Tissue-Resident CD169+ macrophages as a frontline of host defense in Plasmodium infection

• Main Author: Pravesh Gupta
• Other Authors: Ruedl Christiane
• Format: Theses and Dissertations
• Language: English
• Published: 2017
• Subjects: DRNTU::Science::Biological sciences
• Online Access: http://hdl.handle.net/10356/70327
• Institution: Nanyang Technological University

Macrophages are professional phagocytic cells that comprise tissue-resident and monocyte-derived subsets with pleiotropic functions ranging from tissue homeostasis, clearance of senescent erythrocytes and cell debris, antigen presentation as well as regulation of innate and adaptive immune responses to pathogens. The complex diversity of macrophage subpopulations across different organs requires that the individual subsets should be considered separately in terms of their functional specializations during inflammation and disease, including malaria. The precise role of tissue-resident macrophages during blood-stage malarial infection and resulting multifaceted malarial syndromes remains obscure. To this end, here we focused on a distinct subset of tissue-resident CD169+ macrophages that occupies a privileged micro anatomical location at the blood entry sites, such as marginal zone in the spleen, hepatic sinusoids in the liver, perivascular regions of brain and kidney, with the property to capture blood-borne pathogens in a glycan dependent manner. In this study, we exploited a CD169-DTR mouse strain and demonstrated that tissue-resident CD169+ macrophages are specifically and efficiently ablated in all the tested organs during steady state and Plasmodium infection. Using a P. berghei ANKA (PbA) infection model we show that the absence of CD169+ macrophages results in accelerated mouse mortality due to exacerbated parasite sequestration, hemozoin tissue deposition and vascular leakage. This led to development of overlapping pathologies such as cerebral malaria (CM), acute lung, liver, kidney and heart injury culminating into widespread tissue damage and inflammation, characteristic of malarial syndrome. Except for the development of CM, similar pathologies in different organs were recapitulated in P. yoelii non-lethal (Py) infection model as well. Thus the CD169+ macrophages play a crucial role in restraining the parasite burden and its sequestration in different tissues and therefore regulate the outcome of Plasmodium induced inflammation and pathogenesis. Functionally, we observed an attenuated T cell effector response in CD169-DTR mice during the Plasmodium infection. In addition, parasite specific antibody responses were compromised during Py infection. Furthermore, CD169+ macrophages are a predominant constant source of anti-inflammatory cytokine IL-10 during the entire course of PbA infection. Therefore, our results demonstrate that CD169+ macrophages possess an intrinsic anti-inflammatory property and are regulators of anti-malarial innate and adaptive immune responses during Plasmodium infection.