The plague, author of some of civilization’s darkest chapters, has managed to keep many of its secrets. In particular, how does it manage to evade the immune system? This trick is especially deadly in cases of pneumonic plague, which occurs when the bacterium Yersina pestis enters the lungs. Without treatment, the respiratory infection is 100% fatal, often within a matter of days. Even though treatment with antibiotics is effective, delays in treatment or misdiagnosis can be deadly—a sobering thought, given that pneumonic plague is reemerging as a public health concern in multiple countries in Africa. Also, Y. pestis may serve as a weapon of bioterrorism or biowarfare.
A less alarming reason to unravel the secrets of Y. pestis is simply to learn what mechanisms the bacterium shares with other organisms. Any common themes that emerge among disparate infectious processes could point investigator to fruitful lines of inquiry. At least, such thinking helped motivate scientists at Northwestern University. Led by Wyndham Lathem, Ph.D., assistant professor in microbiology-immunology, a team of researchers at Northwestern has been studying Y. pestis for years.
Back in 2007, they demonstrated that the presence of a protein called the plasminogen activator protease (Pla) is required for Y. pestis to live inside the lungs. And now, as a result of more recent work, they have determined that Pla shuts down a molecule, Fas ligand (FasL), which stimulates a form of programmed cell death known as apoptosis. The result is a disrupted immune response during infection. This allows Y. pestis to overwhelm the lungs, causing death.
“This is the first time anyone has shown how bacteria can subvert apoptotic cell death by directly destroying Fas ligand,” said Dr. Lathem.
Dr. Lathem and colleagues described their work April 9 in Cell Host & Microbe, in an article entitled “The Pla Protease of Yersinia pestis Degrades Fas Ligand to Manipulate Host Cell Death and Inflammation.” This article describes how they added Pla to glass slides with various fluorescently tagged proteins. If the protease showed an affinity for a specific protein, it would chew off pieces, making it appear less florescent when viewed under a microscope.
“We knew that Pla must be chopping up host proteins in some manner and we looked to discover exactly what proteins were being affected,” said first author Adam Caulfield, Ph.D., a research associate in Dr. Lathem’s lab.
“As we reviewed possible hits, the ‘aha moment’ came when we saw Fas ligand on the list of affected proteins, because we know Fas is an integral receptor for controlling cell death,” recalled Dr. Lathem. “The process of Pla degrading Fas ligand effectively prevents the lungs from being able to clear the infection.”
After verifying their findings using cell cultures, Dr. Lathem conducted preclinical tests using mice, arriving at the same conclusion. In the article, the authors wrote that “wild-type Y. pestis, but not a Pla mutant (Δpla), degrades FasL, which results in decreased downstream caspase-3/7 activation and reduced apoptosis. Similarly, lungs of mice challenged with wild-type Y. pestis show reduced levels of FasL and activated caspase-3/7 compared to Δpla infection.”
“The loss of FasL or inhibition of caspase activity alters host inflammatory responses and enables enhanced Y. pestis outgrowth in the lungs,” they added. “Thus, by degrading FasL, Y. pestis manipulates host cell death pathways to facilitate infection.”
“Now that we have identified this as a method by which plague bacteria can manipulate the immune system, we have something to look for when studying other respiratory infections,” Dr. Lathem concluded. “This could be a common feature, where we see other bacteria manipulating cell death pathways by altering Fas signaling.”
Dr. Lathem believes that a restoration of Fas signaling may give antibiotics more time to work, and scientists in his lab are exploring that possibility. They will also be looking at different bacterial infections to see if any manipulate cell death by altering Fas signaling in a similar manner.