When Bacteria Band Together – How Interactions Between Bacteria Can Change the Course of Disease

Bacteria are constantly fighting to preserve themselves; to survive in an environment that is too salty, acidic, or nutrient poor, dodging assault from immune cells and attack by stronger, deadlier microorganisms (“There’s always a bigger fish”). In this hostile landscape, bacteria often persist by working together. Researchers are investigating these cooperative inter-bacterial interactions and what they mean for human health.

When a group of researchers train their investigative eyes on the interaction between two bacteria, they usually do so with a specific disease in mind. It could be a disease like cystic fibrosis (CF), where the dysfunctional CFTR chloride channel causes the accumulation of thick, sticky mucus in the lungs and other organs. This makes patients susceptible to colonization by microbial pathogens¹. For people with CF, there is in fact a list of common pathogens – bacteria and fungi – that are well known to colonize the lungs². CF will be the focus of this article, though the kind of research I describe is also conducted for other diseases where patients are more susceptible to infection, such as COPD or inflammatory bowel disease^3,4. 

After the initial discovery that certain pathogens are more prevalent in people with CF, researchers usually start by studying each pathogen on its own to determine its disease-causing characteristics. At some point in time, however, scientists see fit to study interactions between these pathogens, reasoning that there may be emergent properties of the disease that can only be observed when two or more pathogens are acting together.

One study, conducted by researchers from the University of Alabama at Birmingham, has demonstrated this principle by examining the interaction between CF pathogens Pseudomonas aeruginosa and Stenotrophomonas maltophilia, which often colonize the lungs of CF patients together. They found that P. aeruginosa helps S. maltophilia adhere to lung cells and also promotes the formation of drug-resistant structures called biofilms⁵. 

To understand this kind of interaction, researchers like to ask what proteins are involved. Proteins are the molecular tools that all cellular organisms (from multi-cellular mammals to single-celled microorganisms) use to carry out basic functions like maintaining cellular integrity, interacting with other cells, and moving cellular materials around. Often, researchers don’t measure the activity of proteins directly, but instead measure mRNA transcripts. All genes are initially transcribed into mRNA transcripts before ultimately being translated into functional proteins (this is the so-called Central Dogma of biology). There is not a perfect correspondence between mRNA and protein expression, but counting mRNA transcripts is technically easier and a reasonably good indicator of protein activity. 

To get at which genes / proteins were participating in the interaction between P. aeruginosa, then S. maltophilia, the University of Alabama researchers first infected mice with each pathogen alone, then infected the mice with both pathogens at once. This allowed them to see whether there were any differences in the behavior of the two bacteria – differences in protein production – when the two bacteria were growing together vs. on their own.

The researchers saw that expression of the S. maltophilia chpA gene was significantly increased when S. maltophilia was grown together with P. aeruginosa – and therefore reasoned that it played a key role in the interaction between the two species. To confirm that chpA was essential to the interaction, the researchers created a mutant S. maltophilia strain lacking the chpA gene. When the chpA gene was deleted, S. maltophilia was no longer as capable of adhering to human airway cells.

Researchers also keyed in on another protein, this one from P. aeruginosa, that they thought might be participating in the interaction between the two species as well. This protein is called lasB, and prior research has shown that it can break down the tight junctions that link host cells (of mice, or humans) together. Hypothesizing that the action of lasB would make it easier for S. maltophilia to establish an infection, the researchers knocked out lasB, and found that S. maltophilia indeed became less capable of colonizing the mice⁵.

At the end of their study, the researchers had established several key facts – that two common CF pathogens are interacting in the lungs in a way that is likely detrimental to patient health, and also that certain key proteins are essential for this interaction and its negative effects. Other groups of researchers are performing studies along the same lines, extending our knowledge further.

Here is a second example from the University of Alabama, which seems to be a hotspot for this kind of research, that has uncovered a molecular interaction between P. aeruginosa and another CF lung pathogen called Streptococcus salivarius. Interestingly, this study compared several different strains of P. aeruginosa and found that some promote S. salivarius biofilm formation while others do not. The difference hinges on whether P. aeruginosa is producing the compound alginate or not. Alginate-producing (‘mucoid’) isolates generally do not promote S. salivarius biofilm formation, while non-mucoid isolates typically do. Because chronic P. aeruginosa isolates in the CF lungs often exist in the mucoid state, these findings suggest that the collaborative interaction between the two species may be lost over time as chronic infection is established⁶. Given that other studies have found Streptococcus species to be associated with improved lung function and clinical stability in CF patients, this shift in inter-species interactions could be detrimental to patient health⁷. At the end of the day, the interactions between two microbes may be good or bad for human health – it depends on the context.

Once researchers identify the genes and proteins that participate in inter-bacterial interactions, or do damage to host cells, antibiotic compounds can be developed to target these proteins⁸. Paeonol is a good example. The compound is isolated from traditional Chinese medicinal herbs and reduces the activity of many disease-associated proteins in P. aeruginosa, including lasB⁹. What’s more, the compound also has broader anti-inflammatory effects¹⁰, and is currently being tested as a treatment for cardiovascular disease and osteoarthritis^11,12.