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 Candida albicans (Ca) and Staphylococcus aureus (Sa) IAI that results in acute lethal sepsis. Prior intraperitoneal or intravenous inoculation with low virulence Candida dubliniensis (Cd) confers high level protection against lethal Ca/Sa IAI and sepsis. Protection via Cd 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 Cd-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 Ca/Sa, Ca/Escherichia coli (Ca/Ec), LPS or untreated zymosan. Results showed that live Cd immunization was protective against sepsis induced by Ca/Ec 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 Ca/Sa or Ca/Ec, 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 Cd 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 Cd for protection against lethal polymicrobial sepsis.

Effect of MMR Vaccination to Mitigate Severe Sequelae Associated With COVID-19: Challenges and Lessons Learned

“…10 The original impetus for this concept came from our recently published studies using an animal model of polymicrobial sepsis. [6][7][8][9] We discovered that systemic immunization with a live attenuated fungal strain (Candida dubliniensis) or abiotic cell wall products could protect mice against lethal sepsis (intravenous C. albicans or intra-abdominal infection with C. albicans and Staphylococcus aureus). [6][7][8][9] In these models of infection, unimmunized animals succumb to sepsis in 24-48 h while immunized animals exhibit very low sepsis scoring and eventually clear the infection with little to no mortality.…”

“…[6][7][8][9] We discovered that systemic immunization with a live attenuated fungal strain (Candida dubliniensis) or abiotic cell wall products could protect mice against lethal sepsis (intravenous C. albicans or intra-abdominal infection with C. albicans and Staphylococcus aureus). [6][7][8][9] In these models of infection, unimmunized animals succumb to sepsis in 24-48 h while immunized animals exhibit very low sepsis scoring and eventually clear the infection with little to no mortality. Accordingly, these studies demonstrated that protection was associated with reduction in systemic proinflammatory cytokines.…”

“…Accordingly, these studies demonstrated that protection was associated with reduction in systemic proinflammatory cytokines. [6][7][8][9] Subsequent mechanistic studies identified Gr-1+ MDSCs as critical for protection and suppression of systemic cytokines [6][7][8][9] . In addition, the ability of the live attenuated fungal strain to induce protection correlated with the infiltration of the fungi into the bone marrow.…”

“…Unlike other forms of TII, we discovered that protection against sepsis is mediated by long-lived Gr-1+ myeloid-derived suppressor cells (MDSCs). [6][7][8][9] In other experimental sepsis models, MDSCs have been shown to inhibit pathological inflammation and prevent mortality (reviewed in 10 ). Therefore, we have proposed the term trained tolerogenic immunity 10 to discriminate this form of TII from the previously identified trained immunity involving enhanced inflammatory responses.…”

Autologous cryo-shocked neutrophils enable targeted therapy of sepsis via broad-spectrum neutralization of pro-inflammatory cytokines and endotoxins

“…Sepsis is defined as a dysregulated host inflammatory response to infection (bacterial, fungal, or viral) ( Goldfarb et al, 2002 ; Harriett et al, 2022 ; Tian et al, 2023 ) that is often life-threatening and is the leading cause of death in the intensive care unit (ICU) ( Angus and van der Poll, 2013 ). One of its hallmarks is an over-activated immune response and systemic inflammatory response syndrome (SIRS), which, in severe cases, can lead to a “cytokine storm” ( Huang et al, 2019 ).…”