Hemophagocytosis induced by Leishmania donovani infection is beneficial to parasite survival within macrophages
Open Access
- 18 November 2019
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Neglected Tropical Diseases
- Vol. 13 (11), e0007816
- https://doi.org/10.1371/journal.pntd.0007816
Abstract
Visceral leishmaniasis (VL) is caused by parasitic protozoa of the genus Leishmania and is characterized by clinical manifestations such as fever, hepatosplenomegaly and anemia. Hemophagocytosis, the phenomenon of phagocytosis of blood cells by macrophages, is found in VL patients. In a previous study we established an experimental model of VL, reproducing anemia in mice for the first time, and identified hemophagocytosis by heavily infected macrophages in the spleen as a possible cause of anemia. However, the mechanism for parasite-induced hemophagocytosis or its role in parasite survival remained unclear. Here, we established an in vitro model of Leishmania-induced hemophagocytosis to explore the molecules involved in this process. In contrast to naïve RAW264.7 cells (mouse macrophage cell line) which did not uptake freshly isolated erythrocytes, RAW264.7 cells infected with L. donovani showed enhanced phagocytosis of erythrocytes. Additionally, for hemophagocytes found both in vitro and in vivo, the expression of signal regulatory protein α (SIRPα), one of the receptors responsible for the ‘don’t-eat-me’ signal was suppressed by post-transcriptional control. Furthermore, the overlapped phagocytosis of erythrocytes and Leishmania parasites within a given macrophage appeared to be beneficial to the parasites; the in vitro experiments showed a higher number of parasites within macrophages that had been induced to engulf erythrocytes. Together, these results suggest that Leishmania parasites may actively induce hemophagocytosis by manipulating the expression of SIRPα in macrophages/hemophagocytes, in order to secure their parasitism. Parasites can manipulate host immune responses to build favorable environment to them. Because this parasite-driven immune modulation is often linked to symptoms in infected individuals, not only parasiticidal compounds but also immunological interventions limiting such the parasites’ abilities will serve as treatment options. In this study, we studied the mechanism and its role of hemophagocytosis (the phenomenon whereby macrophages engulf erythrocytes) caused by Leishmania donovani, a causative agent of VL. In vitro experiments revealed parasites have ability to directly disrupt macrophage’s recognition of self-cells, and that the induced engulfment of erythrocytes by L. donovani infection is beneficial to the parasites for their intracellular survival. These results suggest that Leishmania parasites actively induce hemophagocytosis by manipulating the ‘don’t-eat-me’ signal in macrophages for their survival. Although it is still to be determined how Leishmania parasites change the ‘don’t-eat-me’ signal in macrophages, our study may facilitate development of an immunotherapy which limits the change and lead to improvement of anemia due to hemophagocytosis as well as control of parasite survival.Keywords
Funding Information
- Japan Society for the Promotion of Science (17J06910)
- Japan Society for the Promotion of Science (18H02649)
- Japan Agency for Medical Research and Development
- Takeda Science Foundation
This publication has 48 references indexed in Scilit:
- Heme Uptake by Leishmania amazonensis Is Mediated by the Transmembrane Protein LHR1PLoS Pathogens, 2012
- Heme Oxygenase-1 Promotes the Persistence ofLeishmania chagasiInfectionThe Journal of Immunology, 2012
- LFR1 Ferric Iron Reductase of Leishmania amazonensis Is Essential for the Generation of Infective Parasite FormsOnline Journal of Public Health Informatics, 2011
- Hemophagocytosis causes a consumptive anemia of inflammationThe Journal of Experimental Medicine, 2011
- A new ATP‐binding cassette protein is involved in intracellular haem trafficking in LeishmaniaMolecular Microbiology, 2011
- Chronic Murine Typhoid Fever Is a Natural Model of Secondary Hemophagocytic LymphohistiocytosisPLOS ONE, 2010
- Leishmania donovanidepletes labile iron pool to exploit iron uptake capacity of macrophage for its intracellular growthCellular Microbiology, 2009
- LPS-induced down-regulation of signal regulatory protein α contributes to innate immune activation in macrophagesThe Journal of Experimental Medicine, 2007
- A Leishmania amazonensis ZIP family iron transporter is essential for parasite replication within macrophage phagolysosomesThe Journal of Experimental Medicine, 2006
- The Genome of the Kinetoplastid Parasite, Leishmania majorScience, 2005