Abstract
Toxoplasma gondii is a neurotropic protozoan parasite, which is linked to neurological manifestations in immunocompromised individuals as well as severe neurodevelopmental sequelae in congenital toxoplasmosis. While the complement system is the first line of host defense that plays a significant role in the prevention of parasite dissemination, Toxoplasma artfully evades complement-mediated clearance via recruiting complement regulatory proteins to their surface. On the other hand, the details of Toxoplasma and the complement system interaction in the brain parenchyma remain elusive. In this study, infection-induced changes in the mRNA levels of complement components were analyzed by quantitative PCR using a murine Toxoplasma infection model in vivo and primary glial cells in vitro. In addition to the core components C3 and C1q, anaphylatoxin C3a and C5a receptors (C3aR and C5aR1), as well as alternative complement pathway components properdin (CFP) and factor B (CFB), were significantly upregulated 2 weeks after inoculation. Two months post-infection, CFB, C3, C3aR, and C5aR1 expression remained higher than in controls, while CFP upregulation was transient. Furthermore, Toxoplasma infection induced significant increase in CFP, CFB, C3, and C5aR1 in mixed glial culture, which was abrogated when microglial activation was inhibited by pre-treatment with minocycline. This study sheds new light on the roles for the complement system in the brain parenchyma during Toxoplasma infection, which may lead to the development of novel therapeutic approaches to Toxoplasma infection-induced neurological disorders.
Highlights
Toxoplasma gondii is a highly prevalent neurotropic parasite, infecting over one third of the global population
Toxoplasma infection induced a marked up-regulation of properdin (Cfp) and CFB (Cfb), which was abrogated by anti-Toxoplasma drug treatment
These results suggest that Toxoplasma infection enhances alternative complement pathway activity as well as anaphylatoxin signaling in the brain parenchyma
Summary
Toxoplasma gondii is a highly prevalent neurotropic parasite, infecting over one third of the global population In healthy individuals, it is typically asymptomatic or presents with only mild symptoms such as malaise and fever, which are selfresolving [1]. Vertical transmission of Toxoplasma increases the risk of premature birth and stillbirth [3, 4] It has a significant impact on the fetal brain development, resulting in congenital toxoplasmosis with devastating neurological impairments, including blindness, retinochoroiditis, seizures, and increased lifetime risk for mental illnesses, such as schizophrenia, autism, bipolar disorder, and depression, that may develop later in life [2, 3, 5]. After release into the intestinal epithelium, those parasites transform into fastreplicating tachyzoites, the tissue-damaging life stage of T. gondii. By controlling the proliferation of tissue-damaging tachyzoites via recruitment of immune cells and molecules, cytokines, including interleukin 12 (IL-12) and interferon g (IFN-g), play a central role in the suppression of acute toxoplasmosis [7]
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