Central carbon flux controls growth/damage balance for Streptococcus pyogenes.
Central carbon flux controls growth/damage balance for Streptococcus pyogenes.
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中心碳通量控制化脓性链球菌的生长/损伤平衡。
DOI：
10.1371/journal.ppat.1011481
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发表时间：
2023-06
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
微生物病原体在生长和组织损伤之间取得平衡，以实现最大限度的健康。中枢碳代谢与生长有关，但它如何影响生长/损害平衡在很大程度上尚不清楚。在这里，我们研究了通过致病乳酸菌化脓性链球菌的唯一发酵代谢的碳流量如何影响生长模式和组织损伤。使用软组织感染的小鼠模型，我们系统地检查了单个和成对突变体，这些突变体通过化脓性链球菌用于减少糖酵解中间体丙酮酸的三个主要途径限制碳流，揭示了不同的疾病后果。其典型的乳酸途径(通过乳酸脱氢酶)对毒力的贡献很小。相反，它的两条平行的混酸发酵途径发挥了重要但不重叠的作用。厌氧混酸发酵(通过丙酮酸甲酸裂解酶)是组织生长所必需的，而好氧混酸途径(通过丙酮酸脱氢酶)不是生长所必需的，而是调节组织损伤的水平。巨噬细胞的体外感染表明，丙酮酸脱氢酶需要防止吞噬溶酶体酸化，这改变了免疫抑制细胞因子IL-10的表达。IL-10缺陷小鼠的感染证实了有氧代谢调节IL-10水平的能力在化脓性链球菌调节组织损伤水平的能力中起着关键作用。综上所述，这些结果显示了无氧代谢和有氧代谢在软组织感染中的关键作用不重叠，并为氧和碳流如何协调作用以调节生长/损伤平衡提供了一种机制。可以开发针对碳流的治疗方法来减轻严重化脓性链球菌感染期间的组织损伤。革兰氏阳性杆菌化脓性链球菌引起一系列在组织损伤方面有明显不同的疾病，包括坏死性筋膜炎(食肉性疾病)，它可导致皮肤和下层组织的严重破坏。严重疾病的治疗通常需要手术干预，包括截肢，以移除受感染的组织。化脓性链球菌是如何引起轻微或组织破坏性感染的，目前还不清楚。在这项研究中，我们研究了不同的链球菌能量产生途径如何将宿主来源的碳源转化为细胞能量，从而影响化脓性链球菌所能产生的组织损伤水平。利用皮肤感染的小鼠模型，我们发现混酸发酵的两条平行途径发挥着重要而不重叠的作用。化脓性链球菌在组织中生长需要一种被氧抑制的途径(使用丙酮酸甲酸裂解酶)。第二种需要氧气(使用丙酮酸脱氢酶)，而不是生长所必需的，而是通过支持化脓性链球菌操纵宿主细胞因子的产生来控制免疫反应来调节组织损伤的水平。了解新陈代谢如何影响组织损伤，有助于解释化脓性链球菌疾病的严重程度如何不同，并确定新的治疗目标，以限制严重感染的组织损伤。
Microbial pathogens balance growth against tissue damage to achieve maximum fitness. Central carbon metabolism is connected to growth, but how it influences growth/damage balance is largely unknown. Here we examined how carbon flux through the exclusively fermentative metabolism of the pathogenic lactic acid bacterium Streptococcus pyogenes impacts patterns of growth and tissue damage. Using a murine model of soft tissue infection, we systematically examined single and pair-wise mutants that constrained carbon flux through the three major pathways that S. pyogenes employs for reduction of the glycolytic intermediate pyruvate, revealing distinct disease outcomes. Its canonical lactic acid pathway (via lactate dehydrogenase) made a minimal contribution to virulence. In contrast, its two parallel pathways for mixed-acid fermentation played important, but non-overlapping roles. Anaerobic mixed acid fermentation (via pyruvate formate lyase) was required for growth in tissue, while aerobic mixed-acid pathway (via pyruvate dehydrogenase) was not required for growth, but instead regulated levels of tissue damage. Infection of macrophages in vitro revealed that pyruvate dehydrogenase was required to prevent phagolysosomal acidification, which altered expression of the immunosuppressive cytokine IL-10. Infection of IL-10 deficient mice confirmed that the ability of aerobic metabolism to regulate levels of IL-10 plays a key role in the ability of S. pyogenes to modulate levels of tissue damage. Taken together, these results show critical non-overlapping roles for anaerobic and aerobic metabolism in soft tissue infection and provide a mechanism for how oxygen and carbon flux act coordinately to regulate growth/damage balance. Therapies targeting carbon flux could be developed to mitigate tissue damage during severe S. pyogenes infection. The Gram-positive bacterium Streptococcus pyogenes causes a wide range of diseases that differ significantly in tissue damage, including necrotizing fasciitis (flesh-eating disease) which can cause severe destruction of skin and underlying tissue. Treatment of severe disease often requires surgical intervention, including amputation, to remove infected tissue. How S. pyogenes can cause either mild or tissue-destructive infections is not well-understood. In this study, we examined how different streptococcal energy-producing pathways that convert host-derived carbon sources into cellular energy influence the levels of tissue damage that S. pyogenes can produce. Using a mouse model of cutaneous infection, we found that two parallel pathways for mixed-acid fermentation play important and non-overlapping roles. One pathway that is inhibited by oxygen (using the enzyme pyruvate formate lyase) is required for S. pyogenes to grow in tissue. The second requires oxygen (using the enzyme pyruvate dehydrogenase), is not required for growth, but instead regulates levels of tissue damage by supporting the ability of S. pyogenes to manipulate host cytokine production to control the immune response. Understanding how metabolism influences tissue damage helps to explain how S. pyogenes diseases can differ in severity and identifies new targets for treatments to limit tissue damage in severe infections.
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