Access to highly specialized growth substrates and production of epithelial immunomodulatory metabolites determine survival of Haemophilus influenzae in human airway epithelial cells.
Access to highly specialized growth substrates and production of epithelial immunomodulatory metabolites determine survival of Haemophilus influenzae in human airway epithelial cells.
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获得高度特化的生长底物和上皮免疫调节代谢物的产生决定了流感嗜血杆菌在人气道上皮细胞中的存活。
DOI：
10.1371/journal.ppat.1010209
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发表时间：
2022-01
期刊：
影响因子：
6.7
通讯作者：
Kappler U
中科院分区：
文献类型：
--
作者：
Hosmer J;Nasreen M;Dhouib R;Essilfie AT;Schirra HJ;Henningham A;Fantino E;Sly P;McEwan AG;Kappler U
流感嗜血杆菌 (Hi) 感染与儿童和成人慢性呼吸道疾病的反复急性发作有关，包括中耳炎、肺炎、慢性阻塞性肺病和哮喘。在这里，我们表明 Hi 感染的持续和复发与 Hi 代谢特性密切相关，其中优选的生长底物与人气道上皮表面的代谢组一致，包括乳酸、戊糖和核苷，但不包括通常用于体外 Hi 生长研究的葡萄糖。酶学和生理学研究表明，利用乳酸（优选的 Hi 碳源）需要 LldD L-乳酸脱氢酶（保守性：98.8% 的菌株），但不需要两种氧化还原平衡 D-乳酸脱氢酶 Dld 和 LdhA。优选底物的利用与 Hi 感染和持久性直接相关。当无法利用 L-乳酸或被迫依赖回收的鸟嘌呤时，Hi 在小鼠肺部感染模型和原代正常人鼻上皮中表现出细胞外和细胞内持久性降低，在竞争性感染中观察到高达 3000 倍的衰减。相反，与野生型菌株相比，D-乳酸脱氢酶突变体仅表现出非常轻微的减少。有趣的是，乙酸盐（主要的 Hi 代谢终产物）在存在活 Hi 而非热灭活 Hi 的情况下对培养的人体组织细胞具有抗炎作用，这表明代谢终产物也会影响 HI 与宿主的相互作用。我们的工作为 Hi 与宿主细胞接触持久性代谢的关键作用提供了重要的新见解，并首次揭示了 Hi 代谢物的免疫调节潜力。获得合适的生长基质并利用它们产生能量的能力对于细菌病原体在宿主体内的生存至关重要，但人们往往对此了解不够。其中包括高度流行的呼吸道病原体流感嗜血杆菌（Hi），它会引起肺炎和中耳炎，并使几种常见的慢性呼吸道感染恶化，例如哮喘、支气管扩张和慢性阻塞性肺病。在这里，我们表明，Hi 代谢特别适合人类呼吸道，并且需要获得首选的生长底物（包括 L-乳酸），才能使 Hi 在原代人上皮细胞中长期持续存在，包括宿主细胞的细胞内定植。代谢在宿主相互作用中的作用不仅限于生长底物，还扩展到 Hi 代谢终产物，我们能够将免疫代谢产物乙酸盐与宿主对 Hi 感染的免疫反应的减少联系起来。这是首次在宿主体内建立代谢与 Hi 持久性之间的特定联系。
Haemophilus influenzae (Hi) infections are associated with recurring acute exacerbations of chronic respiratory diseases in children and adults including otitis media, pneumonia, chronic obstructive pulmonary disease and asthma. Here, we show that persistence and recurrence of Hi infections are closely linked to Hi metabolic properties, where preferred growth substrates are aligned to the metabolome of human airway epithelial surfaces and include lactate, pentoses, and nucleosides, but not glucose that is typically used for studies of Hi growth in vitro. Enzymatic and physiological investigations revealed that utilization of lactate, the preferred Hi carbon source, required the LldD L-lactate dehydrogenase (conservation: 98.8% of strains), but not the two redox-balancing D-lactate dehydrogenases Dld and LdhA. Utilization of preferred substrates was directly linked to Hi infection and persistence. When unable to utilize L-lactate or forced to rely on salvaged guanine, Hi showed reduced extra- and intra-cellular persistence in a murine model of lung infection and in primary normal human nasal epithelia, with up to 3000-fold attenuation observed in competitive infections. In contrast, D-lactate dehydrogenase mutants only showed a very slight reduction compared to the wild-type strain. Interestingly, acetate, the major Hi metabolic end-product, had anti-inflammatory effects on cultured human tissue cells in the presence of live but not heat-killed Hi, suggesting that metabolic endproducts also influence HI-host interactions. Our work provides significant new insights into the critical role of metabolism for Hi persistence in contact with host cells and reveals for the first time the immunomodulatory potential of Hi metabolites. The ability to access suitable growth substrates and use them for energy generation is essential for the survival of bacterial pathogens in their host but is often not well understood. This includes the highly prevalent respiratory pathogen Haemophilus influenzae (Hi), which causes pneumonia and otitis media, and worsens several common chronic respiratory infections such as asthma, bronchiectasis, and chronic obstructive pulmonary disease. Here we have shown that Hi metabolism is specifically adapted to the human respiratory tract, and access to preferred growth substrates, which included L-lactate, is required for Hi long-term persistence in primary human epithelia, including intracellular colonization of the host cells. The role of metabolism for host interactions was not limited to growth substrates but extended to Hi metabolic endproducts where we were able to link the immunometabolite acetate to a reduction of the host immune response to Hi infection. This is the first time that a specific link between metabolism and Hi persistence in the host has been established.
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影响因子：
6.4
作者：
Atack, John M.;Ibranovic, Ines;McEwan, Alastair G.
通讯作者：
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影响因子：
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APICELLA, MA
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