Two studies by researchers at the University of Chicago show how the bacteria that cause the plague manage to outsmart the immune system and how, by slightly altering one of the microbe's tools, the researchers produced what may be the first safe and effective vaccine.
Both papers -- one published online July 28 in Science Express and one in the August issue of Infection and Immunity -- focus on aspects of the type-III pathway, a molecular syringe that Yersinia pestis, the bacterium that may have killed more people throughout history than any other infectious disease, uses to disable its host's immune system.
"Yersinia pestis is the nastiest thing alive," said study author Olaf Schneewind, M.D., Ph.D., professor and chairman of microbiology at the University of Chicago and director of the Great Lakes Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Research (GLRCE). "It's the most virulent bacterial organism known to mankind. But we now know a little more about how it exercises those powers and we think we can use that knowledge to prepare a preemptive strike."
Historically, the terms "plague" or "Black Death" have referred to the bubonic plague, caused by Yersinia pestis and spread by the bites of infected fleas, which acquire the germ from infected rodents. In the mid-14th century, the plague swept through Europe killing nearly one-third of the population. It returned with a slightly reduced death count about once a generation for centuries.
Although far less common now, the plague has not entirely gone away. There are fewer than 2,000 cases a year worldwide, including 10 to 20 each year in the western United States. One out of seven persons infected dies, even with aggressive treatment.
Since 2001, however, many people have worried that terrorists could exploit Y. pestis as a weapon, spreading it widely and rapidly as an aerosol rather than through fleabites and rodents. Contracted this way -- infecting the lungs rather than the bloodstream -- the disease is known as pneumonic plague. This form of the infection progresses faster, spreads easier from person to person, and is far more deadly, killing 100 percent of those who do not receive the right antibiotics soon after exposure. "There is," the authors note, "an urgent need for vaccine development."
One of this microbe's enduring mysteries has been how it gains a foothold in the host without triggering a protective immune response. In the Science Express paper, Schneewind and colleagues show how Y. pestis annihilates the first line of defense in the host's immune system before it can generate a full response.
The researchers infected mice with Y. pestis. Two to three days later they harvested cells from organs where the bacteria tend to cluster. They used a dye to stain those cells green.
When Y. pestis attacks a cell it uses the type-III pathway -- a needle-like projection -- to inject various toxins into the cell, killing it. The researchers endowed these bacteria with an additional enzyme, which the microbes also injected in cells. This enzyme can snip the green dye into two pieces. When that happens, those cells, when exposed to fluorescent light, glow blue instead of green.
This technique enabled the team to identify the cell types targeted by the bacteria. Two days after the mice were infected, their spleens were filled with bacteria. Although the overwhelming majority of immune cells in the spleen are B cells or T cells, nearly all of the infected cells were macrophages, neutrophils or dendritic cells.
These cells make up what immunologists call the "innate" immune system. They are the first to respond to a bacterial invasion. Their role is to rush to the infection site, engulf the bacteria, chew them up into smaller pieces and present those pieces to the T and B cells -- the "adaptive" immune system -- which enter the fray more slowly but bring powerful and very specific weapons targeted at those individual pieces.