Cryptococcus neoformans GXM Mimotopes: Bioactivity and Modulation of Human Inflammatory Response and Oxidative Burst...

Beyond their diagnostic potential, mimotopes of the Cryptococcus neoformans glucuronoxylomannan (GXM) capsule may act as potent immunomodulators. This study investigated the biological effects of three GXM-mimetic peptides: linear peptide (PL), cyclic (PC), and double-cyclic peptide (PD) on the activation of human peripheral blood mononuclear cells and granulocytes. Our results reveal a distinct structure-function relationship in immune signaling. The PD variant significantly enhanced the oxidative burst in granulocytes stimulated by phorbol ester, whereas the PL variant inhibited reactive oxygen species (ROS) production under zymosan-opsonized stimulus. Cytokine profiling showed that PL effectively reduced IL-12p40 levels, mimicking the immunosuppressive nature of native GXM. Conversely, PC and PD variants triggered a pro-inflammatory shift, significantly increasing the secretion of IL-1β and the chemokine CXCL8. Metabolic activity assays confirmed that all mimotopes lacked intrinsic cytotoxicity, maintaining PBMC viability above 98%. These findings demonstrate that GXM-mimetic peptides can either replicate the fungus's immune evasion mechanisms or actively stimulate host defense pathways depending on their conformational state. By transforming fungal evasion motifs into "danger signals," structural stabilization through cyclization provides a molecular switch to bypass the immunological paralysis typically induced by GXM. Such bioactivity positions these peptides as chemically defined candidates for future developing of novel antifungal vaccines and next-generation immunotherapeutic strategies against cryptococcosis.