AUTHOR=Harriett Amanda J. , Esher Righi Shannon , Lilly Elizabeth A. , Fidel Paul , Noverr Mairi C. 

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.898030

DOI=10.3389/fcimb.2022.898030

ISSN=2235-2988

ABSTRACT=<p>Fungal-bacterial intra-abdominal infections (IAI) can lead to sepsis with significant morbidity and mortality. We have established a murine model of <italic>Candida albicans</italic> (<italic>Ca</italic>) and <italic>Staphylococcus aureus</italic> (<italic>Sa</italic>) IAI that results in acute lethal sepsis. Prior intraperitoneal or intravenous inoculation with low virulence <italic>Candida dubliniensis (Cd)</italic> confers high level protection against lethal <italic>Ca/Sa</italic> IAI and sepsis. Protection <italic>via Cd</italic> immunization is associated with decreased pro-inflammatory cytokines and mediated by Gr-1<sup>+</sup> 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 <italic>Cd</italic>-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 <italic>Ca/Sa, Ca</italic>/<italic>Escherichia coli</italic> (<italic>Ca/Ec</italic>), LPS or untreated zymosan. Results showed that live <italic>Cd</italic> immunization was protective against sepsis induced by <italic>Ca/Ec</italic> 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 <italic>Ca/Sa</italic> or <italic>Ca/Ec</italic>, 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 <italic>Cd</italic> 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 <italic>Cd</italic> for protection against lethal polymicrobial sepsis.</p>