Again We Meet at the Corner of Religion and Science

Bugging bugs: Learning to speak microbe

05 March 2010


by Hayley Birch

DEEP in your lungs, there's a battle raging. It's a warm, moist environment where the ever-opportunistic bacterium Pseudomonas aeruginosa has taken up residence. If your lungs are healthy, chances are the invader will be quickly dispatched. But in the mucus-clogged lungs of people with cystic fibrosis, the bacterium finds an ideal habitat. First, the microbes quietly multiply and then they suddenly switch their behaviour. A host of biochemical changes sticks the population of cells together, forming a gluey biofilm that even a potent cocktail of antibiotics struggles to shift.

Microbes like P. aeruginosa were once thought of as disorganised renegades, each cell working alone. Microbiologists like Thomas Bjarnsholt, who is battling to understand how P. aeruginosa causes chronic infection in people with cystic fibrosis, now know otherwise. They are up against a highly organised army, using a sophisticated communication system to coordinate its behaviour.

But it's Bjarnsholt's latest discovery that reveals microbes' gift for language: the bacteria aren't just talking amongst themselves, but also quietly listening in on signals sent by their human host. So when a cavalry of white blood cells arrives to repel the invading bacteria, the entrenched biofilm senses their presence, and launches a coordinated counterattack (Microbiology, vol 155, p 3500). The microbes release deadly compounds called rhamnolipids, which burst the white blood cells, killing them before they can even take aim, says Bjarnsholt, who is at the University of Copenhagen in Denmark.

Examples like this belie the notion that bacteria are simple, silent loners. Over recent decades, many species of bacteria have been shown to be in constant communication with each other. But now an even more sophisticated picture is emerging, one in which bacteria not only receive signals from each other, but also intercept them from the cells of their plant or animal hosts, including us.

Bacteria don't just listen in on each other, but also on their plant or animal hosts - including us.

These communication skills seem to offer invading bacteria quite an advantage on the battlefield. But they are also drawing the attention of researchers looking for new ways to fight microbes. If these "cross-kingdom" signals are indeed widespread, then intercepting or subverting them would offer a whole new way of tackling infection, not only in cystic fibrosis, but also in a wide range of other diseases. Such an approach would simply block the signals prompting the bacterial army to mobilise, rather than trying to wipe it out as antibiotics do. Bacteria would then no longer be forced to evolve drug resistance to survive, potentially bringing to an end the scourge of the superbug.

If cross-kingdom signals are widespread, then intercepting them would offer a whole new way of tackling infection

Bacteria communicate using chemical signals, releasing and receiving signalling molecules in a process known as quorum sensing. In its simplest form, bacteria use quorum sensing to keep track of their neighbours. Some bioluminescent bacteria, for example, light up when their population exceeds a threshold size (Journal of Bacteriology, vol 104, p 313).

Studies of the phenomenon in 1970 discovered that bioluminescent bacteria were using molecules called N-acyl homoserine lactones (ALHs) to coordinate this behaviour - an early hint that bacteria are a talkative bunch. But it wasn't until the early 1990s, with the discovery that ALHs are produced by many species of microbe, that it started becoming clear that quorum sensing was common throughout the bacterial kingdom. And this signalling isn't all friendly chatter, some bacteria intercept and break down the signals from other species, or even release signals to trick others into changing their behaviour.

But in a research review published in August 2009, Steve Atkinson and Paul Williams, microbiologists at the University of Nottingham in the UK, brought home just how widespread these signalling networks are: they reach far beyond the humble bacteria into other kingdoms, including plants, fungi, and our own (Journal of the Royal Society Interface, vol 6, p 959). As Atkinson puts it, "There's a war going on out there."

Take Candida albicans, the yeast that causes thrush infections. This organism likes the same warm, moist habitats as P. aeruginosa and the two battle it out in a bid to colonise their human hosts, deploying quorum-sensing signals as weapons against each other. The yeast fires off signals that trick the bacterium into slashing production of one of its armaments - a reactive chemical called pyocyanin, which makes life particularly uncomfortable for the yeast. The bacterium, meanwhile, produces signals that keep the yeast's growth in check, preventing it from transforming itself from a single-celled yeast into a branching, multicellular fungus.

Then there's our own immune system's battle to prevent P. aeruginosa making itself at home in our lungs. Bjarnsholt is hunting for the signal P. aeruginosa uses to "listen out" for white blood cells, and ways to block it. He doesn't think of the bacteria as being physically aware of their hosts. To them, the signals they detect are just foreign compounds they have to fend off. But it's certainly a far more sophisticated take on the host-pathogen relationship than we're used to, notes Atkinson. "Rather than the pathogen just piling into the host cell and taking over its DNA, it's about signal production, interception - and maybe even coercion of the host to do something that it wouldn't normally do."

Microbe management

This coercion might even extend to including bacteria that can modify the way our bodies work, says Vanessa Sperandio, a microbiologist working on quorum sensing at the University of Texas Southwestern Medical Center in Dallas. "It's a little out there," she admits, "but there are some good examples. Kids who have certain bacterial infections can be very compulsive about touching their mouths, which helps the spread. I think we're going to start seeing lots of examples like that."

Many of the early examples of cross-kingdom communication that Atkinson and Williams catalogued are less than congenial, but there is also good evidence for cooperative interaction between bacteria and their hosts, says Atkinson - particularly between ourselves and our microbiome, the huge population of bacteria that live in us and on us.

These days we're all well acquainted with the millions of microbes lining our insides. Yogurt adverts have taught us nothing if not to love the friendly bacteria which line our guts, helping to keep nastier bugs at bay. Microbes don't just make themselves at home in the intestines, however. They're in your mouth, up your nose, and covering your skin, all the while releasing a cacophony of quorum-sensing signals.

Atkinson thinks our own cells exploit this same signalling system to monitor and cajole our personal population of microbes, just as they eavesdrop on and manipulate us. In other words, we don't passively host this bacterial colony, but actively engage it in conversation. We've evolved together, he says. "We have to consider that we're intrinsically linked."

Sperandio, who is studying how bacteria sense and respond to human stress hormones like adrenalin, agrees. "I think that if you consider how much we interact with microbes, it's not surprising that you're going to have some chemical signalling. Just consider in your intestine, you have 10 times more bacterial cells than you have your own."

Picking out these chemical signals from the maelstrom of molecules that swirl in our gut is proving to be a battle, but that's exactly where some of these cooperative signals have been spotted. Take those friendly gut bacteria, for example, and in particular one that goes by the name of Bacillus subtilis. Not a natural gut bacterium, B. subtilis has long been used as a probiotic agent in food. Though its health-boosting properties were not well understood, some have suggested it gently stimulates the immune system, priming it for action against less friendly bugs.

Then in 2007 a team led by Eugene Chang at the University of Chicago suggested a route by which these bacteria could influence the health of intestinal cells - a route involving quorum-sensing molecules. The team discovered that a certain B. subtilis signalling molecule, known as competence and sporulation factor (CSF), is detected by human gut cells (Cell Host & Microbe, vol 1, p 299). Chang thinks of this signal detection as a kind of "bacteriostat" mechanism: our cells are monitoring CSF as a way of detecting and adapting to important changes in the gut flora.

Cracking the code

"The idea is that when quorum sensing molecules are secreted, it usually signals some change in the balance of the bacterial population," says Chang. So by listening for signals, our cells can adjust to these changes. In this case, the detection of CSF causes our cells to fire up the production of molecules called heat shock proteins, protective molecules known to help cells maintain crucial machinery during times of stress - from temperature extremes to toxins.

Perhaps the most intriguing evidence for the importance of monitoring our microbiome comes from the gut's CSF receptor itself. This receptor was previously thought to be a simple nutrient transporter, despite being found in even the furthermost reaches of the intestine, where most nutrients would already have been absorbed. Its blueprint is encoded in a region of the human genome in which mutations are associated with inflammatory bowel disease. This suggests that without these receptors, we're unable to maintain a normal, healthy gut.

Such examples suggest cross-kingdom signalling has medical implications far beyond infectious diseases. Several other illnesses, including Crohn's disease and some cancers, have been linked to imbalances in the species of bacteria that live in our guts. Sperandio suggests that any number of illnesses could be associated with your balance of bacteria, and that these illness might be tackled using signal interference.

But with so many bacteria - hundreds of different species can inhabit your skin alone - how can we begin to master this chemical language to examine its medical potential? Is there a better way to spot these signals than to pick them out one by one? Pieter Dorrestein and his team at the University of California, San Diego, and Paul Straight at Texas A&M University in College Station, have been developing a tool that could accelerate efforts to crack the code of microbial communication.

The team is using an imaging system based on mass spectrometry to detect swathes of signals at the same time. They grow their bacteria on a stainless steel plate, and use a laser to vaporise their signalling molecules, feeding these into a mass spectrometer to catalogue the molecules present.

As proof of principle, Dorrestein and Straight have mapped the interactions between two species of soil-dwelling bacteria (Nature Chemical Biology, vol 5, p 885). Even in this simple case, the instrument detected as many as 100 different signalling molecules fired off by the two bacteria, only 10 of which the team managed to match to known molecules. Despite the huge scale of the problem, the team is already starting to translate their work into inter-kingdom studies, probing the interactions between bacteria and cells of the human immune system. By imaging cross-talk between different species, they even hope to identify inhibitors for Staphylococcus aureus, the hospital superbug that has evolved to defend itself against whole groups of our most effective antibiotics.

The method should provide food for thought for Bjarnsholt, who has yet to find any serious candidate compounds for signal-blocking in P. aeruginosa infections in people with cystic fibrosis. His best bet for a drug lead is an extract of garlic, although the active component that interferes with the signal remains unknown. He thinks it will be a few years yet before quorum sensing inhibitors come into their own. "I don't think it's just around the corner - there's got to be a lot more research," he says. But when it comes to fighting drug resistance, the more targets we go after the better, he adds. We need to target signalling, biofilm formation and classical biological processes like bacteria cell wall formation, all at once.

Whatever the potential for medical advancement, the growing recognition of cross-kingdom signalling has a more immediate philosophical implication: we're going to have to start changing the way we think about microbes. Bacteria aren't just isolated cells, or even isolated populations, but multi-species communities that communicate with each other and, crucially, us. We are, almost certainly, more intimately connected with the bacteria that inhabit us than we ever would have believed. "We'd be naive to believe that we exist in splendid isolation from all other organisms," says Atkinson. "We've thought that way for too long."

My Comment: I wonder if grammar can be considered scientific. For instance, after reading this article, define “I”. First person pronoun, refers to....not such a simple answer anymore. "I think therefore I am" appears a bit naive now, doesn't it? This also happens to be one of the foundational quests of religion, the search for "I". These findings definitely once again shed light on the questions of self, consciousness, and the fractal nature of Judaism, if not all religions. Just saying.