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The Puzzling Physiology of Tuberculosis

Publication date: Nov. 28, 2022

Researchers in the Center for Global Infectious Disease Research at Seattle Children’s Research Institute have discovered how nutrients traverse the fortress-like outer cell wall of Mycobacterium tuberculosis, shedding light on a longstanding mystery in the biology of the bacteria that causes tuberculosis, a potentially life-threatening disease primarily of the lungs.

The findings, published in the journal PLOS Biology, identified a new and unusual protein transporter, the PE15/PPE20 complex, that moves calcium — an essential nutrient for many organisms — across the cell’s outer membrane. Together with a previous study on three related transporters, this work suggests a family-wide function of the nearly 170 proteins and provides a likely answer of how the bacteria takes up nutrients.

Dr. Christoph Grundner, principal investigator at the research institute and an associate professor in the Department of Pediatrics at the University of Washington, led the study, along with Drs. Vishant Boradia and Andrew Frando, postdoctoral fellows in his lab.

Gaining these types of insights into tuberculosis is critical, given the widespread nature of this “permanent pandemic,” said Grundner, who has been studying TB for two decades.

“TB kills almost 1.5 million people every year — close to COVID’s toll at the height of that pandemic — and it’s been this way for hundreds of years,” he said. “There are an average of 10 million cases of active TB annually, and it's actually become more prevalent during the COVID pandemic because people had to stay home and couldn’t get treatment.”

Grundner said the transport process is essential for TB’s survival: “It needs to get nutrients. And drugs use these natural processes to get in and out of the cells so it has relevance for TB treatment.”

For example, TB drug resistance is significantly affected by efflux pumps, transporters that sit in the inner membrane of the bacteria and get rid of toxic metabolic byproducts.

“These efflux pumps are often activated in drug resistance,” Grundner said. “Whatever drug the bug takes up, they just pump right back out. But TB also has an outer membrane, so this new transporter family is potentially an answer to how drugs get in through this membrane and might come back out as well.”

Grundner and his team plan to test other proteins in this sub-family to see if they also work as transporters and to determine if they transport just a single nutrient or several, as well as further investigating their molecular structure.

Most importantly, the researchers aim to comprehend the function of these transporters in drug resistance. “There are some indications that these transporters may really play an important role in drug resistance so we want to test that and understand in what ways they affect treatment and resistance,” Grundner said.

The research was supported by the NIH’s National Institute of Allergy and Infectious Diseases.

— Colleen Steelquist