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New Molecular Insight into Amboebic Dysentery

06/14/2008

New Molecular Insight into Amboebic Dysentery

In the June 15th issue of G&D, Dr. Sinisa Urban (Johns Hopkins University School of Medicine) and colleagues reveal a potential role for the rhomboid enzyme, EhROM1, in the pathogenesis of the enteric protozoan parasite, E. histolytica. This discovery posits EhROM1 as a prospective target in the treatment of amoebic dysentery, which affects 1/10th of the global population (~500 million people) and represents the second most common disease in the world.

"New drug targets are needed for amebiasis as current treatments have associated toxicities and drug resistance is a concern." said Dr. Upinder Singh, a clinician at Stanford University and co-author of the study.

E. histolytica is a single-celled intestinal parasite that infects the lower GI tract, causing amoebiasis, and can invade the intestinal wall and spread to the bloodstream, causing potentially fatal amoebic liver abscesses. The parasite is transmitted through fecally contaminated food or water, and is a major public health threat in the developing world.

Dr. Urban and colleagues uncovered new insight into the activity of E. histolytica's single rhomboid protease protein, EhROM1, which suggests that it helps the parasite evade the host's immune response. In order to escape immune detection, E. histolytica trophozoites concentrate immune system-eliciting surface proteins towards the rear of the cell and then expel them. Dr. Urban's team discovered that EhROM1 processes surface lectin proteins, and collaborators at Stanford University found that it re-localizes posteriorly during lectin shedding.

These findings suggest that EhROM1 facilitates lectin shedding and host immune system evasion by this pathogenic parasite. "New drug targets are needed for amebiasis as current treatments have associated toxicities and drug resistance is a concern." said Dr. Upinder Singh, a clinician at Stanford University and co-author of the study.Dr. Urban is excited by the new findings, since "Enzymes have served as particularly successful drug targets in the past, so it's exciting to discover an ameba rhomboid enzyme with similar properties as a malaria rhomboid. We're hopeful that with additional work, we will be able to develop rhomboid inhibitors and evaluate if they could be applied as a more general anti-parasitic strategy in the future." added Dr. Urban.

Novel Model of Osteosarcoma

In the upcoming issue of G&D, Dr. Stuart Orkin (HHMI, Dana-Farber Cancer Institute, Children’s Hospital Boston) and colleagues present a new mouse model of osteosarcoma.

Osteosarcoma is the most common type of malignant bone cancer, and one of the most lethal: The 5-year survival rate is only about 60%, and this statistic drops steeply once the cancer spreads. Osteosarcoma results from the dysregulated growth of osteoblasts (the cells that form the bone matrix). It primarily develops near the ends of the femur, tibia or humerus, and is usually diagnosed during adolescence, when the long bones of the body are undergoing rapid growth.

While the precise causes of osteosarcoma are unknown, it is evident that two tumor suppressor genes – p53 and Rb – are involved, as children with familial mutation syndromes affecting either of these genes have higher incidences of osteosarcoma.

Dr. Orkin's team has developed a novel experimental system to model the genetics of human osteosarcoma. The researchers generated a strain of transgenic mice lacking specifically the p53 and Rb genes in an early osteoblast progenitor cell population. All mutant animals rapidly developed osteosarcomas, with clinical, histo-cytological and molecular features closely recapitulating the human disease.

The scientists concluded that p53 loss is essential for the development of osteosarcoma, and that while Rb gene mutation acts synergistically with p53 loss to facilitate carcinogenesis, loss of Rb, alone, is not sufficient to induce osteosarcomagenesis.

Ultimately, this high-fidelity animal model will further elucidate the genetic contributions to osteosarcoma, and enable researchers to rationally design and test new therapies. Dr. Orkin is hopeful that "our work will stimulate translational efforts to develop novel therapies for this devastating bone tumor".


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