Abstract
The protozoan parasite Trypanosoma cruzi circulates in the blood upon infection and invades various cells. Parasites intensively multiply during the acute phase of infection and persist lifelong at low levels in tissues and blood during the chronic phase. Natural killer (NK) and NKT cells play an important role in the immune control of T. cruzi infection, mainly by releasing the cytokine IFN-γ that activates the microbicidal action of macrophages and other cells and shapes a protective type 1 immune response. The mechanisms by which immune cells are regulated to produce IFN-γ during T. cruzi infection are still incompletely understood. Here, we show that urokinase plasminogen activator (uPA) is induced early upon T. cruzi infection and remains elevated until day 20 post-infection. We previously demonstrated that the inhibitory receptor Ly49E, which is expressed, among others, on NK and NKT cells, is triggered by uPA. Therefore, we compared wild type (WT) to Ly49E knockout (KO) mice for their control of experimental T. cruzi infection. Our results show that young, i.e., 4- and 6-week-old, Ly49E KO mice control the infection better than WT mice, indicated by a lower parasite load and less cachexia. The beneficial effect of Ly49E depletion is more obvious in 4-week-old male than in female mice and weakens in 8-week-old mice. In young mice, the lower T. cruzi parasitemia in Ly49E KO mice is paralleled by higher IFN-γ production compared to their WT controls. Our data indicate that Ly49E receptor expression inhibits the immune control of T. cruzi infection. This is the first demonstration that the inhibitory Ly49E receptor can interfere with the immune response to a pathogen in vivo.
Highlights
Trypanosoma cruzi is an intracellular protozoan parasite infecting 8–10 million people, especially in endemic areas of Latin America
As we previously showed that urokinase plasminogen activator (uPA) triggers the inhibitory Ly49E receptor [24], we first analyzed, in wild type (WT) male mice, circulating basal uPA levels in mice of different age and whether uPA is induced upon T. cruzi infection
The protective effect of IFN-γ mainly relies on activation of macrophages and other cells to limit T. cruzi replication during the acute phase of infection [40]
Summary
Trypanosoma cruzi is an intracellular protozoan parasite infecting 8–10 million people, especially in endemic areas of Latin America. Ly49E Inhibits Trypanosoma cruzi Infection evolves in two phases: 1) the initial or acute phase, which lasts for approximately 10 weeks after infection and is characterized by a high number of parasites present in blood and tissues, mostly without symptoms though it may be life-threatening, in children, and 2) the chronic phase during which parasites persist lifelong at very low levels in different tissues. This phase is asymptomatic until 30–40% of the individuals develop severe cardiac or digestive damages that may be lethal. Autoantibodies and a hypercoagulability state might be involved [1,2,3]
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