Susceptibility to microbial infection is strongly influenced by the efficacy of the host's immune response, which is known to fluctuate in animals depending on the time of day (termed circadian-regulated immunity). However, the mechanistic basis of this phenomenon is poorly understood. In a recent issue of PLoS Pathogens, Stone et al. describe how a component of the Drosophila melanogaster circadian machinery, the transcription regulator Timeless (TIM), mediates resistance to specific bacterial infections.

the reduced resistance of the D. melanogaster tim-null mutant to S. pneumoniae infection was caused by loss of phagocytic activity.

Previous studies have demonstrated that the circadian immune response of D. melanogaster is pathogen specific. In agreement with this, Stone et al. found that, compared with wild type, a D. melanogaster mutant lacking TIM was more sensitive to infection with Streptococcus pneumoniae and Serratia marcescens but not with Burkholderia cepacia or Salmonella enterica subsp. enterica serovar Typhimurium. Further investigations revealed that the resistance of wild-type flies to S. pneumoniae infection varied with the time of day and was positively correlated with TIM levels. In addition, wild-type flies depleted of TIM, as a result of constant light exposure, replicated the tim-null phenotype.

How does TIM regulate resistance to infection? The authors found that two of the three major immune defence pathways in D. melanogaster — the generation of reactive oxygen species through melanization, and antimicrobial-peptide synthesis — were not circadian-regulated responses. By contrast, the ability of D. melanogaster to phagocytose Staphylococcus aureus did follow a circadian rhythm, being low during the day and high at night, and this effect was TIM dependent. TIM appears to stimulate a bacterium-specific step of phagocytosis, such as substrate recognition or receptor binding, as the presence of TIM did not upregulate phagocytosis of Escherichia coli. Finally, the authors were able to demonstrate that the reduced resistance of the D. melanogaster tim-null mutant to S. pneumoniae infection was caused by loss of phagocytic activity.

Taken together, these data indicate that phagocytosis in D. melanogaster is circadian regulated and are certain to spur further research in this poorly explored facet of infection biology.