BdlA, DipA and induced dispersion contribute to acute virulence and chronic persistence of Pseudomonas aeruginosa.
BdlA, DipA and induced dispersion contribute to acute virulence and chronic persistence of Pseudomonas aeruginosa.
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DOI：
10.1371/journal.ppat.1004168
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发表时间：
2014-06
期刊：
影响因子：
6.7
通讯作者：
Sauer K
中科院分区：
文献类型：
--
作者：
Li Y;Petrova OE;Su S;Lau GW;Panmanee W;Na R;Hassett DJ;Davies DG;Sauer K
人类病原体铜绿假单胞菌能够引起急性和慢性感染。毒力的差异可归因于生长方式：浮游生长的细菌引起急性感染，而在被称为生物膜的基质封闭聚集体中生长的细菌与慢性、持续性感染有关。虽然浮游和生物膜的生长模式对毒力的贡献现在被广泛接受，但对分散在毒力中的作用知之甚少，这是生物膜细菌切换回浮游生长模式的主动过程。在这里，我们证明了铜绿假单胞菌分散细胞显示出不同于浮游细胞和生物膜细胞的毒力表型。在浮游细胞的上清液中检测到能够分解聚合物基质成分的细胞毒性酶和降解酶的最高活性，分散细胞上清液的酶活性与生物膜上清液相似。不分散ΔbdlA生物膜的上清液的特点是缺乏许多降解活性。与浮游细胞相比，生物膜细胞中与铜绿假单胞菌毒力有关的基因表达减少了近30倍。基因表达分析表明，分散的细胞在从生物膜分散并返回到单细胞生活方式时，与生物膜和浮游细胞不同，其毒力转录物水平比浮游细胞降低了150倍。相比之下，与野生型浮游细胞相比，非分散的ΔbdlA和ΔdipA生物膜中的毒力基因转录水平显著增加。尽管如此，在跨门急性毒力模型中，bdlA和dipA失活，导致无法在体外分散，与致病性和竞争力降低相关。相比之下，bdlA失活使铜绿假单胞菌在小鼠肺部的慢性定植更加持久，总体上表明这种分散可能有助于急性和慢性感染。致病菌，包括人类病原体铜绿假单胞菌，可引起急性和慢性感染。这些感染模式的差异可以用细菌的生长方式来解释。当单个细菌迅速复制，产生高水平的毒力因子并从感染病灶传播时，就会发生急性感染。当细菌附着在组织或植入的医疗设备上并形成称为生物膜的多细胞基质包裹聚集体时，就会发生慢性感染。当细菌从浮游生长转变为生物膜生长时，就会发生急性到慢性感染的转换。然而，细菌离开生物膜恢复浮游生长的过程——分散的作用仍不清楚。在这里，我们证明，虽然留下了生物膜，但分散细胞在基因表达、基质降解酶的释放和致病性方面与浮游细胞不同。我们发现，在植物和小鼠宿主中，一个突变体在营养诱导的分散中受损，同时增强慢性感染，在急性感染中受损。总的来说，这项工作建立了分散细胞具有独特的毒力表型，营养诱导的分散不仅是急性和慢性感染的组成部分，而且是感染控制的潜在机制。
The human pathogen Pseudomonas aeruginosa is capable of causing both acute and chronic infections. Differences in virulence are attributable to the mode of growth: bacteria growing planktonically cause acute infections, while bacteria growing in matrix-enclosed aggregates known as biofilms are associated with chronic, persistent infections. While the contribution of the planktonic and biofilm modes of growth to virulence is now widely accepted, little is known about the role of dispersion in virulence, the active process by which biofilm bacteria switch back to the planktonic mode of growth. Here, we demonstrate that P. aeruginosa dispersed cells display a virulence phenotype distinct from those of planktonic and biofilm cells. While the highest activity of cytotoxic and degradative enzymes capable of breaking down polymeric matrix components was detected in supernatants of planktonic cells, the enzymatic activity of dispersed cell supernatants was similar to that of biofilm supernatants. Supernatants of non-dispersing ΔbdlA biofilms were characterized by a lack of many of the degradative activities. Expression of genes contributing to the virulence of P. aeruginosa was nearly 30-fold reduced in biofilm cells relative to planktonic cells. Gene expression analysis indicated dispersed cells, while dispersing from a biofilm and returning to the single cell lifestyle, to be distinct from both biofilm and planktonic cells, with virulence transcript levels being reduced up to 150-fold compared to planktonic cells. In contrast, virulence gene transcript levels were significantly increased in non-dispersing ΔbdlA and ΔdipA biofilms compared to wild-type planktonic cells. Despite this, bdlA and dipA inactivation, resulting in an inability to disperse in vitro, correlated with reduced pathogenicity and competitiveness in cross-phylum acute virulence models. In contrast, bdlA inactivation rendered P. aeruginosa more persistent upon chronic colonization of the murine lung, overall indicating that dispersion may contribute to both acute and chronic infections. Pathogenic bacteria, including the human pathogen Pseudomonas aeruginosa, can cause acute and chronic infections. The difference in these infection modes can be explained by how bacteria grow. Acute infections occur when individual bacteria rapidly replicate, produce high levels of virulence factors, and disseminate from the nidus of infection. Chronic infections occur when bacteria adhere to tissue or implanted medical devices and form multi-cellular, matrix-encased aggregates known as biofilms. The acute-to-chronic infection switch occurs when bacteria transition from planktonic to biofilm growth. However, the contribution of dispersion, the process by which bacteria leave a biofilm to return to planktonic growth, remains unclear. Here, we demonstrate that, while having left a biofilm, dispersed cells are distinct from planktonic cells with respect to gene expression, release of matrix-degrading enzymes, and pathogenicity. We found that a mutant impaired in nutrient-induced dispersion, while enhancing chronic infections, is impaired in mounting acute infections in both plant and mouse hosts. Overall, this work establishes that dispersed cells have a unique virulence phenotype, with nutrient-induced dispersion not only serving as an integral part of both acute and chronic infections but also as a potential mechanism of infection control.
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