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.
Highlights
Leishmaniasis is a family of related protozoal diseases occurring in the New- and Old World and is caused by Leishmania parasites responsible for clinical features ranging from cutaneous, mucocutaneous to visceral manifestations
We evaluated the infection of different L. infantum and L. donovani promastigote laboratory strains and clinical isolates in bone marrow-derived macrophages either or not subjected to stimulation with IFN-α
The present study provides evidence for an enhanced infection of Leishmania in macrophages that are stimulated with type I interferon
Summary
Leishmaniasis is a family of related protozoal diseases occurring in the New- and Old World and is caused by Leishmania parasites responsible for clinical features ranging from cutaneous, mucocutaneous to visceral manifestations. Visceral leishmaniasis (VL), known as kala-azar, is a lethal neglected tropical disease caused by Leishmania donovani and L. infantum and responsible for ∼0.2–0.4 million cases each year [1]. It is a vector-borne disease transmitted by the bites of infected female phlebotomine sand flies [2]. Recent reports described that Sn recognizes the sialic acid moieties onto the Leishmania surface [3, 23, 24] and is responsible for phagocytosis during a Leishmania infection [3] Other pathogens such as Campylobacter jejuni [25], group B Streptococcus [26] and Trypanosoma cruzi [27] were shown to be phagocytosed by macrophages using the Sn-sialic acid interaction. Since Sn expression was described to be upregulated by type I IFN, we further unraveled the role of Sn during in vitro and in vivo Leishmania infections
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