Phagocytosis of hemozoin by RAW 264.7 cells, but not THP-1 cells, promotes infection by Leishmania donovani with a nitric oxide-independent mechanism.
During its intra-erythrocytic development, the malaria parasite Plasmodium falciparum synthesizes insoluble hemozoin (HZ) crystals that are released into the circulation upon rupture of parasitized red blood cells, and rapidly phagocytized by host mononuclear cells. Here, HZ persists undigested, causing functional impairment and possibly leading to increased host susceptibility to secondary infections. In patients with malaria and visceral leishmaniasis (VL) co-infections, HZ-loaded macrophages are likely to co-harbor Leishmania donovani parasites, but whether this might influence the course of the Leishmania infection is unknown. In this study, L. donovani amastigote growth was monitored in mouse RAW 264.7 macrophages and PMA-differentiated THP-1 cells previously exposed to increasing amounts of HZ or its synthetic analogue β-hematin (BH). Latex beads were used as a phagocytic control. Data demonstrate that phagocytosis of HZ and BH by RAW 264.7 cells promoted infection therein by L. donovani parasites in a dose-dependent fashion. Similar results were not observed when using THP-1 cells, despite a clear persistence of undigested heme up to 48h after phagocytosis. Conditioning with lipopolysaccharide (LPS)/interferon (IFN)-γ prior to Leishmania infection triggered the release in RAW 264.7 cells of nitric oxide (NO), a highly leishmanicidal metabolite. However, neither HZ nor BH pre-ingestion were able to inhibit NO production following stimulation with LPS/IFN-γ, suggesting that the HZ- and BH-promoting effect on L. donovani infection occurred with an NO-independent mechanism. In conclusion, these preliminary findings highlight a possible detrimental effect of HZ on the course of VL, warranting further investigation into the clinical relevance of the current models.
Parasitology Unit, Department of Biomedical Research, Royal Tropical Institute (KIT), Meibergdreef 39, 1105 AZ Amsterdam, The Netherlands. Electronic address: Erika.vandenbogaart@mondialdx.com.
Erika
E
van den Bogaart
Parasitology Unit, Department of Medical Microbiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Pètra F
PF
Mens
Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Pl, Liverpool, Merseyside L3 5QA, United Kingdom.
Emily R
ER
Adams
Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Martin P
MP
Grobusch
Parasitology Unit, Department of Medical Microbiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Henk D F H
HDFH
Schallig
D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D006420:Hemeproteins / Q000276:immunology; D006427:Hemin / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007893:Leishmania donovani / Q000737:chemistry / Q000254:growth & development* / Q000276:immunology / Q000648:ultrastructure; D008070:Lipopolysaccharides / Q000276:immunology; D049449:Luminescence; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology*; D051379:Mice; D008863:Microspheres; D009569:Nitric Oxide / Q000378:metabolism; D059208:Parasite Load; D010587:Phagocytosis; D000067996:RAW 264.7 Cells
D006420:Hemeproteins; D008070:Lipopolysaccharides; D009569:Nitric Oxide; C020753:hemozoin; D006427:Hemin; D007371:Interferon-gamma
Co-infection; Hemozoin; Leishmania donovani; Macrophage; Nitric oxide; Plasmodium falciparum