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Just like every organism on this planet, bacteria seek to understand their environment to respond to it in the most appropriate way.

Pseudomonas aeruginosa (P. aeruginosa) is a type of bacteria well-known to cause infections, such as acute and chronic lung infections, wound infections, and infections from medical devices, to name a few. An increase in temperature for an infection-causing bacterium like P. aeruginosa often means that it has successfully conquered a host and found a new location to live. In this case, the bacterium needs to change its virulence, which is its ability to efficiently infect the host.

Dr. , PhD, associate professor and microbiologist, biochemist, and molecular geneticist in the — together with a transdisciplinary team of researchers — has shown how a P. aeruginosa strain learns about a temperature change and decides to switch its virulence program into ‘settling’ mode.

Harrison hopes this discovery will lead to future applications in biotechnology involving heat-activated processes.

Bacteria seek to recognize, react to surroundings when becoming more infectious

Bacteria need to understand their surroundings to control their metabolism. For this, they use a small molecule called c-di-GMP. This molecule can bind to proteins and regulate the swimming behaviour of bacteria and the production of biofilm.

Unfortunately, these attributes are also important virulence weapons for bacteria to infect human bodies. When bacteria decide to settle down in a human body, they produce biofilm, which is bacteria surrounded in a sticky, slimy layer of its own secretions. This slime protects P. aeruginosa from the host’s immune system and antibiotics. Due to this, many antibiotics become useless in the fight against this bacterium while the immune system also struggles to clear the bacterial infection. As such, P. aeruginosa biofilms are major burdens in hospital settings.

Harrison, doctoral student Trevor Randall, postdoctoral fellow Dr. Henrik Almblad, PhD, and Dr. Justin MacCallum, PhD, associate professor in the , identified a new c-di-GMP-producing enzyme that has a thermometer as a sensory domain.

“When a signal is sensed, bacteria start a series of chemical events that make them adapt to that environment,” Harrison says. “We discovered that for some P. aeruginosa strains, that reaction is linked to the perception of heat.”

For a bacterium like P. aeruginosa, heat means temperatures close to that of the human body. When this bacterium feels the warmth of a human body, the thermometer domain of this enzyme becomes active and produces c-di-GMP. With a lot of c-di-GMP inside the bacterium, it understands that it has successfully made its way into a human body.

Having learned about its new location, P. aeruginosa changes its virulence strategy as it aims to settle down inside its new host. “They feel the heat of a host body, and switch on all of their machines to make biofilms that make people sick." Harrison says.

Decade of teamwork unravels bacterial heat-sensing discovery

By using a multidisciplinary approach, Harrison and his team learned more about how a strain of P. aeruginosa decides when to produce biofilm in an infection. This bacterium produces the protein TdcA that reacts to the temperature of the bacterium's surroundings. Bacterial colonies with active TdcA proteins looked completely different depending on different temperatures.

Like many ‘eureka’ moments in science, part of this discovery happened as a result of an unexpected setback.

Somehow, when these bacterial strains were shipped to my lab in a FedEx envelope, we’d found they’d lost their ability to produce biofilms. We thought there might have been something wrong with the bacteria. We re-grew them in the incubator and they grew normally — then it occurred to me that the only difference was the heat.

Harrison’s collaborators Weerayuth Kittichotirat and Roger Bumgarner from the helped identify the thermometer-sensing component with a novel genome sequencing technology.

The team’s research showed that TcdA does more than just observing the temperature. It also controls the weapons that P. aeruginosa uses to infect and kill its host. Collaborators Karen Brassinga and Ayush Kumar from the and , MD, from the revealed that the bacteria killed waxworms, roundworms and mice more efficiently depending on temperature and when they produced the TcdA thermometer.

Harrison says he hopes to apply this discovery as a basis for future applications to help fight infections.

“Just because something’s bad in nature doesn’t mean that it’s bad in its purpose,” he says. “It could be repurposed for something good. For example, I could take the parts of P. aeruginosa that cause it to respond to heat and use it to produce a medication that can treat something else.

"If you understand mechanistically why something acts the way it does, you can pull apart the bits of the cell so that you can engineer them and put them back together in a helpful way.”

The results were in the journal Nature Communications.