Clocks and Immunity

This EurekAlert title got my attention this morning: Immunity stronger at night than during day:

The immune system's battle against invading bacteria reaches its peak activity at night and is lowest during the day.

Experiments with the laboratory model organism, Drosophila melanogaster, reveal that the specific immune response known as phagocytosis oscillates with the body's circadian rhythm, according to Stanford researchers who presented their findings at the American Society for Cell Biology (ASCB) 48th Annual Meeting, Dec. 13-17, 2008 in San Francisco.

"These results suggest that immunity is stronger at night, consistent with the hypothesis that circadian proteins upregulate restorative functions such as specific immune responses during sleep, when animals are not engaged in metabolically costly activities," explains Mimi Shirasu-Hiza of Stanford University.

Snoring or Soaring? Strength of Fruit-Fly Immune System Varies With Daily Cycle, Stanford Researchers Find:

In previously published research, when Shirasu-Hiza and her colleagues had infected normal flies with measured doses of two noted human pathogens, Streptococcus pneumoniae or Listeria monocytogenes, the sickened flies' circadian rhythms were disturbed. They stumbled around more randomly, and stood still for relatively shorter periods. Moreover, genetic mutants lacking circadian cycles of rest and activity died more quickly on infection with these pathogens than normal flies did.

In the new round of experiments, the researchers observed that, consistent with those earlier findings, the activity of phagocytes in normal fruit flies oscillates with their circadian rhythms. Flies infected with S. pneumonia or L. monocytogenes during resting periods ("nighttime") also survive significantly longer than those infected during active periods ("daytime"). Further, by injecting fluorescently labeled dead bacteria into flies at different points in their circadian cycle, the investigators could see increased phagocyte function at night for those two pathogens: there was an increase in the number of bacteria ingested by phagocytes in flies infected during resting versus active phases. Likewise, circadian-mutant flies "trapped" in the active phase had decreased phagocyte function, demonstrating that phagocyte activity is subject to regulation by circadian proteins whose activity, in turn, is disrupted by these mutations.

Strangely, though, infecting the flies with a third bacterial pathogen, Burkholderia cepacia, produced the opposite result. Circadian-mutant flies coped better with the infection than did normal flies, suggesting that in this case, a disrupted circadian rhythm might actually be good for the flies.

Nice, but why go back to the Drosophila model, when this has been studied for decades in vertebrates?

Just look at the Google Scholar searh for "circadian+immunity" - about 23,400 hits! Here is a nice review. And here and here are papers I am very familiar with (along several others on the related topics from the same lab). In that last one: "The responses were inverse to one another during the daily light-dark cycle with the cellular response being maximal during the daily light period and the humoral response being maximal during the daily dark period." which may also explain the Drosophila data in some equivalent way.

If one wants to do research relevant to human medicine which does not rely on the ability to genetically manipulate the lab animals, then using vertebrates makes more sense. On the other hand it is nice to know that this also works in Drosophila, as much of vertebrate literature focuses, perhaps without warrant, on the role of melatonin. If immunity cycles in fruitflies and disruption of the clock disrupts immunity, then a purely circadian mechanism, independent of melatonin, may also be at play in vertebrates. Just some food for thought....