Investigational Drug Traps Parasites Inside Their Hosts' Cells
By LabMedica International staff writers
Posted on 30 Jan 2013
A recent paper described the molecular pathways utilized by intracellular parasites such as Plasmodium falciparum and Toxoplasma gondii to survive in and escape from host cells and suggested that the investigational drug sotrastaurin may prove to effectively prevent infection by these pathogens.Posted on 30 Jan 2013
Investigators at the University of Pennsylvania (Philadelphia, USA) and Johns Hopkins University (Baltimore, MD, USA) wrote in the January 16, 2013, issue of the journal Cell, Host and Microbe that they had identified a G-alpha-q-coupled host-signaling cascade required for the escape of both P. falciparum and T. gondii from host cells. G-alpha-q-coupled signaling resulted in protein kinase C (PKC)-mediated loss of the host cytoskeletal protein adducin and weakening of the cellular cytoskeleton. This damage to the cytoskeleton induced catastrophic Ca2+ influx mediated by the cation channel TRPC6, which activated host calpain that proteolyzed the host cytoskeleton allowing parasite release.
Image: A P. falciparum parasite exits a host erythrocyte loaded with the calcium concentration indicator. High fluorescence of the calcium indicator indicates increased calcium concentration within the host cell. The image is pseudocolored, tending from black (the lowest calcium concentration), through green and yellow to red (the highest calcium concentration) to indicate relative calcium concentration within the host cell. Increased calcium induces calpain activation at the time of parasite egress, as a consequence of upstream host cell signaling. The nuclei of daughter parasites are stained blue in a diagonal pattern from the upper right to the lower left as the parasites are actively exiting the cell. The host cell is no longer uniformly circular since it has been lysed. This shows a high concentration of calcium within the host cell at the end of the parasite cycle, when the host cell lyses and necessary for host calpain activation and break down of the host cytoskeleton (Photo courtesy of Doron Greenbaum, PhD, Perelman School of Medicine, University of Pennsylvania).
Calpains have been implicated in apoptotic cell death, and appear to be an essential component of necrosis. Calpain is also involved in skeletal muscle protein breakdown due to exercise and altered nutritional states. Overexpression of calpain has been implicated as a factor in muscular dystrophy, AIDS, Alzheimer's disease, multiple sclerosis, and cancer.
Mammalian PKC inhibitors, such as sotrastaurin, have demonstrated activity in mouse models of malaria and toxoplasmosis. Furthermore, sotrastaurin prolonged survival in an experimental cerebral malaria model. Thise drug has already passed Phase I safety trials and is currently undergoing Phase II trials for various indications.
"We found an entire signaling pathway in the human host cell that the parasite engages, starting from a G-protein-coupled receptor, that the parasite uses to dismantle the cytoskeleton of the host cell, causing it to collapse," said senior author Dr. Doron Greenbaum, assistant professor of pharmacology at the University of Pennsylvania. "There is a complex series of proteins in this signaling cascade. One of the key proteins is protein kinase C (PKC). We found a tremendous amount of biological validation for the existence and use of this pathway in both parasitic organisms. PKC is a human enzyme that we are targeting, and by inhibiting it, we have basically blocked the parasites from getting out. They are trapped and die within the host cells."
"Targeting a host protein will engender less resistance because the parasite has no genetic control over the host," said Dr. Greenbaum. "We are quite excited about that. We have found a compound that is already been used in trials in humans and is deemed safe. This approach could be used as both a prophylactic and a treatment." Greenbaum says. "We have some indication that it could also be used to block transmission."
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