Aerobactin Mediates Virulence and Accounts for Increased Siderophore Production under Iron-Limiting Conditions by Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae
Aerobactin Mediates Virulence and Accounts for Increased Siderophore Production under Iron-Limiting Conditions by Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae
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DOI：
10.1128/iai.01667-13
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发表时间：
2014-06-01
影响因子：
3.1
通讯作者：
Gulick, Andrew M.
中科院分区：
文献类型：
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作者：
Russo, Thomas A.;Olson, Ruth;Gulick, Andrew M.
超强毒力(高粘滞性)肺炎克雷伯氏菌(HvKP)菌株是一种新出现的“经典”肺炎克雷伯菌(CKP)变异株，可在健康人中引起器官和危及生命的感染。对HvKP特异性毒力机制的理解是有限的，这些机制使得CKP能够进化。我们小组的观察和之前发表的分子流行病学数据使我们假设hvKP株比CKP株产生更多的铁载体，这一特征增强了hvKP的毒力。对12株HvKP菌株的定量分析表明，与14株CKP菌株相比，12株HvKP菌株的铁载体产量显著增加6至10倍。令人惊讶的是，hvKP菌株hvKP1、A1142和A1365及其等基因好氧肌动蛋白缺陷(Delta IUCA)衍生物的高压液相色谱-质谱分析和表征表明，需氧肌动蛋白是铁载体产量增加的绝大多数原因，这不是由于基因拷贝数造成的。此外，需氧肌动蛋白是条件培养液中促进hvKP1在人腹水中生长/存活的主要因素。值得注意的是，hvKP1 Delta IUCA在人腹水中的体外生长/存活显著低于hvKP1，并且用hvKP1皮下或腹膜内攻击的杂交CD1小鼠的存活率显著低于hvKP1 Delta IUCA攻击的小鼠。最低的皮下接种和腹腔接种分别为3×10(2)和3.2×10(1)CFU，致死率为100%，显示了hvKP1的毒力和在低剂量下引起感染的能力。这些数据有力地支持，与CKP相比，好氧肌动蛋白是HvKP铁载体产量增加的原因(这是一个潜在的定义特征)，是一个重要的毒力因素。
Hypervirulent (hypermucoviscous) Klebsiella pneumoniae (hvKP) strains are an emerging variant of "classical" K. pneumoniae (cKP) that cause organ and life-threatening infection in healthy individuals. An understanding of hvKP-specific virulence mechanisms that enabled evolution from cKP is limited. Observations by our group and previously published molecular epidemiologic data led us to hypothesize that hvKP strains produced more siderophores than cKP strains and that this trait enhanced hvKP virulence. Quantitative analysis of 12 hvKP strains in iron-poor minimal medium or human ascites fluid showed a significant and distinguishing 6- to 10-fold increase in siderophore production compared to that for 14 cKP strains. Surprisingly, highpressure liquid chromatography (HPLC)-mass spectrometry and characterization of the hvKP strains hvKP1, A1142, and A1365 and their isogenic aerobactin-deficient (Delta iucA) derivatives established that aerobactin accounted for the overwhelming majority of increased siderophore production and that this was not due to gene copy number. Further, aerobactin was the primary factor in conditioned medium that enhanced the growth/survival of hvKP1 in human ascites fluid. Importantly the ex vivo growth/survival of hvKP1 Delta iucA was significantly less than that of hvKP1 in human ascites fluid, and the survival of outbred CD1 mice challenged subcutaneously or intraperitoneally with hvKP1 was significantly less than that of mice challenged with hvKP1 Delta iucA. The lowest subcutaneous and intraperitoneal challenge inocula of 3 x 10(2) and 3.2 x 10(1) CFU, respectively, resulted in 100% mortality, demonstrating the virulence of hvKP1 and its ability to cause infection at a low dose. These data strongly support that aerobactin accounts for increased siderophore production in hvKP compared to cKP (a potential defining trait) and is an important virulence factor.