Mycobacterial para-Hydroxybenzoic Acid-Derivatives (pHBADs) and Related Structures Induce Macrophage Innate Memory.,ACS Chemical Biology

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Mycobacterial para-Hydroxybenzoic Acid-Derivatives (pHBADs) and Related Structures Induce Macrophage Innate Memory.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-08-07 , DOI: 10.1021/acschembio.0c00378
Mimmi Lundahl _{1,

2} , Dylan M Lynch ₁ , Danielle Barnes ₁ , Lauren McSweeney ₁ , Aoife Gorman ₂ , Filipa Lebre ₂ , Stephen V Gordon ₃ , Ed C Lavelle ₂ , Eoin M Scanlan ₁

Affiliation

Macrophages are key immune cells for combatting Mycobacterium tuberculosis. However, M. tuberculosis possesses means to evade macrophage bactericidal responses by, for instance, secretion of the immunomodulatory para-hydroxybenzoic acid derivatives (pHBADs). While these molecules have been implicated in inhibiting macrophage responses in an acute context, little is known about their ability to reprogram macrophages via induction of long-term innate memory. Since innate memory has been highlighted as a promising strategy to augment bactericidal immune responses against M. tuberculosis, investigating corresponding immune evasion mechanisms is highly relevant. Our results reveal for the first time that pHBAD I and related molecules (unmethylated pHBAD I and the hexose l-rhamnose) reduce macrophage bactericidal mechanisms in both the short- and the long-term. Moreover, we demonstrate how methyl-p-anisate hinders bactericidal responses soon after exposure yet results in enhanced pro-inflammatory responses in the long-term. This work highlights new roles for these compounds in M. tuberculosis pathogenesis.

中文翻译：

分枝杆菌对羟基苯甲酸衍生物（pHBADs）和相关结构诱导巨噬细胞先天记忆。

巨噬细胞是抵抗结核分枝杆菌的关键免疫细胞。但是，结核分枝杆菌具有逃避巨噬细胞杀菌反应的手段，例如通过分泌免疫调节对羟基苯甲酸衍生物（p HBADs）。尽管这些分子在急性情况下可能与抑制巨噬细胞反应有关，但对它们通过诱导长期先天记忆来重新编程巨噬细胞的能力知之甚少。由于先天记忆已被认为是增强针对结核分枝杆菌的杀菌免疫反应的一种有前途的策略，因此研究相应的免疫逃逸机制非常重要。我们的结果首次揭示出p HBAD I和相关分子（未甲基化的p HBAD I和己糖1-鼠李糖）在短期和长期内均会降低巨噬细胞的杀菌机制。此外，我们证明了对位茴香酸甲酯如何在暴露后立即阻碍杀菌反应，但长期而言却导致增强的促炎反应。这项工作突出了这些化合物在结核分枝杆菌发病机理中的新作用。

更新日期：2020-09-20

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