Grant Renewal Extends Project Past 30-Year Mark

The Scripps Research Institute has received a $3 million grant renewal from the National Institutes of Health (NIH) for support of scientist James Hoch’s studies on bacterial signaling proteins. The four-year award will fund the ninth term of a grant that began in 1973—making it one of the longest-running NIH grants awarded to Scripps Research.

“We started out with an important problem that no one knew much about or had good tools to study,” said Hoch, a professor in Scripps Research’s Department of Molecular and Experimental Medicine. “Our tools have become more sophisticated over the years, but our awareness of the true complexity of bacterial signaling has grown, too.”

Hoch’s research under the grant was initially aimed at understanding the signals that trigger “sporulation,” the developmental process by which some bacteria suspend their normal growth and form tough, seed-like spores. One of the best-known spore-forming species, the infamous anthrax bacterium Bacillus anthracis, can survive this way indefinitely in soil or air; when its spores are inhaled or otherwise get into the body of a host, they switch back to growth-mode and cause frequently lethal infections.

Hoch and his lab at Scripps Research first identified the master gene that was required for sporulation in Bacillus subtilis, a closely related but safer-to-work-with species. In the mid-1980s, with the advent of gene cloning and DNA sequencing, the team purified the gene’s product, a DNA-binding protein called Spo0A that serves as the bacterium’s master trigger for sporulation.

Hoch’s studies of Spo0A and its partner signaling proteins led to one of the earliest descriptions of a “two-component signaling pathway,” a simple communication network that enables bacteria to sense and respond to specific stimuli. Such pathways start at the surface of bacterial cells, where sensor histidine kinase enzymes detect specific environmental factors and become activated; these activated enzymes in turn activate “response regulator” proteins inside the bacterial cell, which then switch on the appropriate bacterial gene responses.

“Bacteria use these signal transduction pathways to recognize and respond to the host tissue environment, the presence of other bacteria, and the presence of antibiotics or innate antibacterial peptides,” Hoch said, “so the understanding of these interactions is essential to understanding bacterial infections.”

In 1990, Hoch and his colleagues described a common biochemical mechanism used in these signaling pathways, a “phospho-relay” in which activating phosphate groups are passed from one signaling molecule to the next. A decade later, the researchers showed with crystal structure experiments precisely how these relay interactions occur. In 2009, in collaboration with physicist Terence Hwa at the University of California, San Diego, they developed a new cutting-edge computational technique—undreamt of four decades ago—to predict interaction sites on a large set of bacterial signaling proteins.

Hoch’s major aim continues to be the identification and analysis of bacterial signaling interactions—basic bacterial biology, in other words. But his findings have revealed innate signal-blocking enzymes and signal-transmitting protein interaction sites, both of which suggest strategies for translational medicine.

“Signal transduction pathways have not been widely exploited as antibiotic targets,” he said, “yet by disrupting them one could stop the production of toxins and other virulence factors, and even interfere directly with essential bacterial functions.”

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