From infection to cutaneous leishmaniasis: no real need for amastigotes to leave the macrophages

The interactions between Leishmania and host macrophages play a central role in the pathogenesis of infection. Parasites ability to establish a successful infection is initially related to complement system survival as well as competency to bind and enter a number of host cells. But the only cells within which parasites can replicate are the macrophages. Once the amastigote has established itself inside the macrophage and has replicated, the next step is spreading to uninfected phagocytes. Given the modest number of parasites inoculated during natural transmission (1-1000), the spread of amastigotes to uninfected macrophages is crucial to the development of the disease. The mechanism through which this takes place is largely unknown. However it is understood that the first steps of infection take place silently and that ulceration develops few weeks to months from the sandfly bite. Since apoptosis causes cells to be phagocytosed by macrophages without eliciting an inflammatory response, we suggest it could be involved with the mechanism through which Leishmania parasites spread. Apoptotic cells are also known to be able to release “come and get me signals” which in the Leishmania model would induce movement of uninfected macrophages to the site of infection, also facilitating spreading. Moreover parasites could hide within macrophages apoptotic bodies and easily spread to neighbouring cells without having to come into contact with the complement system. Previous studies on the effects of Leishmania on host macrophages have shown negative modulation of host cell apoptosis at early stages of infection but such effect fades as infection progresses. Moreover late stages of infection have shown an increase in the number of apoptotic cells both in vitro and in vivo. This work investigates the effect of three Leishmania species responsible for cutaneous leishmaniasis on human host cells apoptosis and also the effect of apoptosis induction on infection. Macrophages infected with various Leishmania species were studied for early apoptotic characteristics. Infection and apoptosis was detected simultaneously thanks to the use of GFP expressing parasites. The effect of apoptotic induction on infection was also evaluated. The results presented support the theory that apoptosis induction on host cells could play a role in silent parasites spreading between human host cells.