intensive care.
The Pseudomonas species targeted in the research is alsoresponsible for the untreatable lung inflammations whichdevastate the lives of half a million people with cysticfibrosis. In addition, it belongs to the same group ofgram-negative bacteria as E. coli, Salmonella, and themicrobe responsible for plague, all of which may becandidates for the same immunization strategy developed bythe scientific team.
"All these species utilize the same combination of proteinsto deliver deadly toxins to host cells," says JeanineWiener-Kronish, MD, professor of anesthesiology and medicineUC San Francisco and one of the senior authors on the NatureMedicine paper. "We have developed an antibody against oneof these proteins and shown that it blocks Pseudomonas frominjecting toxins into lung cells. This antibody may wellprovide immunization against these other bacteria speciestoo."
Senior author on the Nature Medicine paper is Dara W. Frank,PhD, professor of microbiology and molecular genetics at theMedical College of Wisconsin. The collaboration involvedseven scientists from the two institutions, combining basicresearch in critical patient care and bacterial genetics todevelop the antibody and demonstrate its ability to provideimmunity against the Pseudomonas bacterium. First author onthe paper is Teiji Sawa, MD, PhD, adjunct assistantprofessor of anesthesiology at UCSF.
The bacterium employs what is known as a type III secretorysystem to infect lung cells. A combination of at least 25bacterial proteins work in concert to allow the microbeaccess to penetrate the outer surface of the host cell andinject toxins into it. The toxins are particularly difficultfor the cell to defend against, Wiener-Kronish explained,because they wipe out the primary line of defense -- themacrophages which would normally engulf such invaders.
The research team developed antibodies to five of theproteins in the bacterium's toxin delivery system and testedthe ability of each to block the deadly process. One of thefive, an antibody to the bacterium's PcrV antigen, preventedthe invading microbe from destroying the lung cellmacrophages. As a result, the cells could mount a defenseagainst the bacteria and prevent delivery of the toxin.Most importantly, lung cells were protected, the researchersreport.
The scientists do not yet know the precise role of thebacterial protein they have blocked. They know it is neededfor successful delivery -- or translocation -- of the toxinfrom the bacterium to the lung tissue, and that it itself isnot a toxin, they report.
Immunization could be useful not only against thePseudomonas-induced pneumonia, but also against thedevastating lung inflammations suffered by people withcystic fibrosis, says Wiener-Kronish. These same virulentbacteria cause the chronic inflammations of cystic fibrosis,and sufferers are never able to clear their lungs of themicrobes. A systemic approach such as immunization may holdmore promise than efforts at control through antibiotics,she says.
The bacteria also cause sepsis, or infection of the blood,by passing from the lungs into the bloodstream, and thescientists hope that sepsis too may be controlled throughantibody therapy.
The research group is now working with InterMunePharmaceutical, Inc. to develop an antibody therapy and avaccine for use in clinical trials with patients. Thescientists are also seeking to better understand how thebacterial type III secretory system works, expecting thatfurther refinements in the immunization strategy might bepossible.
"We're still in the development stages, but we think thatstudying PcrV may well reveal significant information aboutthe process of intoxication by type III systems," said DaraFrank of the Medical College of Wisconsin.
Collaborating in the research and on the paper with Sawa,Frank and Wiener-Kronish were Maria Ohara, MD, and KiyoyasuKurahashi MD, both Fellows in anesthesiology and MichaelGropper, MD, PhD, assistant professor of anesthesiology, allat UCSF, and Timothy L. Yahr, PhD, a postdoctoral scientistat Dartmouth Medical School. The research was funded by theNational Institutes of Health and the Cystic FibrosisFoundation.
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