Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States.
Center of Excellence in Oral and Craniofacial Biology, Louisiana State University Health Sciences Center School of Dentistry, New Orleans, LA, United States.
Front Cell Infect Microbiol. 2022 Jun 13;12:898030. doi: 10.3389/fcimb.2022.898030. eCollection 2022.
Fungal-bacterial intra-abdominal infections (IAI) can lead to sepsis with significant morbidity and mortality. We have established a murine model of () and () IAI that results in acute lethal sepsis. Prior intraperitoneal or intravenous inoculation with low virulence confers high level protection against lethal IAI and sepsis. Protection 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 -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 / (), LPS or untreated zymosan. Results showed that live immunization was protective against sepsis induced by 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 or , 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 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 for protection against lethal polymicrobial sepsis.
真菌-细菌腹腔内感染（IAI）可导致脓毒症，发病率和死亡率高。我们已经建立了一种（）和（）IAI 的小鼠模型，导致急性致命性脓毒症。先前腹腔内或静脉内接种低毒力（）可提供针对致命性 IAI 和脓毒症的高水平保护。保护免疫与减少促炎细胞因子有关，并由 Gr-1 假定的髓源抑制细胞（MDSC）介导，代表一种新形式的训练性先天免疫（TII）。这些研究的目的是确定 - 介导的 TII 对广泛来源的脓毒症的程度，并探索真菌细胞壁成分作为诱导 TII 的非生物免疫原的潜力，包括 TLR2 活性耗尽的酵母聚糖（d-zymosan）或纯化的β-葡聚糖制剂。免疫接种小鼠在免疫接种后 14 天用一系列致命的活或非生物性脓毒症诱导物（包括/（）、LPS 或未经处理的酵母聚糖）进行挑战。结果表明，活免疫接种可预防（）和酵母聚糖引起的脓毒症，但不能预防 LPS。与对 Ca/Sa 的保护作用相似，存活依赖于 Gr-1+细胞，巨噬细胞没有作用。在真菌细胞壁化合物作为免疫原中，用 d-zymosan 和碱处理形式的β-葡聚糖免疫接种也可显著预防（）或（）引起的脓毒症，但不能预防 LPS 脓毒症。同样，保护作用强烈依赖于 Gr-1+细胞，但有一个例外，即在用碱处理的β-葡聚糖诱导的保护作用中，巨噬细胞起额外作用。总体而言，这些结果表明，用（）以及非生物真菌细胞成分免疫接种能够针对广泛微生物来源的脓毒症进行 Gr-1+细胞介导的训练性先天免疫保护。此外，非生物β-葡聚糖代表了针对致命性多微生物脓毒症的活（）的潜在替代品。
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