Efficacy of Candida dubliniensis and Fungal β-Glucans in Inducing Trained Innate Immune Protection Against Inducers of Sepsis

Abstract

Fungal-bacterial intra-abdominal infections (IAI) can lead to sepsis with significant morbidity and mortality. We have established a murine model of <i>Candida albicans</i> (<i>Ca</i>) and <i>Staphylococcus aureus</i> (<i>Sa</i>) IAI that results in acute lethal sepsis. Prior intraperitoneal or intravenous inoculation with low virulence <i>Candida dubliniensis (Cd)</i> confers high level protection against lethal <i>Ca/Sa</i> IAI and sepsis. Protection <i>via Cd</i> immunization is associated with decreased pro-inflammatory cytokines and mediated by Gr-1⁺ putative myeloid-derived suppressor cells (MDSCs) representing a novel form of trained innate immunity (TII). The objective of these studies was to determine the extent of <i>Cd</i>-mediated TII against sepsis of broad origin and explore the potential of fungal cell wall components as abiotic immunogen alternatives to induce TII, including zymosan depleted of TLR2 activity (d-zymosan), or purified preparations of β-glucan. Immunized mice were challenged 14 days post-immunization with a lethal array of live or abiotic inducers of sepsis, including <i>Ca/Sa, Ca</i>/<i>Escherichia coli</i> (<i>Ca/Ec</i>), LPS or untreated zymosan. Results showed that live <i>Cd</i> immunization was protective against sepsis induced by <i>Ca/Ec</i> and zymosan, but not LPS. Similar to protection against Ca/Sa, survival was dependent on Gr-1+ cells with no role for macrophages. Among the fungal cell wall compounds as immunogens, immunization with d-zymosan and an alkali-treated form of β-glucan also resulted in significant protection against sepsis induced by <i>Ca/Sa</i> or <i>Ca/Ec</i>, but not LPS sepsis. Again, there was a strong dependence on Gr-1+ cells for protection with one exception, an added role for macrophages in the case of protection induced by alkali-treated β-glucan. Overall, these results demonstrate that immunization with <i>Cd</i> as well as abiotic fungal cell components are capable of Gr-1+ cell-mediated trained innate immune protection against sepsis of broad microbial origin. In addition, abiotic β-glucans represent potential alternatives to live <i>Cd</i> for protection against lethal polymicrobial sepsis.