Cellular Pathway May Be a Route For Disease
DURHAM, N.C. – Microbiologists at Duke University Medical Center show from a review of studies that a particular depression in cells may serve as an invading pathway for pathogens such as the AIDS virus HIV and other viruses and toxins.
What's more, the depressions, called caveolae, could possibly serve as a transport for drugs designed to kill the pathogens it assists, the researchers said.
Writing in the journal Science, the Duke scientists said a number of prominent pathogens, such as HIV, parasites that carry malaria, tuberculosis-causing bacteria and bacterial toxins such as those that lead to cholera, which causes stomach ulcers, all appear to use the pathways created by the caveolae to penetrate the cell.
"All of these pathogens and bacterial toxins appear to enter the cell through the caveolae," said Soman N. Abraham, associate professor of pathology and microbiology and senior author of the perspective that appears in the Aug. 24 issue of Science. "Cells possess highly efficient defense systems and extrinsic agents that enter the cell are typically transported to lysosomes (a chamber in the cell) where they are broken down. It appears that pathogens and toxins avoid this defense system by entering via caveolae."
The perspective is based on a review of recent findings from several laboratories, including previous work by Abraham published in Science.
"By seeking refuge in cells, pathogens can avoid attack from the body's immune cells or even from antibiotics. Because these pathogens discovered this route (through the caveolae) millions of years before man did, they have been able to evolve ways to commandeer caveolae to enter, survive and eventually exit the cell," he said in an interview.
Abraham and Jeoung-Sook Shin, a doctoral candidate in pathology and lead author of the perspective, also suggested that caveolae could be an effective avenue for drug delivery.
"By following these pathogens, we can use them as tools to understand how caveolae function and how molecules that compromise caveolae dictate the trafficking of agents into the cells. Ultimately, these studies will help us find ways for preventing infections of these cells by pathogens and find ways of getting drugs into a cell with out degradation," Abraham said.
Caveolae, which are flask-shaped pits measuring about 50 nanometers (a billionth of a meter) in diameter, are found on the plasma membrane of a cell. They were discovered in Japan by electron microscopist Eichi Yamada in the 1950s. Caveolae have been detected in almost all cell types and are particularly abundant in endothelial cells, adipocytes and smooth muscle cells.
Even though scientists have known that caveolae exist, the researchers were unsure of their role until new research in recent years identified caveolin, a protein that serves as a maker for caveolae. Scientists also credit new methods of labeling caveolae in microscopic studies using anti-caveolin antibodies or albumin-gold, and new methods to isolate caveolae from the cell membrane.
Scientists have long suspected that caveolae are involved in cholesterol transport, the transport of chemical signals, such as chemokines, across endothelial cells, tumor suppression and signal transduction.
The finding that caveolae can promote uptake of soluble as well as particulate agents into cells suggests the existence of an alternate, but more benign entry pathway where the transported material avoids degradation, Abraham said.
"We know for a fact that cells internalize various material without destruction, but how that is achieved has remained largely a mystery. Perhaps caveolae are the critical portal of entry of such materials," he said.