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In two studies published this week, University of Toronto scientists take a close look at how harmful bacteria feast on our bodies’ nutrients – with certain proteins pillaging our iron and zinc, and others devouring phosphorylated sweets. 

Stealthy invaders
Researchers have learned how harmful bacteria evade the body’s natural defenses and compete for nutrients within our bodies. Understanding how these invaders are able to grow and prosper in their human host could help scientists develop new ways of fighting these bugs, including possible vaccines against diseases such as meningitis and gonorrhea. 

The battle for resources between bacteria and our bodies is complex. Humans have evolved to possess ‘nutritional immunity,’ by sequestering zinc and iron and limiting its availability to any invading bacteria. But bacteria always seem to be a step ahead of our defenses, evolving quickly to overcome this barrier. 

Using 3D structural models, Associate Professor Trevor Moraes identified how certain bacteria manoeuvre around this barrier and analyzed their surface receptors for potential culprits. A particular receptor called ZnuD seemed to be playing a crucial role in seizing zinc. Moraes and colleagues followed its twists and turns, and found that indeed this receptor is essential for the bacteria to cause systemic disease. 

Then, looking for weak spots that might be flagged to trigger our body’s immune system, the team used data from actual patients infected with meningococcus bacteria – the type that can lead to meningitis – to map it onto their 3D model.

They found several regions of the ZnuD receptor that could set off an immune response, but they also saw how quickly the receptor changes shape, in an apparent ploy to remain undetected by the body’s defences.

“We’ve shown how the bacteria are able to acquire zinc and not elicit an immune response, perhaps because of the large changes it undergoes,” says Moraes, of the department of biochemistry. “The next step will be to use parts of these surface proteins as antigens in mice, to see whether we have potential for a vaccine.”

ZnuD surface receptors can be found in many different pathogenic bacteria, including those that cause respiratory infections, painful middle ear infections, even chronic obstructive pulmonary disease (COPD). Therefore a vaccine targeting ZnuD could potentially help with many ailments. 

Moraes, a Canada Research Chair in the Structural Biology of Protein Membranes, said the 3D structure of this receptor was critical in making these insights possible. 

“It’s like getting snapshots of the proteins within the surface of bacteria to show us how they function,” he says. “Now we hope to learn how to exploit them.”

Moraes collaborated with Faculty of Medicine faculty members Scott D. Gray-Owen and Régis Pomès,  postdoctoral fellows Charles Calmettes and Carolyn Buckwalter, and others on this work. The results were published in the journal on August 18. 

Bacteria’s Sweet Tooth

In the second study, Moraes found another bacterial protein that has a sweet tooth. While we already know that certain bacteria consume sugars, what’s new is the type of sugar this transporter protein is built to take in: sugar phosphate. 

Previous research suggested these bacterial proteins don’t come anywhere near sugar phosphates because it was thought this sugar stays inside cells while the bacteria remains outside. 

“We never thought our bodies would have sugar phosphates outside our cells,” says Moraes. “That’s been hammered into us in biochemistry. But now it looks like sugar phosphates are available in the gut milieu.”

Using a similar 3D structural investigation as in the other study, Moraes and his team found that the bacterial AfuABC transporter – which was originally thought to take up iron – actually had a sugar phosphate attached to it. The researchers followed up with several tests to make sure this transporter was indeed bringing in sugar phosphates. In collaboration with Bruce Vallance at the University of British Columbia, they conducted experiments on mice and showed that AfuABC’s role was key to powering an intestinal pathogen’s transmission from host to host. 

“Our work shows that bacteria use these understudied sugar phosphates as nutrients during infection,” says Brandon Sit, who played a central role in this research as an undergraduate student. “We need to broaden the search for more sugars that bacteria are using when they infect us. The fact that we have discovered one transporter with unexpected sugar-targeting activity suggests that many others could be hiding in plain sight.” 

The AfuABC transporter is found in the genomes of numerous pathogens, including those that cause cholera, food poisoning and respiratory illnesses, and this discovery could lead to new approaches in the fight against these ailments. With rising rates of antimicrobial resistance, these types of bacterial intelligence operations might open up new strategies in our age-old struggle with bacteria.

This study was published in the journal on August 21.