Host-derived O-glycans inhibit toxigenic conversion by a virulence-encoding phage in Vibrio cholerae.
Host-derived O-glycans inhibit toxigenic conversion by a virulence-encoding phage in Vibrio cholerae.
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DOI：
10.15252/embj.2022111562
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发表时间：
2023-02-01
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霍乱弧菌的流行性和地方性菌株源自 CTXφ 噬菌体的产毒转化，这是 CTXφ 感染霍乱弧菌非产毒菌株的过程。 CTXφ编码霍乱毒素，这是一种导致与霍乱感染相关的水样腹泻的肠毒素。尽管 CTXφ 在感染过程中发挥着关键作用，但影响 CTXφ 驱动的产毒转化或 CTXφ 编码的霍乱毒素表达的信号仍然知之甚少，特别是在肠粘膜环境中。在这里，我们确定粘蛋白聚合物是霍乱弧菌中 CTXφ 驱动的致病性的有效调节剂。我们的结果表明，粘蛋白相关的 O 聚糖通过干扰 TcpP/ToxR/ToxT 毒力途径，阻断 CTXφ 的产毒转化，并抑制 CTXφ 相关毒力因子的表达，包括毒素共同调节的菌毛和霍乱毒素。通过从头合成单个粘蛋白聚糖结构，我们将 Core 2 基序确定为控制这种毒力减弱的关键结构。总的来说，我们的结果强调了粘蛋白及其相关的 O-聚糖结构影响 CTXφ 介导的霍乱弧菌进化和致病性的新机制，强调了粘液中潜在的调节能力。 粘蛋白以依赖于其核心 2 聚糖结构的方式抑制霍乱弧菌毒力。
Pandemic and endemic strains of Vibrio cholerae arise from toxigenic conversion by the CTXφ bacteriophage, a process by which CTXφ infects nontoxigenic strains of V. cholerae. CTXφ encodes the cholera toxin, an enterotoxin responsible for the watery diarrhea associated with cholera infections. Despite the critical role of CTXφ during infections, signals that affect CTXφ‐driven toxigenic conversion or expression of the CTXφ‐encoded cholera toxin remain poorly characterized, particularly in the context of the gut mucosa. Here, we identify mucin polymers as potent regulators of CTXφ‐driven pathogenicity in V. cholerae. Our results indicate that mucin‐associated O‐glycans block toxigenic conversion by CTXφ and suppress the expression of CTXφ‐related virulence factors, including the toxin co‐regulated pilus and cholera toxin, by interfering with the TcpP/ToxR/ToxT virulence pathway. By synthesizing individual mucin glycan structures de novo, we identify the Core 2 motif as the critical structure governing this virulence attenuation. Overall, our results highlight a novel mechanism by which mucins and their associated O‐glycan structures affect CTXφ‐mediated evolution and pathogenicity of V. cholerae, underscoring the potential regulatory power housed within mucus. Mucins suppress V. cholerae virulence in a manner dependent on their core 2 glycan structure.