Nav: Home

Removing body clock gene protects mice against pneumonia

January 06, 2020

Most living things have an internal body clock which regulates when they sleep and when they wake up. A complex set of genes turning on and off, make this body clock run over roughly 24 hours, and a gene known by the acronym BMAL1 is one of the master regulators of this clock, controlling many other body clock genes and pathways.

The internal body clock being out of alignment with the environment is why we get jet lag, but more recently, scientists have also found that the body clock affects immunity too.

"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," said Oxford University's Professor David Ray, who led the study. "But we had no idea how this was happening."

To find out how the body clock might be influencing the body's infection fighting cells, Gareth Kitchen, a researcher at the University of Manchester, 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,' said Professor Ray. 'Almost everything we've learnt about the body clock so far, whether it's studies in shift workers or experiments in mice, says that disrupting the body clock makes people and animals more likely to get ill, not less."

To find out what was making these mice pneumonia-resistant, the team focussed on a key immune cell, known as a macrophage. Macrophages are specialised cells in blood and tissue that detect, engulf and ultimately destroy bacteria and other harmful organisms that enter the body.

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.

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.

What's more, it was only the BMAL1 clock gene which 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," said Professor Ray. "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."

Dr Kitchen, a clinician scientist who as an anaesthetist looks after critically unwell patients in intensive care and in the operation theatre said: "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."

"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."

The research team are now working out how to make immune cells more effective to help treat infections.
-end-
The study was funded by Medical Research Council, and the Wellcome Trust.

Notes for editors

The full paper is available on https://www.pnas.org/content/early/2020/01/02/1915932117. For further information, including for interviews, please contact david.ray@ocdem.ox.ac.uk. A video of some of the results from the paper is available on https://www.dropbox.com/sh/ph48bpjsxe5myax/AABMKc4-lNW4hzt6gq7iibpya?dl=0.

The video shows bacteria-eating macrophages fighting off pneumonia-causing bacteria (in yellow). The macrophages' actin 'skeleton' (in red) is much more active when they don't have a key clock gene, making the clock-less macrophages better at fighting off the bacteria (video credit: Dr Gareth Kitchen).

University of Oxford

Related Pneumonia Articles:

Elderly patients with pneumonia twice as likely to die as those with broken hips, yet underestimate the danger of pneumonia
Elderly patients who are hospitalised with pneumonia are twice as likely to die as those hospitalised with hip fractures -- yet many elderly people fail to accurately assess their risk of pneumonia, concludes research due to be presented at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).
Pneumonia recovery reprograms immune cells of the lung
Researchers have determined that after lungs recover from infection, alveolar macrophages (immune cells that live in the lungs and help protect the lungs against infection) are different in multiple ways and those differences persist indefinitely.
Skin and mucous membrane lesions as complication of pneumonia
Painful inflammatory lesions of the skin and mucous membranes may occur in children who develop bacterial pneumonia.
Vaccine reduces likelihood of severe pneumonia
A new study has found severe pneumonia decreases by 35 per cent in children who receive a vaccine against a pneumonia-causing bacteria.
Bacteria in pneumonia attack using bleaching agent
Research shows that bacteria use hydrogen peroxide to weaken the immune system and cause pneumonia.
Many kids with pneumonia get unnecessary antibiotics, chest X-rays
Preschool children with community-acquired pneumonia often receive unnecessary tests and treatment at outpatient clinics and emergency departments, according to a nationally representative study led by Todd Florin, M.D., MSCE, from Ann & Robert H.
Certain psychiatric drugs linked with elevated pneumonia risk
A review of published studies indicates that use of benzodiazepines and benzodiazepine related drugs (BZRDs), which are prescribed to treat various psychiatric diseases, may increase the risk of pneumonia.
Bacterial pneumonia far more dangerous to the heart than viral pneumonia, study finds
Heart complications in patients diagnosed with bacterial pneumonia are more serious than in patients diagnosed with viral pneumonia, according to new research.
Research suggests vapers are vulnerable to pneumonia
The vapor from e-cigarettes seems to help pneumonia-causing bacteria stick to the cells that line the airways, according to research published in the European Respiratory Journal.
Pneumonia: Treatment with vaccines instead of antibiotics
A properly functioning immune system is key to resolve bacterial pneumonia.
More Pneumonia News and Pneumonia Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.