Bacteria Put on an Invisibility Cloak to Cause Asymptomatic Infections

ABOVE: New research shows that biofilm forming bacteria in lung infections can hide from sensory neurons that relay information to the brain. ©istock, wildpixel

When someone catches a lung infection, be it viral or bacterial, they usually show tell-tale symptoms, such as weakness, breathing difficulties, or brain fog. These indicators signal others to keep a safe distance from the contagious individual. But Pseudomonas aeruginosa can cause a range of lung infections, from mild bronchitis to life-threatening pneumonia, that are acutely asymptomatic yet cause inflammation and destruction of tissue.¹

In chronic infections, these bacteria form a biofilm of extracellular polymer matrix around themselves that shields them from antimicrobials, enzymes, and neutrophils.² Now, in a paper published in Cell, a group of scientists investigated the underlying mechanism and reported that the biofilm hides Pseudomonas bacteria from sensory neurons in mice, preventing signals from reaching the brain and reducing sickness symptoms.³ These findings provide a deeper understanding of how biofilm-forming bacteria evade the lung-to-brain communication channel, a potentially crucial tactic in persistent infections.

A three-panel image of a mouse brain after a lung infection with Pseudomonas that do not form biofilm. The left panel shows the nuclei of the neurons in blue, the middle panel shows the activated neurons in green, and the right panel shows a merged image of the first two.

Neurons in the paraventricular nucleus (PVN) were activated (green; nuclei stained blue) following a lung infection with bacteria that do not form biofilm.

Parisa Moazen and Deborah Kurrasch, University of Calgary, Canada.

Almost a decade ago, Elise Granton, currently a physician-immunologist at the University of Calgary and coauthor of the study, tested the effects of P. aeruginosa in mouse lungs using two variants: one that formed a biofilm and one that did not. “We thought this would be pretty simple,” said Bryan Yipp, a physician-immunologist at the University of Calgary and coauthor of the study. “We just could not pin down the exact reason why some of the mice were sick without the biofilm and the biofilm mice were completely unsick,” he added. The team knew that neutrophils could sense the bacteria with or without biofilm, so they started to look beyond the immune system. “Maybe the biofilm is hiding the bacteria. What could it be hiding?” Yipp wondered.

An illustration of the lung-brain neuronal communication axis in mice.

Pseudomonas bacteria (green) affect how lung sensory neurons communicate with the PVN of the hypothalamus via the vagal nerve.

Jesse Horne.

Previous studies showed that one of the main bacterial toxins, a surface molecule called lipopolysaccharide (LPS), that causes inflammation and other symptoms is shielded by biofilm components.⁴ To understand how the exposure of LPS causes sickness, the team studied the role of toll-like receptor 4 (TLR4), an LPS receptor. When mice lacking TLR4 in nociceptive sensory neurons were infected with non-biofilm forming bacteria, they showed reductions in hypothermia and overall sickness scores. To tease this apart further, the researchers specifically knocked out TLR4 in the lung nociceptive neurons and exposed the cells to bacteria that did not form a biofilm. Mice with intact TLR4 displayed characteristic illness symptoms, while those lacking the receptor showed drastically reduced sickness symptoms.

The turning point came when Luke Brown, a PhD candidate at the University of Calgary and coauthor of the study, joined the project. Once they knew that sensory neurons could ‘see’ the bacteria, Yipp and his team wondered how this interaction might send signals to the brain to bring about behavioral changes. They reached out to Deborah Kurrasch and Jaideep Bains, behavioral neuroscientists at the University of Calgary, to find answers to their questions.

“[We] asked them, ‘Are we totally crazy?’” Yipp recounted. “And quite quickly, the people that are invested in stress responses and behavior said it's probably the hypothalamus and it's probably these neurons. To them, it made perfect sense!”

Following up on this thread, the team looked into the hypothalamus and saw that a greater number of corticotropin-releasing hormone (CRH) neurons showed activity after treating the lungs with LPS in control mice as compared to those lacking TLR4 in neurons. CRH neurons respond to stress and modify behavior accordingly.⁵ Blocking the activity of CRH neurons in mice treated with non-biofilm bacteria alleviated their symptomatic sickness.

An illustration of the differences in the body’s response to infection by biofilm forming and non-forming Pseudomonas bacteria.

Biofilm masks the bacteria from being detected by the lung sensory neurons, resulting in limited sickness (left). In the absence of biofilm, lung sensory nerves detect the bacteria via TLR4 and LPS and transmit signals through vagal nerve to the PVN of the hypothalamus. PVN neurons become activated and release CRH which mediates the sickness phenotype (right).

Jesse Horne

“We're just beginning to understand how the brain becomes aware that there are infections in the body. What's exciting is that now there seems to be a diversity of different neurons that can detect different types of pathogens and relay the signals to the brain to evoke sickness,” said Stephen Liberles, a neuroscientist at Harvard Medical School who was not involved in the study.

Next, the team will study different types of lung infections and their interactions with the nervous and immune systems. “We're totally thinking in a different way. How many neurological processes, your mood, and definable pathological diseases might originate because of things that have gotten into the lung and activated the neural system,” Yipp said.

References

Grant SS, Hung DT. Persistent bacterial infections, antibiotic tolerance, and the oxidative stress response. Virulence. 2013;4(4):273-283.
Costerton JW, et al. Bacterial biofilms: A common cause of persistent infections. Science. 1999;284(5418):1318-1322.
Granton E, et al. Biofilm exopolysaccharides alter sensory-neuron-mediated sickness during lung infection. Cell. 2024;187(8):1874-1888.e14.
Lu YC, et al. LPS/TLR4 signal transduction pathway.Cytokine. 2008;42(2):145-151.
Daviu N, et al. Paraventricular nucleus CRH neurons encode stress controllability and regulate defensive behavior selection. Nat Neurosci. 2020;23(3):398-410.