While the appropriate regulation of the body’s biological clock has well-documented health benefits, its proper operation may not always be working in the best interests of the immune system. For instance, new research from investigators at the University of Manchester and Oxford University has found that a master regulator of the body’s clock—a gene called BMAL1—might be influencing how the body fights infections like pneumonia.
“We’ve previously found that the mice were worse at fighting off the pneumococcal bacteria that cause pneumonia when they got infected during the day, compared to infection at night,” explained senior study investigator David Ray, PhD, professor at Oxford University. “But we had no idea how this was happening.”
Findings from the new study were published recently in PNAS through an article titled “The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia.”
To find out how the body clock might be influencing the body’s infection-fighting cells, the research team genetically engineered mice so that they didn’t have the BMAL1 clock gene.
“We were really surprised to find that these mice, which had no clock in a set of immune cells, were more resistant to bacterial pneumonia,” noted Ray. “Almost everything we’ve learned about the body clock so far, whether it’s studied in shift workers or experiments in mice, says that disrupting the body clock makes people and animals more likely to get ill, not less.”
While looking to determine what was making these mice pneumonia-resistant, the team focused on a key immune cell, known as a macrophage. The researchers found that deleting the BMAL1 gene in the macrophages supercharged them, making them more mobile, and better able to engulf and destroy bacteria, both in a petri-dish and inside the mice. The clock gene deletion set of a cascade of changes which ultimately triggered a switch which made the macrophages “skeleton” (made up of a protein called actin) less rigid, making it easier for the cells to move and engulf bacteria.
Interestingly, when the researchers blocked the actin skeleton change, the macrophages were no longer supercharged, even with their clock genes deleted. This shows that it is the strengthening of the cells’ actin skeleton that was making them more effective. Moreover, it was only the BMAL1 clock gene that controlled the actin cell skeleton switch in macrophages—the researchers found that deleting other body clock genes did not have the same effect.
“As we enter an era of bacterial resistance to antibiotics, it is becoming more and more important to understand how our innate immunity works,” Ray remarked. “We might be able to use some of the drugs currently being tested to change the body clock to supercharge macrophages, but our body clocks are also affected by things like when we sleep and eat.”
Excited by their findings, the research team is now working out how to make immune cells more effective to help treat infections.
“Multi-drug resistant bacteria is one of the biggest problems facing modern medicine, so discovering that BMAL1 may be a target for future medicines to combat infection is very exciting,” concluded lead study investigator Gareth Kitchen, PhD, a clinical lecturer at the University of Manchester. “In the future, doctors may change the time that vulnerable patients are offered meals or go to sleep so that the patients’ body clocks boost rather than hinder their innate immunity when they most likely to be exposed to infection.”
