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

Abstract

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.

Circadian Control of the Response of Macrophages to Plasmodium Spp.–Infected Red Blood Cells

“…We previously showed that Leishmania major infection is regulated by the host circadian clock, such that parasite development, inflammation, and recruitment of innate immune cells at the site of infection, as well as the production of cytokines and chemokines, were all varying according to the time of infection ( 26 ). Interestingly, circadian rhythms were also found at the cellular level, upon infection of bone marrow–derived macrophages (BMDMs) by Leishmania parasites , and these rhythms were lost in cells lacking a functional circadian clock (lacking the essential clock gene Bmal1 ) ( 26 , 27 ).…”