Abstract

Malaria-associated acute lung injury (ALI) is a frequent complication of severe malaria that is often caused by “excessive” immune responses. To better understand the mechanism of ALI in malaria infection, here we investigated the roles of galectin (Gal)-1, 3, 8, 9 and the receptors of Gal-9 (Tim-3, CD44, CD137, and PDI) in malaria-induced ALI. We injected alpha (α)-lactose into mice-infected with Plasmodium berghei ANKA (PbANKA) to block galectins and found significantly elevated total proteins in bronchoalveolar lavage fluid, higher parasitemia and tissue parasite burden, and increased numbers of CD68+ alveolar macrophages as well as apoptotic cells in the lungs after blockage. Additionally, mRNA levels of Gal-9, Tim-3, CD44, CD137, and PDI were significantly increased in the lungs at day 5 after infection, and the levels of CD137, IFN-α, IFN-β, IFN-γ, IL-4, and IL-10 in the lungs were also increased after α-lactose treatment. Similarly, the levels of Gal-9, Tim-3, IFN-α, IFN-β, IFN-γ, and IL-10 were all significantly increased in murine peritoneal macrophages co-cultured with PbANKA-infected red blood cells in vitro; but only IFN-α and IFN-β were significantly increased after α-lactose treatment. Our data indicate that Gal-9 interaction with its multiple receptors play an important role in murine malaria-associated ALI.

Highlights

  • Malaria is still a major global health problem

  • Higher level of total protein in the bronchoalveolar lavage fluid (BALF) was observed in malarial mice treated with α-lactose on day 7 p.i. (P < 0.05) in comparison of that on day 5 p.i., indicating a disruption of the alveolar-capillary membrane barrier as a result of P. berghei ANKA (PbANKA) infection

  • The parasite burdens in lung tissues were measured using quantitative real-time PCR (qRT-PCR); there was significantly increased parasite burden on day 5 p.i. (P < 0.05) in malarial mice treated with α-lactose in comparison of malarial mice; no significant difference of parasite burden was detected on day 7 p.i. (P > 0.05) between the two groups (Fig. 1d)

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Summary

Introduction

Malaria is still a major global health problem. Severe malaria, associated with high morbidity and mortality, is characterized by cerebral malaria, severe anemia, acidosis and hypoglycemia, pulmonary edema, and acute kidney injury[1]. The high mortality of ALI during severe malaria highlights the importance of this syndrome during malarial infection, the immunopathological mechanisms that lead to ALI/ARDS in malarial infection remain largely unknown. It is not clear what role of galectins play in malaria associated-ALI and whether manipulating galectin binding to their receptors can influence the magnitude and effectiveness of malarial immunity. We demonstrated that interactions of Gal-9 and its receptors (Tim-3, CD44, CD137, and PDI) play a role in the development of ALI in PbANKA-infected mouse model, providing an important mechanism for severe malaria

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