Huffines Joshua T, Kiedrowski Megan R
bioRxiv. 2024 Sep 25:2024.09.24.614779. doi: 10.1101/2024.09.24.614779.
In chronic rhinosinusitis (CRS) disease, microbial dysbiosis is considered a key contributor to inflammation and pathogenicity, with increased prevalence of upper respiratory tract (URT) pathogens concomitant with decreased abundance of commensal species. is a common URT pathobiont associated with higher carriage rates in CRS. secreted toxins are implicated in CRS pathogenesis, and toxins and antibodies to secreted factors have been observed in tissue from CRS subjects. CRS disease severity is positively correlated with immune reactivity to proteins. Prior studies have examined polymicrobial interactions between and URT commensals, however, no studies to date have described possible methods employed by to outcompete commensals leading to a dominant microbiome as seen in CRS. This study addresses this gap in knowledge by characterizing how a CRS-associated secreted toxin from can inhibit aggregation in commensal URT species. Using a model URT commensal, , we identified a CRS-associated secreted protein from , δ-toxin (Hld), that can inhibit aggregation at biologically relevant concentrations. Furthermore, we observed recombinant δ-toxin reduces adherence and aggregation on human nasal epithelial cells in an air-liquid interface cell culture model. These results define a novel mechanism by which can disrupt URT commensal lifestyles of microbial competitors, contributing to the establishment of microbial dysbiosis.
Microbial dysbiosis in the upper respiratory tract (URT) is associated with disease pathogenicity in chronic rhinosinusitis (CRS). There are significant links between and worse CRS outcomes, but no studies to date have demonstrated if outcompetes other URT microbes through direct interactions. Here, we report that δ-toxin, a secreted protein found in CRS patient tissue, can inhibit the ability of commensal bacteria to aggregate, adhere to, and grow in association with human nasal epithelial cells. These results suggest a potential mechanism for to establish dominance in the URT microbiome through direct antagonism of commensals with a disease-associated toxin.
在慢性鼻-鼻窦炎（CRS）疾病中，微生物群落失调被认为是炎症和致病性的关键因素，上呼吸道（URT）病原体的患病率增加，同时共生菌的丰度降低。是一种常见的URT致病共生菌，在CRS中携带率较高。其分泌的毒素与CRS发病机制有关，在CRS患者组织中已观察到毒素及针对分泌因子的抗体。CRS疾病严重程度与对蛋白的免疫反应呈正相关。先前的研究已考察了与URT共生菌之间的多种微生物相互作用，然而，迄今为止尚无研究描述为在CRS中形成优势微生物群落而用于胜过共生菌的可能方法。本研究通过表征来自的一种与CRS相关的分泌毒素如何抑制共生URT菌种的聚集来填补这一知识空白。使用一种URT共生模型菌，我们鉴定出一种来自的与CRS相关的分泌蛋白，δ-毒素（Hld），其在生物学相关浓度下可抑制聚集。此外，我们观察到重组δ-毒素在气液界面细胞培养模型中可降低在人鼻上皮细胞上的黏附及聚集。这些结果确定了一种新机制，通过该机制可破坏微生物竞争者的URT共生生活方式，从而导致微生物群落失调的形成。
上呼吸道（URT）中的微生物群落失调与慢性鼻-鼻窦炎（CRS）的疾病致病性相关。与更差的CRS结局之间存在显著关联，但迄今为止尚无研究证明是否通过直接相互作用胜过其他URT微生物。在此，我们报告在CRS患者组织中发现的一种分泌蛋白，δ-毒素，可抑制共生细菌聚集、黏附于以及与人鼻上皮细胞共同生长的能力。这些结果提示了通过与疾病相关毒素直接拮抗共生菌在URT微生物群落中建立优势的潜在机制。
