In and out: Leishmania metastasis by hijacking lymphatic system and migrating immune cells

Abstract

The lymphatic system plays a crucial role in mounting immune response against intracellular pathogens, and recent studies have documented its role in facilitating tumor dissemination linked largely with cancer cells. However, in mucocutaneous leishmaniasis (MCL) caused by Leishmania Viannia subgenus showing infectious metastasis and resulting in severe distant secondary lesions, the route of escape of these parasites to secondary sites has not yet been investigated in detail. Our results demonstrated that when infection was associated with inflammation and additionally exacerbated by the presence of dsRNA viral endosymbiont (LRV1), lymphatic vessels could serve as efficient routes for infected cells to egress from the primary site and colonize distant organs. We challenged this hypothesis by using the intracellular Leishmania protozoan parasites Leishmania guyanensis (Lgy) associated with or without a dsRNA viral endosymbiont, exacerbating the infection and responsible for a strong inflammatory response, and favoring metastasis of the infection. We analyzed possible cargo cells and the routes of dissemination through flow cytometry, histological analysis, and in vivo imaging in our metastatic model to show that parasites disseminated not only intracellularly but also as free extracellular parasites using migrating immune cells, lymph nodes (LNs), and lymph vessels, and followed intricate connections of draining and non-draining lymph node to finally end up in the blood and in distant skin, causing new lesions.

Unveiling drug-tolerant and persister-like cells in Leishmania braziliensis lines derived from patients with cutaneous leishmaniasis

“…The only report currently available on in-vivo quiescence in the context of chemotherapy revealed, in miltefosine-treated L. mexicana -infected BALB/c mice, the presence of quiescent amastigotes in collagen-rich, dermal mesothelium surrounding granulomas ( Kloehn et al., 2021 ): the authors concluded that quiescence, together with the lack of miltefosine accumulation in the mesothelium, may contribute to drug failure and non-sterile cure. The potential for DT and persistence shown here by L. braziliensis strains and by L. lainsoni ( Jara et al., 2022 ) might explain several (sub)clinical features associated with the species of subgenus Viannia , like i) the presence of parasites in 80% of scars, years after treatment with pentavalent antimony therapy ( Schubach et al., 1998 ); ii) the mucosal metastases from healed primary cutaneous lesions ( Jha et al., 2022 ); and iii) the treatment failure in the absence of DR ( Yardley et al., 2006 ). Longitudinal studies of infected individuals and monitoring of quiescence are needed to test these hypotheses.…”

Analysis of theLeishmania mexicanapromastigote cell cycle using imaging flow cytometry provides new insights into cell cycle flexibility and events of short duration

“…IFC has been used to assess morphological changes occurring during promastigote to amastigote differentiation in L. donovani (64), to assess colocalisation of mCLING and lysotracker fluorescent stains in T. brucei (32) and to assess PI live/dead staining and for morphological measurements in L. mexicana (34). IFC has also been employed extensively to study host-parasite interactions for Leishmania and other intracellular pathogens) (19,(65)(66)(67)(68) as well as to detect Leishmania infections in blood and parasite dissemination to organs around the body (69). It has also been used to study trogocytosis by Entamoeba histolytica (70) and for drug screening in Plasmodium falciparum (71).…”

Unveiling drug tolerant and persister-like cells inLeishmania braziliensislines derived from patients with cutaneous leishmaniasis

“…)clinical features associated with species of subgenus Viannia, like (i) the presence of parasites in 80% of scars, years after treatment with pentavalent antimony therapy (Schubach et al, 1998); (ii) the mucosal metastases from healed primary cutaneous lesions (Jha et al, 2022) and (iii) the treatment failure in absence of DR (Yardley et al, 2006). Longitudinal studies of infected individuals and monitoring of quiescence is needed to test these hypotheses.…”