Interferon Alpha Favors Macrophage Infection by Visceral Leishmania Species Through Upregulation of Sialoadhesin Expression

Abstract

Type I interferons (IFNs) induced by an endogenous Leishmania RNA virus or exogenous viral infections have been shown to exacerbate infections with New World Cutaneous Leishmania parasites, however, the impact of type I IFNs in visceral Leishmania infections and implicated mechanisms remain to be unraveled. This study assessed the impact of type I IFN on macrophage infection with L. infantum and L. donovani and the implication of sialoadhesin (Siglec-1/CD169, Sn) as an IFN-inducible surface receptor. Stimulation of bone marrow-derived macrophages with type I IFN (IFN-α) significantly enhanced susceptibility to infection of reference laboratory strains and a set of recent clinical isolates. IFN-α particularly enhanced promastigote uptake. Enhanced macrophage susceptibility was linked to upregulated Sn surface expression as a major contributing factor to the infection exacerbating effect of IFN-α. Stimulation experiments in Sn-deficient macrophages, macrophage pretreatment with a monoclonal anti-Sn antibody or a novel bivalent anti-Sn nanobody and blocking of parasites with soluble Sn restored normal susceptibility levels. Infection of Sn-deficient mice with bioluminescent L. infantum promastigotes revealed a moderate, strain-dependent role for Sn during visceral infection under the used experimental conditions. These data indicate that IFN-responsive Sn expression can enhance the susceptibility of macrophages to infection with visceral Leishmania promastigotes and that targeting of Sn may have some protective effects in early infection.

Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition

“…Infected C57Bl/6 and/or C57Bl/6 IFN-γ reporter mice were sacrificed at 1, 7 and 21 dpi. Spleen and liver were isolated after transcardial perfusion with 10 mL KREBS Henseleit solution supplemented with 10 U/mL heparin (Sigma-Aldrich, USA) [ 47 ]. Tissue imprints of infected livers and spleens were made on glass slides, fixed with methanol, Giemsa-stained and evaluated microscopically to determine the level of infection.…”

Macrophages as host, effector and immunoregulatory cells in leishmaniasis: Impact of tissue micro-environment and metabolism

“…(c) IFN-β promoted the growth of L. amazonensis or L. braziliensis in human monocyte-derived macrophages, which was due to the induction of superoxide dismutase 1 and an ensuing suppression of ROS production [228] . (d) Stimulation of bone-marrow-derived macrophages with IFN-α raised the uptake of L. donovani or L. infantum promastigotes, which was causally linked to an increased surface expression of sialoadhesin (Siglec-1/CD169) [229] . (e) In VL due to L. donovani or L. infantum , type I IFNs, which were mainly produced by plasmacytoid DCs and not by myeloid DCs or macrophages [78] , [230] , strongly acted on myeloid DCs to suppress the production of IFN-γ and to enhance the expression of IL-10 by parasite-specific CD4 + T cells, leading to increased parasite loads in liver and spleen [231] .…”

Miltefosine enhances infectivity of miltefosine-resistantLeishmania infantumby attenuating innate immune recognition

“…Infected C57Bl/6 and/or C57Bl/6 IFN-γ reporter mice were sacrificed at 1, 7 and 21 dpi. Spleen and liver were isolated after transcardial perfusion with 10 mL KREBS Henseleit solution supplemented with 10 U/mL heparin (Sigma-Aldrich, USA) (74). Tissue imprints of infected livers and spleens were made on glass slides, fixed with methanol, Giemsa-stained and evaluated microscopically to determine the level of infection.…”