When the body encounters bacteria, viruses or harmful substances, its innate immune cells, neutrophils, gather at the site to fight the invader.
However, bacteria and viruses have ways of evading these defenses. Yersinia pestis, the bacteria that cause bubonic and pneumonic plague, for example, can hide from the immune system, allowing it to replicate unhindered in the body until it overwhelms the host. This ability allowed Y. pestis to spread the bubonic plague across Europe in the 14thu century, killing a third of the European population.
Although the plague may not pose a serious threat to human health in modern times, researchers at the University of Louisville study Y. pestis better understand its ability to evade the immune system and apply this understanding to control other pathogens.
If you look at the human plague, people don’t show symptoms right away even though they have an active infection because the bacteria is hidden from the immune system. Then suddenly there’s a lot of bacteria, the immune system is overwhelmed and in the case of pneumonic plague, the person dies of pneumonia.”
Matthew Lawrenz, Professor, UofL Department of Microbiology and Immunology
Neutrophils are the first responders of the immune system, sending protein molecules to call other neutrophils to attack and destroy the invader. Among the first molecules sent by neutrophils to signal an infection are the lipid molecules leukotriene B4 (LTB4). Y. pestis interferes with the immune response by suppressing LTB4 signals. Lawrenz received a new four-year, $2.9 million grant from the National Institutes of Health to investigate how Y. pestis LTB4 block. Ultimately, he expects this understanding will lead to ways to prevent it Y. pestis from blocking signals and hopefully apply this understanding to other types of infections.
“This historical pathogen is very good at manipulating the immune system, so we’re using it as a tool to better understand how white blood cells like neutrophils and macrophages respond to bacterial infection,” Lawrenz said. “In this project we use Yersinia to better understand why LTB4 is so important for plague control. This understanding would apply to almost any infection of the lungs or other areas, and probably could apply to viruses as well.”
A member of the UofL Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, Lawrenz has been studying plague bacteria for nearly two decades. His previous work includes discoveries about how Y. pestis acquires iron and zinc to overcome the host’s defense mechanism known as nutritional immunity and has an increased understanding of how Y. pestis resides in spaces within host macrophages to hide from the immune system.
Katelyn Sheneman, a doctoral student in Lawrenz’s lab, has also received a prestigious $100,000 NIH trainee research award. This grant will fund her research to understand how Y. pestis it changes the content of extracellular vesicles, cellular containers produced by immune cells that contain proteins, lipids such as LTB4, and other components. These vesicles are released into the bloodstream to communicate to other cells what is happening in their body part, such as an infection.
“My work examines how Y. pestis it changes the number of vesicles that are produced, what is packed into them, and how other cells respond to them,” Sheneman said. “We have some good evidence that pestis is able to manipulate the production of these vesicles, so we will look at the role that vesicles play in pulmonary infection and how this influence contributes to overall systemic infection.”
Since there is no effective vaccine against infection with Y. pestis and has the potential to be used as a bioweapon, Lawrenz and Sheneman study Y. pestis at the UofL Biosafety Level 3 facility at the Regional Biocontainment Laboratory, part of a network of 12 regional and 2 national biocontainment laboratories for the study of infectious agents. Biosafety Level 3 facilities are built to strict federal safety and security standards to protect researchers and the public from exposure to the pathogens being researched.
