Abstract
Leishmania is an intracellular parasite in vertebrate hosts, including man. During infection, amastigotes replicate inside macrophages and are transmitted to healthy cells, leading to amplification of the infection. Although transfer of amastigotes from infected to healthy cells is a crucial step that may shape the outcome of the infection, it is not fully understood. Here we compare L. amazonensis and L. guyanensis infection in C57BL/6 and BALB/c mice and investigate the fate of macrophages when infected with these species of Leishmania in vitro. As previously shown, infection of mice results in distinct outcomes: L. amazonensis causes a chronic infection in both strains of mice (although milder in C57BL/6), whereas L. guyanensis does not cause them disease. In vitro, infection is persistent in L. amazonensis-infected macrophages whereas L. guyanensis growth is controlled by host cells from both strains of mice. We demonstrate that, in vitro, L. amazonensis induces apoptosis of both C57BL/6 and BALB/c macrophages, characterized by PS exposure, DNA cleavage into nucleosomal size fragments, and consequent hypodiploidy. None of these signs were seen in macrophages infected with L. guyanensis, which seem to die through necrosis, as indicated by increased PI-, but not Annexin V-, positive cells. L. amazonensis-induced macrophage apoptosis was associated to activation of caspases-3, -8 and -9 in both strains of mice. Considering these two species of Leishmania and strains of mice, macrophage apoptosis, induced at the initial moments of infection, correlates with chronic infection, regardless of its severity. We present evidence suggestive that macrophages phagocytize L. amazonensis-infected cells, which has not been verified so far. The ingestion of apoptotic infected macrophages by healthy macrophages could be a way of amastigote spreading, leading to the establishment of infection.
Highlights
Leishmaniasis is a broad spectrum disease caused by over 20 different species of protozoa of the genus Leishmania
Leishmania (Leishmania) amazonensis and L. (Viannia) guyanensis are species associated with cutaneous leishmaniasis, they differ in several aspects, including the kind of lesion and the type of immune response they cause
C57BL/6 mice are usually resistant to infection with L. guyanensis, but develop a chronic disease when infected with L. amazonensis, whereas BALB/c are extremely vulnerable to L. amazonensis, but like C57BL/6, totally resistant to L. guyanensis [9, 10]
Summary
Leishmaniasis is a broad spectrum disease caused by over 20 different species of protozoa of the genus Leishmania. (Viannia) guyanensis are species associated with cutaneous leishmaniasis, they differ in several aspects, including the kind of lesion and the type of immune response they cause. L. amazonensis accounts for a broad spectrum of diseases, with cases of simple cutaneous lesions, and extending from anergic diffuse cutaneous to mucocutaneous or visceralization [4,5,6]. C57BL/6 and BALB/c mice are widely compared strains in the study of leishmaniasis due to their contrasting reactions to infection with some species of Leishmania. In L. amazonensis infections, susceptibility in both mice strains is related with activation of both Th1 and Th2 response, with low production of IFN-γ, IL-10, IL-17 and IL-4 [11, 12]. T regs and IL-10 produced by T CD8+ have a role in the pathogenesis of human L. guyanensis infection [18, 19]
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