Endogenous cathelicidin protects against <i>Toxoplasma gondii-</i> associated liver damage

Toxoplasmosis, a disease caused by apicomplexan <i>Toxoplasma gondii (Tg)</i>, 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 <i>Tg</i> infection in an oral infection model. We challenged wild-type (<i>Camp^+/+</i>) and cathelicidin-deficient (<i>Camp^-/-</i>) mice with low-virulent Type II strain of <i>Tg</i> (ME-49) cysts. Our findings demonstrate that <i>Camp^-/-</i> mice exhibited more severe clinical manifestations, higher mortality rates, and more pronounced hepatic damage compared to their <i>Camp^+/+</i> counterparts. Histological liver examinations indicated significant necrotic hepatitis in <i>Camp^-/-</i> 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 <i>Tg</i> cystogenesis were also observed in <i>Camp^-/-</i> mice. Systemically, <i>Camp^-/-</i> 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 <i>Tg</i> challenge, while <i>Camp^-/-</i> 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 <i>Tg</i> infection by downregulating the synthesis of pro-inflammatory cytokines.