Circadian Regulation of Leishmania Parasite Internalisation in Macrophages and Downstream Cellular Events.

Leishmania spp. parasites use macrophages as a host cell during infection. As a result, macrophages have a dual role: clearing the parasite as well as acting as host cells. Recently, studies have shown that macrophages harbour circadian clocks, which affect many of their functions such as phagocytosis, receptor expression and cytokine release. Interestingly, Leishmania major infection in hosts was also shown to be under circadian control. Therefore, we decided to investigate what underlies the rhythms of L. major infection within macrophages. Using a culture model of infection of bone marrow-derived macrophages with L. major promastigotes, we show that the parasites are internalised into macrophages with a 24-h variation dependent on a functional circadian clock in the cells. This was associated with a variation in the number of parasites per macrophage. The cell surface expression of parasite receptors was not controlled by the cells' circadian clock. In contrast, the expression of the components of the endocytic pathway, EEA1 and LC3b, varied according to the time of infection. This was paralleled by variations in parasite-induced ROS production as well as cytokine tumour necrosis factor α. In summary, we have uncovered a time-dependent regulation of the internalisation of L. major promastigotes in macrophages, controlled by the circadian clock in these cells, as well as subsequent cellular events in the endocytic pathway, intracellular signalling and cytokine production.

The involvement of host circadian clocks in the regulation of the immune response to parasitic infections in mammals.

Circadian rhythms are recurring variations of physiology with a period of ~24 h, generated by circadian clocks located throughout the body. Studies have shown a circadian regulation of many aspects of immunity. Immune cells have intrinsic clock mechanisms, and innate and adaptive immune responses - such as leukocyte migration, magnitude of inflammation, cytokine production and cell differentiation - are under circadian control. This circadian regulation has consequences for infections including parasitic infections. In the context of Leishmania infection, the circadian clock within host immune cells modulates the magnitude of the infection and the inflammatory response triggered by the parasite. As for malaria, rhythms within the immune system were shown to impact the developmental cycles of Plasmodium parasites within red blood cells. Further, host circadian rhythms impact infections by multicellular parasites; for example, infection with helminth Trichuris muris shows different kinetics of worm expulsion depending on time of day of infection, a variation that depends on the dendritic cell clock. Although the research on the circadian control of immunity in the context of parasitic infections is in its infancy, the research reviewed here suggests a crucial involvement of host circadian rhythms in immunity on the development and progression of parasitic infections.

Circadian rhythms in adaptive immunity and vaccination.

Adaptive immunity allows an organism to respond in a specific manner to pathogens and other non-self-agents. Also, cells of the adaptive immune system, such as T and B lymphocytes, can mediate a memory of an encounter with a pathogen, allowing a more efficient response to a future infection. As for other aspects of physiology and of the immune system, the adaptive immune system is regulated by circadian clocks. Consequently, the development, differentiation, and trafficking between tissues of adaptive immune cells have been shown to display daily rhythms. Also, the response of T cells to stimuli (e.g., antigen presentation to T cells by dendritic cells) varies according to a circadian rhythm, due to T cell-intrinsic mechanisms as well as cues from other tissues. The circadian control of adaptive immune response has implications for our understanding of the fight against pathogens as well as auto-immune diseases, but also for vaccination, a preventive measure based on the development of immune memory.