Impact of Galectin-Receptor Interactions on Liver Pathology During the Erythrocytic Stage of Plasmodium berghei Malaria.

Yifan Wu,Fangli Lu,Siyu Xiao,Jian He,Shiguang Huang

doi:10.3389/fimmu.2021.758052

Yifan Wu, Fangli Lu + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2021.758052

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Abstract

Hepatopathy is frequently observed in patients with severe malaria but its pathogenesis remains unclear. Galectins are evolutionarily conserved glycan-binding proteins with pleiotropic roles in innate and adaptive immune responses, and exhibit pivotal roles during Plasmodium spp. infection. Here, we analyzed the impact of blockage of galectin-receptor interactions by treatment with alpha (α)-lactose on liver immunopathology during the erythrocytic stage of malaria in mice infected with Plasmodium berghei ANKA (PbANKA). Our results found that compared with PbANKA-infected mice (malarial mice), blockage of galectin-receptor interactions led to decreased host survival rate and increased peripheral blood parasitemia; exacerbated liver pathology, increased numbers of CD68+ macrophages and apoptotic cells, and increased parasite burden in the livers on days 5 and 7 post infection (p.i.) as well as increased mRNA expression levels of galectin-9 (Gal-9) and its receptor, the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3), interferon (IFN)α, IFNγ, and the triggering receptor expressed on myeloid cells (TREM)-1 in the livers or spleens of PbANKA-infected mice on day 7 p.i. Observed by transmission electron microscopy, the peritoneal macrophages isolated from malarial mice with α-lactose treatment had more pseudopodia than those from malarial mice. Measured by using quantitative real-time reverse transcription-polymerase chain reaction assay, the mRNA expression levels of Gal-9, IFNα, IFNβ, IFNγ, and TREM-1 were increased in the peritoneal macrophages isolated from malarial mice with α-lactose treatment in comparison of those from malarial mice. Furthermore, significant positive correlations existed between the mRNA levels of Gal-9 and Tim-3/IFNγ/TREM-1 in both the livers and the peritoneal macrophages, and between Gal-9 and Tim-3/TREM-1 in the spleens of malarial mice; significant positive correlations existed between the mRNA levels of Gal-9 and IFNγ in the livers and between Gal-9 and IFNα in the peritoneal macrophages from malarial mice treated with α-lactose. Our data suggest a potential role of galectin-receptor interactions in limiting liver inflammatory response and parasite proliferation by down-regulating the expressions of IFNα, IFNγ, and TREM-1 during PbANKA infection.

Highlights

Plasmodium falciparum can cause severe disease manifested by cerebral malaria, difficulty breathing, difficulty urinating, hypoglycemia, lactic acidosis, severe anemia, jaundice, and liver involvement [1]
To test whether galectin-receptor interactions have an impact on functional activation of macrophages by Plasmodium berghei ANKA (PbANKA) infection, we examined the mRNA expression levels of Gal-9, Tim-3, IFNa, IFNb, IFNg, triggering receptor expressed on myeloid cells (TREM)-1, and TREM-2 in the peritoneal macrophages ex vivo isolated from PbANKA-infected mice with or without a-lactose treatment on day 7 p.i
Our data showed that mice infected with PbANKA plus a-lactose treatment had lower survival rate, increased peripheral blood parasitemia and parasite burdens in the liver, more severe hepatocyte damage, and increased apoptotic cells in the liver compared with those of malarial mice

Summary

Introduction

Plasmodium falciparum can cause severe disease manifested by cerebral malaria, difficulty breathing, difficulty urinating, hypoglycemia, lactic acidosis, severe anemia, jaundice, and liver involvement [1]. In malaria patients with jaundice, histopathological changes of damaged hepatocytes, congestion of liver cells, hemozoin deposition, inflammatory infiltrates, and cholestasis as well as hyperplastic Kupffer cells have been demonstrated [2,3,4]. Kupffer cell activation is an effective mechanism for regulating the host response to malaria liver-stage infection [5]. During Plasmodium liver-stage infection, Kupffer cells from Plasmodium-infected livers produce high levels of hepatocyte growth factor, which plays multiple roles during primary malaria hepatocyte infection and triggers apoptosis of infected hepatocytes [5]. A study has demonstrated that Trem-2deficient mice infected with P. berghei ANKA (PbANKA) sporozoites are more susceptible to liver-stage infection than their wild-type counterparts, and TREM-2 is involved in host responses against the malaria parasite [12]

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