LAUSR

Simple Summary Leishmania infantum is a parasite that causes zoonotic visceral leishmaniasis, a disease that affects humans, wild and domestic animals, mainly domestic dogs. This parasite develops inside the macrophages and, concealed inside these cells, the parasite can invade the inner organs such as the spleen and liver, causing life-threatening disease. Therefore, a better understanding of the immune mechanisms exhibited by the macrophages when facing this parasite is needed to improve control strategies. Macrophages are cells of the immune system, existing in the peripheral blood and associated with different tissues in the mammal body, having the task to protect against microbiological threats. Interestingly, Leishmania can manipulate the macrophages into a non-active ghost-like state, allowing the parasite to stay in the host. The liver, which is a vital organ and a target for the parasite, has a resident population of macrophages designated as Kupfer cells. Thus, this study aims to evaluate the innate immune response exhibited by these two distinct cell populations—blood-macrophages and Kupfer cells—against Leishmania parasites. Our findings showed that Leishmania takes advantage of the natural disposition of blood macrophages to perform phagocytosis and facilitate parasite internalization, which rapidly subverts the immune mechanisms of macrophages. On the other hand, Kupfer cells are not extensively immune activated in the first contact with the parasite but seem to be more efficient in parasite infection, thus contributing to the ability of the liver to naturally restrain Leishmania dissemination. Abstract L. infantum is the aetiological agent of zoonotic visceral leishmaniasis (ZVL), a disease that affects humans and dogs. Leishmania parasites are well adapted to aggressive conditions inside the phagolysosome and can control the immune activation of macrophages (MØs). Although MØs are highly active phagocytic cells with the capacity to destroy pathogens, they additionally comprise the host cells for Leishmania infection, replication, and stable establishment in the mammal host. The present study compares, for the first time, the innate immune response to L. infantum infection of two different macrophage lineages: the blood macrophages and the liver macrophages (Kupffer cells, KC). Our findings showed that L. infantum takes advantage of the natural predisposition of blood-MØs to phagocyte pathogens. However, parasites rapidly subvert the mechanisms of MØs immune activation. On the other hand, KCs, which are primed for immune tolerance, are not extensively activated and can overcome the dormancy induced by the parasite, exhibiting a selection of immune mechanisms, such as extracellular trap formation. Altogether, KCs reveal a different pattern of response in contrast with blood-MØs when confronting L. infantum parasites. In addition, KCs response appears to be more efficient in managing parasite infection, thus contributing to the ability of the liver to naturally restrain Leishmania dissemination.