To sleep, perhaps to heal: the newly discovered gene governs the need to sleep when one is sick

PHILADELPHIA – Humans spend nearly a third of their lives, but sleep remains one of the most enduring mysteries of biology. Little is known about the genetic or molecular forces that underlie the need to sleep – until now. In a study of more than 12,000 fruit fly lines, researchers at the Perelman School of Medicine at the University of Pennsylvania discovered a single gene, called nemuri, that increases the need for sleep. These results are published today in Science.

NEMURI protein fights germs through its intrinsic antimicrobial activity. It is secreted by brain cells to allow deep and prolonged sleep after infection.

"While it is common for sleep and healing to be closely related, our study establishes a direct link between sleep and the immune system and provides a possible explanation for the increase in sleep during illness", said Amita Sehgal, lead author, PhD, neuroscience professor and director. of Penn's chronobiology program.

Without the nemuri gene, flies were more easily awakened during daily sleep and their urgent need for more sleep – induced by sleep deprivation or infection – was reduced. On the other hand, sleep deprivation, which increases the need for sleep and, to a certain extent, the infection, prompted the nemuri to express itself in a small group of nested fly neurons near a known structure promoting sleep in the brain. Overexpression of nemuri resulted in increased sleep in bacteria-infected flies and increased survival compared to uninfected control flies.

In response to the infection, NEMURI appears to kill microbes, most likely in the peripheral parts of the fruit fly body, and increases sleep by its action on the brain. Several molecules such as NEMURI, which is an antimicrobial peptide (AMP), have multiple functions that help fight infections, but its role in promoting sleep could be just as important to the host defense, suggest the researchers, since prolonged sleep promotes fly survival.

In addition, the authors note that cytokines such as interleukin-1 (IL-1), an immune cell molecule, are involved in human sleep. The IL-1 can work in the same way as AMPs. It accumulates after prolonged sleep and seems to promote sleep. In mammals, cytokines can induce AMP production, but AMPS can also affect cytokine expression. Given this nested relationship, the researchers conclude that NEMURI is a functional link between immune function and sleep.

"The protein NEMURI is a real factor that keeps sleep in a state of sleep, even when we are sick," said the first author, Hirofumi Toda, PhD, postdoctoral fellow in the laboratory of Sehgal. "In the next phase of our work, we plan to study the mechanism by which NEMURI causes sleep."

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Julie Williams and Michael Gulledge, both of Sehgal's lab, are also co-authors of this paper. This work was funded by the Howard Hughes Medical Institute and the National Institutes of Health (R01GM123783 402).

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman Medical Schools of the University of Pennsylvania (founded in 1765 as the country's first medical school) and the University of Pennsylvania Health System, which together form a 7 $ 8 billion.

According to the US News & World Report's study of research-based medical schools, the Perelman School of Medicine has been among the top medical schools in the United States for more than 20 years. The School consistently ranks among the top recipients of funding from the National Institutes of Health in the country, with $ 405 million awarded in fiscal 2017.

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