Preferential use of central metabolism in vivo reveals a nutritional basis for polymicrobial infection.
Preferential use of central metabolism in vivo reveals a nutritional basis for polymicrobial infection.
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DOI：
10.1371/journal.ppat.1004601
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发表时间：
2015-01
期刊：
影响因子：
6.7
通讯作者：
Mobley HL
中科院分区：
文献类型：
--
作者：
Alteri CJ;Himpsl SD;Mobley HL
人类泌尿生殖道是多种微生物感染的常见解剖学生态位，也是菌血症和脓毒症发生的主要部位。大多数不复杂的社区获得性尿路感染（UTI）是由大肠杆菌引起的，而另一种细菌奇异变形杆菌（Proteus mirabilis）通常与复杂的UTI有关。在这里，我们报告，尿路致病性E。大肠杆菌和奇异变形杆菌尽管定植并占据相同的宿主环境，但对体内特定的中枢通路有不同的要求。利用特定的中枢代谢酶的突变体，我们确定缺乏pgi、tpiA、pfkA或pykA的糖酵解突变体在体内对奇异变形杆菌都有适合度缺陷，但不影响E. UTI期间的大肠杆菌。类似地，氧化戊糖磷酸途径仅对奇异变形杆菌在体内是必需的。相反，只有E.大肠杆菌在体内的适应性。E.在实验性UTI期间，还观察到在sdhB、fumC和frdA中的TCA循环突变体。这些病原体在体内的不同要求表明E。大肠杆菌和奇异变形杆菌在宿主泌尿道营养生态位内不是直接竞争者。为了支持这一点，我们发现，与E。大肠杆菌和奇异变形杆菌野生型菌株增强了UTI期间两种病原体的细菌定植和持久性。我们的研究结果表明，中央碳代谢的互补利用促进多微生物疾病，并表明体内微生物活性改变了宿主尿路营养生态位。人类泌尿道是多种微生物感染以及菌血症和脓毒症发展的主要来源。治疗这些潜在危险的感染最近变得更具挑战性，因为出现了对许多最常用的处方抗生素具有耐药性的尿路致病性菌株。大多数尿路感染（UTI）是由大肠杆菌引起的，而另一种细菌，奇异变形杆菌，更有可能引起导管相关性UTI。在这里，我们报告，尿路致病性E。大肠杆菌和奇异变形杆菌尽管生长在相同的宿主环境中，但营养需求不同。结果表明，E.大肠杆菌和奇异变形杆菌在UTI期间不直接竞争营养物。事实上，我们发现，这两种病原体的持久性增强时，他们共同定殖的主机。这项工作代表了理解导致UTI的两种主要病原体的基本营养需求的重要一步，并显示了混合感染如何改变这些需求。了解细菌在感染过程中如何生长是最终发现对抗日益耐药的细菌感染的新方法的基础。
The human genitourinary tract is a common anatomical niche for polymicrobial infection and a leading site for the development of bacteremia and sepsis. Most uncomplicated, community-acquired urinary tract infections (UTI) are caused by Escherichia coli, while another bacterium, Proteus mirabilis, is more often associated with complicated UTI. Here, we report that uropathogenic E. coli and P. mirabilis have divergent requirements for specific central pathways in vivo despite colonizing and occupying the same host environment. Using mutants of specific central metabolism enzymes, we determined glycolysis mutants lacking pgi, tpiA, pfkA, or pykA all have fitness defects in vivo for P. mirabilis but do not affect colonization of E. coli during UTI. Similarly, the oxidative pentose phosphate pathway is required only for P. mirabilis in vivo. In contrast, gluconeogenesis is required only for E. coli fitness in vivo. The remarkable difference in central pathway utilization between E. coli and P. mirabilis during experimental UTI was also observed for TCA cycle mutants in sdhB, fumC, and frdA. The distinct in vivo requirements between these pathogens suggest E. coli and P. mirabilis are not direct competitors within host urinary tract nutritional niche. In support of this, we found that co-infection with E. coli and P. mirabilis wild-type strains enhanced bacterial colonization and persistence of both pathogens during UTI. Our results reveal that complementary utilization of central carbon metabolism facilitates polymicrobial disease and suggests microbial activity in vivo alters the host urinary tract nutritional niche. The human urinary tract is a leading source for polymicrobial infections and for the development of bacteremia and sepsis. Treating these potentially dangerous infections have recently become more challenging due to the appearance of uropathogenic strains that are resistant to the many of the most commonly prescribed antibiotics. The majority of urinary tract infections (UTI) are caused by Escherichia coli, while another bacterium, Proteus mirabilis, is more likely to cause catheter-associated UTI. Here, we report that uropathogenic E. coli and P. mirabilis have divergent nutritional requirements despite growing in the same host environment. This result indicates that E. coli and P. mirabilis do not directly compete for nutrients during UTI. Indeed, we found that persistence of both pathogens is enhanced when they co-colonize the host. This work represents an important step toward understanding the basic nutritional requirements for two major pathogens that cause UTI and shows how mixed infections can change these requirements. Understanding how bacteria grow during infections is fundamental to ultimately uncover new ways to combat increasingly drug-resistant bacterial infections.
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