Prasadarao V. Nemani, Ph.D.
Prasadarao V. Nemani, Ph.D. and Rahul Mittal, Ph.D., investigators at The Saban Research Institute of Keck School of Medicine-affiliated Children's Hospital Los Angeles, published the first report of the role of neutrophils as essential in the development of Escherichia coli K1 meningitis. The paper appears in Nature Communications.
"This is a significant finding that will ultimately help us protect our most vulnerable patients against the devastation of meningitis," said Brent Polk, M.D., director of The Saban Research Institute.
Bacterial meningitis strikes an average of 1500 Americans each year. Thirty percent of those infected will die. In the U.S., meningitis resulting from E. coli infection primarily occurs in newborn infants, and especially vulnerable premature and low birth weight babies are at four times greater risk for developing the disease. E. coli K1 is the leading cause of meningitis in developing countries where the mortality rates are higher than in the U.S. Without treatment, the mortality rate approaches 100 percent. Even with effective therapy, 15 to 30 percent of affected babies will die while the majority of those who survive will face lifelong consequences including blindness, deafness, and brain damage.
Neutrophils are a type of white blood cell and act as the first responders in battling infection. In this study, the investigators sought to determine the role of neutrophils in the pathogenesis of E. coli K1 meningitis. What they found surprised them. They discovered that the bacteria manipulates the function of the neutrophils by preventing oxidative killing of pathogens within the cell, which in turn allows the level of pathogens to build instead of being cleared from the blood. They also observed that E. coli K1 utilized gp96, a protein located on the surface of the cell, as a receptor to gain entry into the cell.
In contrast to the existing paradigm that neutrophils are protective against infectious disease, the investigators demonstrated that depletion of neutrophils caused mice to be resistant to E. coli K1 meningitis. They also used a novel technique to "knock down" expression of gp96 in mice and were able to show that gp96 is required for E. coli K1 to produce meningitis in mice.
"These findings encourage us to begin identifying small molecule therapeutics that can target gp96 as an effective preventive strategy against E. coli K1 meningitis," said Nemani.
Children's Hospital Los Angeles, named the best children's hospital in California and among the best in the nation for clinical excellence with its selection to the prestigious U.S. News & World Report Honor Roll, has been affiliated with the Keck School of Medicine of the University of Southern California since 1932.