How Rickettsial Pathogens Break Into Cells

New research by a team of scientists in France and the United States has identified both the bacterial and host receptor proteins that enable Rickettsia conorii, the Mediterranean spotted fever pathogen to enter cells. Understanding how this bacterium interacts with the cells of its host could lead to new therapeutic strategies for diseases caused by related pathogens, including Rocky Mountain spotted fever and typhus.

Pascale Cossart, an HHMI international research scholar at the Pasteur Institute in Paris, together with her postdoctoral fellow Juan Martinez and collaborators in Paris and at Case Western Reserve University in Cleveland, Ohio, has identified the first receptor for a Rickettsial bacterium. Their findings will be reported in the December 16, 2005, issue of the journal Cell.

Rickettsial bacteria are transmitted by fleas, ticks, and lice to humans and other mammals, where they can cause dangerous and sometimes fatal infections. There are two types of Rickettsial pathogens—the spotted fever group, which includes the Rickettsia conorii bacteria studied by Cossart and her colleagues, and the typhus group. Both must live inside cells to survive. Rickettsia have been classified by the National Institute of Allergy and Infectious Diseases (NIAID) as agents with potential for use as tools for bioterrorism.

Mediterranean spotted fever is transmitted by a dog tick. The symptoms are generally mild and respond to antibiotics that shorten the course of the disease. But serious complications occur as much as 10 percent of the time, usually in patients who are elderly or who have some other underlying disease. Left untreated, Mediterranean spotted fever can be deadly.

Cossart and her team demonstrated that the Ku70 protein on the surface of host cells is critical for R. conorii to enter the cell, making it the first Rickettsial receptor ever identified. “This receptor is a subunit of a protein complex present mainly in the nucleus, but also in the cell cytoplasm and at the cell membrane,” said Cossart. “We have thus used several approaches to establish our findings definitively.” Ku70 is probably not the only receptor involved in bacterial entry, she noted.

The researchers found that R. conorii specifically binds to Ku70, and that binding and recruitment of Ku70 at the surface of the host cell are important events in R. conorii’s invasion of mammalian cells. In addition, since Ku70 has previously been shown to control cell death, the new findings suggest that Rickettsia, which—like several other intracellular parasites—prevent cell death in order to multiply inside living cells, may also use this property of their receptor for a succesful infection.

“We found that Ku70 interacts with a bacterial protein called rOmpB, which is present on the surface of Rickettsia bacteria,” Cossart said. “The mechanism underlying this interaction remains unclear, so we are now investigating how rOmpB, expressed by R. conorii, interacts with Ku70 and allows bacterial entry.”

Her team has already shown that Ku70 has to be present in certain well-organized regions of the cell membrane called rafts, and that the protein modifier called ubiquitin modifies Ku70 as soon as the bacteria interact with it. This step is critical for cell entry. “Whether other Rickettsia and other pathogens use Ku70 as a receptor is still unknown,” Cossart said.