Researchers from the University of Texas Medical Branch at Galveston have been successful in developing a new treatment plan that that may prove useful against the potential bioterrorism agent and causative pathogen of pulmonary tularemia. This drug agent cystatin-9 exists in the human body as one of the important proteins that is responsible for potentiating human immune responses against a variety of pathogens.
After research on laboratory cell cultures and animal subjects, the research team from the University of Texas Medical Branch at Galveston identified that the activity of this protein is directed against the bacteria that causes tularemia in animal subjects like mice, as well as in cultured macrophages that serve as the primary line of defense against invading microorganisms.
Associate professor Tonyia Eaves-Pyles, who is also the lead author of the paper published recently in the online issue of Molecular Medicine, suggested:
“When we looked at cystatin-9 in the lungs with Francisella tularensis, we saw that it increased killing of the bacteria. Moreover, it did this without inducing the out-of-control immune response that generally accompanies tularemia 24 hours after the bacteria has been inhaled.”
Eaves-Pyles explained that the extensive tissue destruction that is mediated by the immune-mediated cells activated by the bacteria is much more dangerous than the actual infection itself. She suggested that the administration of cystatin -9 can control the intensity of immune response without affecting the ability of macrophages to destroy and engulf the bacteria. In addition, the protein also makes the bacteria less virulent (or less aggressive) by damaging the protective cell wall of the bacteria.
“So it’s two-fold- Cystatin-9 is having effects on the host and it’s also having direct effects on the bacteria,” added Eaves-Pyles.
Francisella tularensis has been used as a lethal weapon by United States and the Soviet Union, since exposure or inhalation of just 10 organisms can cause death in an untreated victims. Due to non-specific early symptoms (mostly flu like presentation for at least 48 to 72 hours), the diagnosis is often delayed. Moreover, the bacterium has a tendency to replicate steadily and divide extensively in lungs.
Cystatin-9 is being used as a prophylactic drug agent to minimize the risk of infection in high risk individuals (or those who are exposed to aerosolized Francisella tularensis) such as U.S. military or other personnel, as envisioned by Eaves-Pyles.
This is primarily because the size and synthesis of this protein is easy and the chemical structure is stable. Eaves-Pyles commented:
“Once we really start defining the mechanism of cystatin-9, we’re going to see how it affects protein changes., and those proteins may be able to be targeted specifically and used to better understand what is a protective immune response versus an unrestrained, damaging inflammatory response. So I think it’s going to give us a lot of information not just about Francisella but other human pathogens as well.”
Other renowned researchers who contributed significantly in this study with Eaves-Pyles are Jignesh Patel and Aaron Miller, and Eric Carlsen, professors Nisha Garg, Richard Pyles, Vsevolod Popov, Lynn Soong and Csaba Szabo, and associate professor Yingzi Cong, graduate students Anthony Cao postdoctoral fellow Ciro Coletta, all from UTMB; Bernard Arulanandam of the University of Texas at San Antonio; Emma Arigi and Igor Almeida of the University of Texas at El Paso; and Monisha Dhiman of the Central University of Punjab, India. National Institutes of Health supported and funded this research.
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