Knocking E.coli off its Pedestal
by Jeffrey Martin ’04, ’05 (M.A.)
The headlines have been becoming more frequent over the last several years: Drug-resistant bacteria are on the rise. As traditional treatments fail, it becomes increasingly important to understand the biology of these bacteria, how they cause sickness and how they can be stopped.
That’s exactly what Shantanu Bhatt, Ph.D., assistant professor of biology, is researching in pathogenic strains of Escherichia coli (E. coli).
The bacterium, which exists as a harmless and even beneficial microbe in the intestines of warm-blooded animals, including humans, has also evolved into at least 11 different disease-causing types. One of those types, enteropathogenic E. coli (EPEC) is at the center of Bhatt’s research.
“EPEC belongs to the attaching/effacing (A/E) family of bacteria,” Bhatt explains. “These bacteria infect intestinal cells, injecting proteins into the cell to destroy, or efface, the cells’ microvilli. Then, they recruit proteins from the effaced microvilli to form pedestal-shaped structures that protrude from infected cells. These protrusions are crowned on top by tightly attached bacteria.”
The disintegration of the microvilli prevents intestinal cells from performing their duty of absorbing nutrients and water, which results in diarrhea. This is especially dangerous for infants and older adults, two groups that have been particularly affected by EPEC infections in the recent past. Alarmingly, treating these vulnerable groups is difficult, because EPEC has developed resistance to multiple antibiotics.
“Now, more than ever before, it is imperative that we understand the mechanisms by which these pathogenic strains of E. coli cause disease,” Bhatt says.
Previous studies on EPEC revealed a cluster of genes called the locus of enterocyte effacement (LEE), which is essential to the infection process. Bhatt’s research aims to find out how the LEE is regulated, specifically by the protein Hfq, which binds to ribonucleic acid.
“Hfq is shaped like a doughnut, with a rough side and a smooth side," Bhatt explains. “On one side, it binds to a regulatory small RNA (sRNA) and on the other side it binds to a messenger RNA (mRNA), bringing the two in close proximity of each other and allowing them to pair. Once paired, the sRNA can dictate whether toxic proteins encoded on the mRNA are expressed or not.”
“Now, more than ever before, it is imperative that we understand the mechanisms by which these pathogenic strains of E. coli cause disease. ”
— Shantanu Bhatt, Ph.D.
Recently, Bhatt’s lab identified the very first Hfq-dependent sRNAs that pair to LEE-encoded mRNAs, shutting off toxic protein production and reducing the infectivity of EPEC. These findings were recently published in the Federation of European Microbiological Societies' journal Pathogens and Disease. His next step is to define the precise mechanism of action of these sRNAs.
“What is remarkable is that these sRNAs represent just the tip of the iceberg, since we have also identified numerous other sRNAs that target the LEE- encoded virulence of EPEC,” Bhatt says. “Collectively, these sRNAs represent a novel palette of molecules that have the potential to be suitable therapeutic candidates to limit disease caused by EPEC.”
Bhatt is enthusiastic about the research that can be conducted in the near future, especially because much of the work in his lab is performed by students. Undergraduate students who study with Bhatt earned several national fellowships, including the American Society for Microbiology Undergraduate Research Fellowship, ThermoFisher Scientific Antibody Scholarship, Sigma Xi Grants-in-Aid for Research and the Sigma Zeta Research Award. Several have also coauthored research papers with Bhatt in peer- reviewed journals.
“I have been able to be so productive in the lab only because of the dedicated and diligent students who have pushed our research to unchartered frontiers,” Bhatt says. “I’m humbled and inspired by their work and confident in their path forward.”