Apoptotic mimicry by an obligate intracellular parasite downregulates macrophage microbicidal activity

Abstract

Programmed cell death by apoptosis of unnecessary or potentially harmful cells is clearly beneficial to multicellular organisms. Proper functioning of such a program demands that the removal of dying cells proceed without an inflammatory reaction. Phosphatidylserine (PS) is one of the ligands displayed by apoptotic cells that participates in their noninflammatory removal when recognized by neighboring phagocytes. PS ligation induces the release of transforming growth factor-beta (TGF-beta), an antiinflammatory cytokine that mediates the suppression of macrophage-mediated inflammation. In Hydra vulgaris, an organism that stands at the base of metazoan evolution, the selective advantage provided by apoptosis lies in the fact that Hydra can survive recycling apoptotic cells by phagocytosis. In unicellular organisms, it has been proposed that altruistic death benefits clonal populations of yeasts and trypanosomatids. Now we show that advantageous features of the apoptotic process can operate without death as the necessary outcome. Leishmania spp are able to evade the killing activity of phagocytes and establish themselves as obligate intracellular parasites. Amastigotes, responsible for disease propagation, similar to apoptotic cells, inhibit macrophage activity by exposing PS. Exposed PS participates in amastigote internalization. Recognition of this moiety by macrophages induces TGF-beta secretion and IL-10 synthesis, inhibits NO production, and increases susceptibility to intracellular leishmanial growth.

Leishmaniadisease development depends on the presence of apoptotic promastigotes in the virulent inoculum

“…Data suggested that Leishmania amastigotes can express PS on their outer membrane leaflet without subsequent apoptotic death. PS-positive amastigotes induced TGF-␤ and IL-10 production by murine MF (20). However, this study does not exclude the possibility that PS-positive amastigotes bear other apoptotic markers such as DNA degradation and in fact are dying because of apoptosis.…”

In vitro study of immunosuppressive effect of apoptotic cells

“…Reiter and Krammer (1999) found that necrotic tumor cells help macrophages kill tumor cells, but that, apoptotic tumor cells decrease the competence of macrophage in clearance of tumor cells, and enhance prompt the growth of tumor cells. In addition, phagocytosis of apoptotic cells was found to inhibit macrophage activity and finally stimulate the growth of Trypanosome cruzi (Frerie-de-Lima et al, 2000;Freitas Balanco et al, 2001). These foundings indicate that apoptotic cells can induce immune tolerance.…”

Exploiting death: apoptotic immunity in microbial pathogenesis

“…Such apoptotic mimicry has been characterized rigorously with several viruses 16,17 and trypanosomatids. [18][19][20] For example, viral internalization and the suppression of host immune responsiveness associated with vaccinia and hepatitis B viruses appear to follow apoptoticlike mechanisms of PS-dependent macropinocytosis and antiinflammatory cytokine induction. Similarly, the internalization of the amastigotes from different species of Leishmania parasitic protists into mammalian macrophage hosts has been shown to occur via an amiloride-sensitive process, dependent on PS exposure and independent of immunoglobulin F c receptors.…”

“…18,21,41,[55][56][57][58][59][60][61][62][63][64] Viruses exploit apoptotic processes as well, especially reducing the death of virally infected cells to facilitate intracellular viral replication. The viral reprogramming of cell death, in contrast, reflects a distinct approach.…”