Lipocalin 2 Bolsters Innate and Adaptive Immune Responses to Blood-Stage Malaria Infection by Reinforcing Host Iron Metabolism

• Published in: Cell host & microbe Vol. 12; no. 5; pp. 705 - 716
• Main Authors: Zhao, Hong, Konishi, Aki, Fujita, Yukiko, Yagi, Masanori, Ohata, Keiichi, Aoshi, Taiki, Itagaki, Sawako, Sato, Shintaro, Narita, Hirotaka, Abdelgelil, Noha H., Inoue, Megumi, Culleton, Richard, Kaneko, Osamu, Nakagawa, Atsushi, Horii, Toshihiro, Akira, Shizuo, Ishii, Ken J., Coban, Cevayir
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.11.2012
• Subjects: Acute-Phase Proteins - metabolism; Adaptive Immunity; Animals; Erythrocytes - parasitology; Granulocytes - immunology; Granulocytes - metabolism; Granulocytes - parasitology; Homeostasis; Host-Parasite Interactions; Humans; Immunity, Innate; Iron - metabolism; Lipocalin-2; Lipocalins - blood; Lipocalins - metabolism; Macrophages - immunology; Macrophages - metabolism; Macrophages - parasitology; Malaria - blood; Malaria - immunology; Malaria - metabolism; Malaria - parasitology; Malaria, Vivax - blood; Malaria, Vivax - immunology; Malaria, Vivax - metabolism; Malaria, Vivax - parasitology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Parasitemia - blood; Parasitemia - immunology; Parasitemia - parasitology; Plasmodium vivax - immunology; Plasmodium yoelii - immunology; Proto-Oncogene Proteins - blood; Proto-Oncogene Proteins - metabolism; Reticulocytosis
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2012.10.010

Plasmodium parasites multiply within host erythrocytes, which contain high levels of iron, and parasite egress from these cells results in iron release and host anemia. Although Plasmodium requires host iron for replication, how host iron homeostasis and responses to these fluxes affect Plasmodium infection are incompletely understood. We determined that Lipocalin 2 (Lcn2), a host protein that sequesters iron, is abundantly secreted during human (P. vivax) and mouse (P. yoeliiNL) blood-stage malaria infections and is essential to control P. yoeliiNL parasitemia, anemia, and host survival. During infection, Lcn2 bolsters both host macrophage function and granulocyte recruitment and limits reticulocytosis, or the expansion of immature erythrocytes, which are the preferred target cell of P. yoeliiNL. Additionally, a chronic iron imbalance due to Lcn2 deficiency results in impaired adaptive immune responses against Plasmodium parasites. Thus, Lcn2 exerts antiparasitic effects by maintaining iron homeostasis and promoting innate and adaptive immune responses. ► Plasmodium vivax induces Lipocalin 2 (Lcn2), which sequesters host iron ► Lcn2 is induced and required for efficient clearance of P. yoeliiNL in mice ► Lcn2 promotes granulocyte/macrophage function and controls reticulocytosis ► Lcn2 -dependent uptake of iron is required for antiparasitic adaptive immune responses