Researchers at the University of Alabama at Birmingham have formulated a new biological model that reveals how tuberculosis can shift from active infection to a dormant and drug-resistant state in humans.

The findings hold promise for combating extreme drug-resistant tuberculosis, or XDR TB, the same microbe that caused an international health scare in May when Atlanta lawyer and TB patient Andrew Speaker traveled overseas.

Before May XDR TB was already a top public health concern since one third of the world’s population is infected with undetectable and drug-resistant forms of TB. The new biological model crafted and tested by UAB will boost anti-B public health efforts and save millions of lives, said Adrie Steyn, PhD, an assistant professor in UAB’s Department of Microbiology.The UAB findings were published this July in the journal Proceedings of the National Academy of Sciences.

Tuberculosis is the leading cause of death in the world from a single bacterial infection, and it kills 1.5 million people per year. The rate of TB disease in Alabama is slightly lower than national rate -- 4.3 TB cases per 100,000 Alabamians vs 4.6 TB cases per 100,000 US residents.

Not much is known about how Mycobacterium tuberculosis (Mtb), the causative agent of TB, can persist in a dormant state in humans for decades then suddenly grow, spread and cause disease. Naturally occurring gases in the lungs, nitric oxide (NO) and oxygen (O2), are thought to trigger Mtb’s change to a dormant state, a condition called TB latency. The UAB findings reveal an important model for how this change to TB latency happens, Steyn said.

In the study, the research team worked with Mtb cells under biosafe laboratory conditions and found certain Mtb proteins ‘sense’ NO and O2 at the molecular level. Furthermore, Steyn’s research team identified a third potential dormancy signal, the naturally occurring gas carbon monoxide (CO), which binds to these proteins. Those interactions under certain conditions lead to a series of biological steps that often ‘lock’ Mtb into TB latency, the study authors said.

“No other model has been proposed that works as well in explaining environmental signals and the impact on Mycobacterium tuberculosis,” Steyn said. “Our data establish a paradigm for understanding the mechanism of latency." In an accompanying study published in the same journal issue, Steyn’s team and chemists at the University of Alabama in Tuscaloosa identified another Mtb sensor protein that directly responds to NO and O2. This Mtb protein syncs the entire mycobacterium metabolism with its environment, which signals Mtb to start feeding off lipids in the lungs to maintain survival.

Based upon both studies scientists now have a much better understanding of the mechanism of TB latency, Steyn said. The Mtb proteins identified in both studies appear to be valuable targets for new drug therapies, he said.

In fact research is underway using UAB’s new model of TB latency along with genetic microbe testing and biochemical

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