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Thursday
Feb162012

Fighting bacterial infections, while you sleep

This post was chosen as an Editor's Selection for ResearchBlogging.org
Circadian rhythms control biochemical, physiological, and behavioral aspects of organisms in a roughly 24-hour cycle. They have been found in microbes as small as bacteria to complex eukaryotes, like humans. It has been known that there is a relationship between the host’s immune response and time of the day (termed circadian-regulated immunity); however, the mechanisms behind this relationship have yet to be understood.

How does circadian rhythm affect immunity?

This question takes into account circadian rhythm controlled aspects of host-pathogen relationships, and that’s not a "smaller question", that’s a huge question. To make the question more approachable researchers looked in the animal model our friend the fruit fly, or Drosophila.

o hai.

Circadian rhythms have been extensively studied in this background, down to microarray analyses of gene expression controlled by circadian-regulation in different tissues and immune cells. Additionally, circadian rhythm mutants (deletions in the genes aptly named Timeless and Period) are more susceptible to specific pathogens (Streptococcus pneumoniae) and more resistant to other pathogens (Pseudomonas aeruginosa).

Here we have to start with a smaller question:

Why are circadian mutants more susceptible to some pathogens?

In Drosophila there are 3 mechanisms for resistance to bacterial pathogens: 1) production of antimicrobial peptides, 2) reactive oxygen species generation, and 3) phagocytosis, or uptake and subsequent destruction of microbes, by immune cells.

Elizabeth Stone and Ben Fulton, et al. hypothesized differences in susceptibility to pathogens in circadian mutants was due to changes in one, two, or all of the mechanisms of resistance to pathogens in Drosophila.

What they found was phagocytosis of bacteria by immune cells was circadian-regulated, and that decreased phagocytic activity significantly contributed to the sensitivity of circadian mutants to certain types of bacterial pathogens.

What links phagocytosis and circadian rhythms?

The Tim protein (encoded by the Timeless gene) is light sensitive and is degraded during prolonged periods of light – therefore Tim is present in higher concentrations at night. They found when Tim expression is higher (night), phagocytic activity was increased in wild-type Drosophila, and when Tim expression is lower (day), phagocytic activity was decreased. In the Tim mutants there was complete loss of the oscillatory patterns of phagocytosis.

Interestingly, this relationship between Tim expression and phagocytosis correlated with susceptibility to Staphylococcus aureus – and they found that Tim mutants were more susceptibile to S. aureus, but not to E. coli, indicating Tim regulates a bacteria-specfic step of phagocytosis (ex: host cell recognition of bacteria or binding to bacteria).

These data are not only significant because they marry circadian rhythm research to host-pathogen interactions, but it’s generally good insight into another reason why keeping a steady circadian rhythm might affect an otherwise healthy individual. Not good news for people who fly a lot (jet lag) or night-shift workers.

ResearchBlogging.orgStone EF, Fulton BO, Ayres JS, Pham LN, Ziauddin J, & Shirasu-Hiza MM (2012). The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila. PLoS pathogens, 8 (1) PMID: 22253593

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Reader Comments (2)

Even better.....it happens in mammals, not just flies (!).

Seems to correlate with TLR9 expression.

It also has some significant ramifications on vaccination. It seems that the time of day in which an animal is vaccinated causes differences in protective abilities.

It was published just in Immunity...which is not freely available. But here is the link anyway:
http://download.cell.com/immunity/pdf/PIIS1074761312000477.pdf?intermediate=true

February 17, 2012 | Unregistered CommenterTim Sampson

If you consider this in mammals like the above reference suggests, what exactly is the adaptive value of a trait like this temporally controlled immunity? Is it a trade-off? Is it simply too costly to have your innate immune system functioning at full capacity at night? Or is it specifically regulated to times when you are most likely to encounter a pathogen? I.e when you're active during the day.

How then does this effect mammals that hibernate, such as bats. How does their immune system deal with this during the months resting?

February 20, 2012 | Unregistered CommenterConnor

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