Washington State University new research receives huge funding

A nearly $3 million grant will enable scientists to uncover how a parasitic bacterium uses a human immune system response to replicate and cause the debilitating disease known as Q fever.

The 5-year grant from the National Institutes of Health brings together researchers at Washington State University’s Paul G. Allen School for Global Health and the University of Nebraska Medical Center to investigate the bacterium behind Q fever, Coxiella burnetii.

C. burnetii naturally infects goats, sheep, and cattle. If transmitted to humans, the infection can lead to diverse clinical outcomes including flu-like symptoms, miscarriage or stillbirth in pregnant women. The infection can also develop to chronic Q fever, which usually manifests as heart inflammation called endocarditis.

C. burnetii mostly infects humans through dust particles contaminated with, for example, material like blood, milk, urine or feces from infected animals. While the bacterium is known to cause Q fever, little is known about how it infects and persists in the human/animal host.

WSU associate professor Anders Omsland and University of Nebraska Medical Center associate professor Stacey Gilk are working to build that understanding.

“We’re trying to figure out fundamental mechanisms involved in how Coxiella causes disease,” Omsland said. “The end goal is to generate more effective treatment strategies, but first we have to understand how this bacterium causes disease in the first place.”

C. burnetii is known to create a homebase inside the host cell by hijacking immune cells known as macrophages. Macrophages function to defend the human body against disease-causing pathogens.

Once a macrophage arrives to kill C. burnetii, the parasite uses that white blood cell to create an acidic compartment within the host cell known as a vacuole. Despite the increased acidity inside this vacuole, which is involved in degrading other bacteria, C. burnetii persists and controls the vacuole’s acidity.

At the College of Veterinary Medicine on the WSU Pullman campus, Omsland is exploring what allows the bacterium to utilize the acidic environment of the vacuole to its own benefit.

“I’ll be testing how Coxiella responds to acidic pH and how Coxiella can survive in an acidic environment,” Omsland said. “Bacteria have all kinds of different mechanisms to protect against acid stress, but how Coxiella does that is not understood.”

Omsland plans to remove, or “delete”, specific genes that may be critical to the bacterium’s ability to survive in an acidic environment. He will start with a gene responsible for C. burnetii’s production of carbonic anhydrase, an enzyme used by bacteria to withstand acid stress.

“If we delete the gene encoding carbonic anhydrase in Coxiella, the expectation is that the resulting mutant will not be able to handle acidic pH as well bacteria containing the gene,” Omsland said.

States away, Gilk plans to examine how the bacterium affects the host cell and a process known as lysosome biogenesis.

Through lysosome biogenesis, lysosomes produced by the host cell carry degradative enzymes to kill invading bacteria. C. burnetii has been shown to block a protein required for effective lysosome production.

Gilk suspects the bacterium either sequesters the protein, called TFEB, in a cell compartment or uses a process known as phosphorylation to manipulate the protein’s function and/or activity. She plans to study how TFEB from infected cells interacts with other proteins and cross-examine those interactions with TFEB from uninfected cells.

Both Omsland and Gilk, who met more than 15 years ago at Rocky Mountain Labs in Hamilton, Montana, are thankful for the collaboration and hopeful to unlock more about C. burnetii.

“We have very different areas of expertise, which makes this an exciting collaboration” Gilk said. “Anders is skilled in bacterial physiology, while my expertise lies in host cell processes. We need to understand both the pathogen and host to get a complete picture of what is going on during infection with a parasitic bacterium.”