Xiaohui Zhou, assistant professor of pathobiology, has received a four-year, $1.5 million NIH Research Project Grant (RO1) to study the foodborne pathogen Vibrio parahaemolyticus. According to the CDC, this strain of Vibrio is responsible for an estimated 45,000 illnesses in the United States every year.
Zhou first began researching this common seafood pathogen while a graduate student at Washington State University. V. parahaemolyticus causes an intestinal disease usually contracted by eating raw or undercooked seafood, particularly oysters. In some people, the illness can be quite serious.
“The overall goal of my study is to develop more effective and efficient approaches to treat infectious disease that is caused by bacterial pathogens,” Zhou says.
To do this, Zhou must first understand how the pathogens cause disease and must identify the proteins, or virulence factors, used by the bacteria to disrupt normal human intestinal cell processes.
Intestinal homeostasis (balanced cell death and proliferation) is a human defense mechanism against bacterial colonization. Many bacterial pathogens promote colonization by inhibiting cell death. However, Zhou discovered that Vibrio attacks its host by injecting certain proteins into intestinal cells, promoting massive cell proliferation that will replenish the intestinal cells damaged during infection and sustain maximal colonization.
The protein is secreted via a T3SS2 apparatus, which is a needle-like structure that Vibrio uses to inject specific proteins into human cells. This action disrupts the signal pathway in the gut, leading to this proliferation of intestinal epithelial cells. The goal of the study is to determine whether this proliferation provides a base that the bacteria use to attach to the intestine. Conversely, if the cells do not proliferate to replenish those damaged during infection, bacterial cells will detach from the intestinal wall through cell sloughing and be unable to colonize.
This project will examine how the protein promotes cell proliferation. “If we understand how this happens, we can develop medication that will disarm the bacteria,” Zhou explains. “Once we identify the proteins in this pathogen, we might also be able to study the mechanisms of other pathogenic foodborne diseases.”
In another study funded by the College, Zhou is looking at antibiotic-resistant bacteria with the goal of reversing resistance to existing antibiotics. Vibrio is currently resistant to penicillin. Zhou’s team discovered a mechanism where the pathogen uses surface protein to sense the presence of an antibiotic, then transmits a signal to turn on the expression of a bacterial enzyme to hydrolyze the antibiotic, rendering it ineffective.
“It is possible that other bacteria species use this mechanism to detect the presence of antibiotics, but it may involve different proteins for different bacteria,” Zhou points out. “We are now testing inhibitors that will prevent a protein from sensing the presence of an antibiotic.”
“Antibiotic resistance is a serious problem,” Zhou says. “Many antibiotics are no longer effective. We have to understand how antibiotic resistance develops because we are becoming short of antibiotics, and it is a slow process to develop new ones. This research could potentially provide new approaches to treating infections by making old antibiotics effective again.”
Zhou is developing a new project that will use CRISPR gene editing to kill bacteria. This approach will use CRISPR technology to cut specific regions of the bacterial DNA. Possible applications might involve treating seafood with a food additive that involves this technology. “The approach is not new, but we are looking at a different method of delivering the CRISPR to the bacteria,” Zhou explains.
“Our approach to treating human infectious diseases is two-prong: Discovering anti-virulence methods that disarm bacteria, and making older medications more effective,” he says. “We really want to develop new ways to control, treat and prevent intestinal infectious diseases.”