Microbiome research has revealed that there are good guy and bad guy bacteria living together in complex communities on our skin, in our mouths, throughout our guts and pretty much everywhere in between. But what do you call a good guy bacterium that is aiding and abetting a disease culprit?
In Marvin Whiteley’s laboratory at The University of Texas at Austin, you call it Streptococcus gordonii. Normally thought of as a harmless commensal bacterium found in the human oral cavity, the Whiteley lab has painted a more sinister picture of this Strep species as an enabler of its pathogen neighbor, Aggregatibacter actinomycetemcomitans (Aa). Aa is associated with aggressive periodontal infections and can also travel to and infect heart valves.
“Now we are starting to understand that a lot of modern infections are not caused by single organisms, but by a community of organisms,” says Whiteley. “Pathogens don’t necessarily cause a lot of disease by themselves.”
Whiteley’s lab has used these two species, which live together in the mouth and can also be found in abscesses of the lungs and brain, as a model to study the intricate relationships forged between bacterial partners living in close proximity. They have shown that while neither Strep nor Aa cause much damage when grown separately in an infection model, when mixed together the two cause a much worse infection.
In addition, they have shown that Strep produces a byproduct, L-lactate, which turns out to be Aa’s preferred food source. However, Aa can only make efficient use of L-lactate as a food source if enough oxygen is present for aerobic respiration. So, they wondered, what effect is the commensal Strep having on the Aa to make it more pathogenic?
“In this study, we took a blind approach, putting the two together and asking what are all the genes that the pathogen needs to survive, with and without the commensal bacterium,” explains Apollo Stacy, a graduate student in Whiteley’s lab and lead author of the study.
They used transposon sequencing (Tn-Seq) to generate lists of disrupted genes that, without which, Aa could not survive in an abscess on a mouse thigh. Stacy generated such gene lists both in the presence and absence of Strep. Comparing the two lists showed him which Aa gene losses Strep’s presence could compensate for.
The bottom line? Published in mBio this week, their genetic sleuthing revealed that Strep’s presence shifts Aa’s metabolism from an anaerobic state to an aerobic one. “The presence of Strep allows Aa to make more energy for itself because of an increased availability of oxygen,” says Stacy. That shift also allows Aa to make use of the L-lactate and flourish.
The researchers call these relationships between Strep and Aa, cross-feeding and cross-respiration. Whiteley likens it to Strep providing Aa with its absolute favorite food, lactate, and at the same time, providing the knife and fork, the oxygen, it needs to be able to eat it effectively. How Strep makes oxygen available to Aa is still up for debate, but Stacy has a few hypotheses. Strep makes hydrogen peroxide, which Aa could degrade to make oxygen. Or the two bacteria could elicit a stronger immune response from their host, stimulating more peroxide production by immune cells or more blood vessels arriving to the site, which could leak oxygen.
However the oxygen arrives, the finding points toward new ways of fighting polymicrobial infections. For one thing, Stacy notes, this opens up a broader palette of antibiotics that could be used against Aa infections, because a drug that targets S. gordonii would also be effective at limiting or shutting down an infection. More broadly, it shows that the cross-talk and co-dependency among bacteria could be targeted by new types of therapies.
“A significant part of the healthcare budget is spent treating infections caused by communities of organisms,” notes Whiteley. “For the most part, we have no idea how these microbes interact. And there are clearly these intricate interactions that promote growth and virulence.” He suspects that basic biochemistry will hold the key to understanding these interactions—that metabolites, such as lactate and hydrogen peroxide, will turn out to be the basic units of bacterial communications.
Whiteley points out that Stacy’s PhD thesis is one of the first attempts to look at the microscale spatial organization between bacterial neighbors. He marvels at bacterial evolutionary ingenuity: “These little bitty organisms with just a couple thousand genes have evolved these amazing mechanisms to assess the environment around them and find out who and what else is there and [use it] to double their population size. That’s pretty cool.” [image: bitmoji of members of the Whiteley lab]