Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC, Australia.
Research Centre for Extracellular Vesicles, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC, Australia.
Front Immunol. 2022 Sep 20;13:970725. doi: 10.3389/fimmu.2022.970725. eCollection 2022.
The release of bacterial membrane vesicles (BMVs) has become recognized as a key mechanism used by both pathogenic and commensal bacteria to activate innate immune responses in the host and mediate immunity. Outer membrane vesicles (OMVs) produced by Gram-negative bacteria can harbor various immunogenic cargo that includes proteins, nucleic acids and peptidoglycan, and the composition of OMVs strongly influences their ability to activate host innate immune receptors. Although various Gram-negative pathogens can produce OMVs that are enriched in immunogenic cargo compared to their parent bacteria, the ability of OMVs produced by commensal organisms to be enriched with immunostimulatory contents is only recently becoming known. In this study, we investigated the cargo associated with OMVs produced by the intestinal commensal and determined their ability to activate host innate immune receptors. Analysis of OMVs revealed that they packaged various biological cargo including proteins, DNA, RNA, lipopolysaccharides (LPS) and peptidoglycan, and that this cargo could be enriched in OMVs compared to their parent bacteria. We visualized the entry of OMVs into intestinal epithelial cells, in addition to the ability of OMVs to transport bacterial RNA and peptidoglycan cargo into Caco-2 epithelial cells. Using HEK-Blue reporter cell lines, we identified that OMVs could activate host Toll-like receptors (TLR)-2, TLR4, TLR7 and nucleotide-binding oligomerization domain-containing protein 1 (NOD1), whereas bacteria could only induce the activation of TLR2. Overall, our data demonstrates that OMVs activate a broader range of host innate immune receptors compared to their parent bacteria due to their enrichment of biological cargo and their ability to transport this cargo directly into host epithelial cells. These findings indicate that the secretion of OMVs by may facilitate immune crosstalk with host epithelial cells at the gastrointestinal surface and suggests that OMVs produced by commensal bacteria may preferentially activate host innate immune receptors at the mucosal gastrointestinal tract.
细菌膜泡（BMVs）的释放已被认为是病原和共生细菌激活宿主固有免疫反应和介导免疫的关键机制。革兰氏阴性菌产生的外膜泡（OMVs）可以含有各种免疫原性货物，包括蛋白质、核酸和肽聚糖，OMVs 的组成强烈影响其激活宿主固有免疫受体的能力。尽管各种革兰氏阴性病原体可以产生比其亲本细菌更富含免疫原性货物的 OMVs，但共生体产生的 OMVs 富含免疫刺激内容的能力直到最近才被知晓。在这项研究中，我们研究了肠道共生菌产生的 OMVs 相关的货物，并确定了它们激活宿主固有免疫受体的能力。对 OMVs 的分析表明，它们包装了各种生物货物，包括蛋白质、DNA、RNA、脂多糖（LPS）和肽聚糖，并且与亲本细菌相比，这些货物可以在 OMVs 中富集。我们观察到 OMVs 进入肠道上皮细胞，以及 OMVs 将细菌 RNA 和肽聚糖货物运送到 Caco-2 上皮细胞的能力。使用 HEK-Blue 报告细胞系，我们确定 OMVs 可以激活宿主 Toll 样受体（TLR）-2、TLR4、TLR7 和核苷酸结合寡聚化结构域蛋白 1（NOD1），而细菌只能诱导 TLR2 的激活。总体而言，我们的数据表明，与亲本细菌相比，由于 OMVs 富含生物货物及其将货物直接运送到宿主上皮细胞的能力，因此 OMVs 可以激活更广泛的宿主固有免疫受体。这些发现表明， 产生的 OMVs 可能促进胃肠道表面宿主上皮细胞与免疫的串扰，并表明共生菌产生的 OMVs 可能优先激活粘膜胃肠道中的宿主固有免疫受体。
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