Endogenous cathelicidin protects against Toxoplasma gondii- associated liver damage

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Abstract
Toxoplasmosis, a disease caused by apicomplexan Toxoplasma gondii (Tg) , is associated with various neuropsychiatric and behavioral conditions. Toxoplasmosis can cause serious complications for those with weakened immune systems and during pregnancy. Cathelicidins, peptides with antimicrobial and immunomodulatory functions, are critical factors in host defense against microbes, but their role in parasitic infections is less well understood. This study demonstrates the protective function of endogenous cathelicidin against hepatic damage caused by Tg infection in an oral infection model. We challenged wild-type ( Camp +/+ ) and cathelicidin-deficient ( Camp -/- ) mice with low-virulent Type II strain of Tg (ME-49) cysts. Our findings demonstrate that Camp -/- mice exhibited more severe clinical manifestations, higher mortality rates, and more pronounced hepatic damage compared to their Camp +/+ counterparts. Histological liver examinations indicated significant necrotic hepatitis in Camp -/- mice, correlating with increased local concentrations of pro-inflammatory cytokines and proteomic upregulation of poly(ADP-ribose) polymerase 3 and guanylate-binding proteins. Increased cerebral inflammation and Tg cystogenesis were also observed in Camp -/- mice. Systemically, Camp -/- mice presented elevated levels of pro-inflammatory mediators, specifically interferon-gamma (Ifn-γ) and tumor necrosis factor-alpha (Tnf-α). In cultured macrophages, endogenous cathelicidin increased after Tg challenge, while Camp -/- bone marrow-derived macrophages released higher amounts of Tnf-α than their counterparts. We conclude that cathelicidin protects against liver injury and systemic deterioration induced by Tg infection by downregulating the synthesis of pro-inflammatory cytokines.
Funding Information
  • Alberta Provincial Government Agriculture Funding Consortium/Results Driven Agriculture Research (2023F205R)
  • Alberta Provincial Government Agriculture Funding Consortium/Results Driven Agriculture Research (2024F2443R)
  • Government of Canada New Frontiers in Research Fund (NFRFE/00280-2024)
  • Alberta Government Major Innovation Fund (RCP-19-003-MIF)
  • Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery (RGPAS-2024)

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