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首页> 外文期刊>MBio >Identification of Zinc-Dependent Mechanisms Used by Group B Streptococcus To Overcome Calprotectin-Mediated Stress
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Identification of Zinc-Dependent Mechanisms Used by Group B Streptococcus To Overcome Calprotectin-Mediated Stress

机译：B组使用锌依赖机制的鉴定血液依赖性机制<斜体链球菌克服CALPROTECIN介导的应力

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Group B Streptococcus (GBS) asymptomatically colonizes the female reproductive tract but is a common causative agent of meningitis. GBS meningitis is characterized by extensive infiltration of neutrophils carrying high concentrations of calprotectin, a metal chelator. To persist within inflammatory sites and cause invasive disease, GBS must circumvent host starvation attempts. Here, we identified global requirements for GBS survival during calprotectin challenge, including known and putative systems involved in metal ion transport. We characterized the role of zinc import in tolerating calprotectin stress in vitro and in a mouse model of infection. We observed that a global zinc uptake mutant was less virulent than the parental GBS strain and found calprotectin knockout mice to be equally susceptible to infection by wild-type (WT) and mutant strains. These findings suggest that calprotectin production at the site of infection results in a zinc-limited environment and reveals the importance of GBS metal homeostasis to invasive disease. ABSTRACT Nutritional immunity is an elegant host mechanism used to starve invading pathogens of necessary nutrient metals. Calprotectin, a metal-binding protein, is produced abundantly by neutrophils and is found in high concentrations within inflammatory sites during infection. Group B Streptococcus (GBS) colonizes the gastrointestinal and female reproductive tracts and is commonly associated with severe invasive infections in newborns such as pneumonia, sepsis, and meningitis. Although GBS infections induce robust neutrophil recruitment and inflammation, the dynamics of GBS and calprotectin interactions remain unknown. Here, we demonstrate that disease and colonizing isolate strains exhibit susceptibility to metal starvation by calprotectin. We constructed a mariner transposon ( Krmit ) mutant library in GBS and identified 258 genes that contribute to surviving calprotectin stress. Nearly 20% of all underrepresented mutants following treatment with calprotectin are predicted metal transporters, including known zinc systems. As calprotectin binds zinc with picomolar affinity, we investigated the contribution of GBS zinc uptake to overcoming calprotectin-imposed starvation. Quantitative reverse transcriptase PCR (qRT-PCR) revealed a significant upregulation of genes encoding zinc-binding proteins, adcA , adcAII , and lmb , following calprotectin exposure, while growth in calprotectin revealed a significant defect for a global zinc acquisition mutant (Δ adcA Δ adcAII Δ lmb ) compared to growth of the GBS wild-type (WT) strain. Furthermore, mice challenged with the Δ adcA Δ adcAII Δ lmb mutant exhibited decreased mortality and significantly reduced bacterial burden in the brain compared to mice infected with WT GBS; this difference was abrogated in calprotectin knockout mice. Collectively, these data suggest that GBS zinc transport machinery is important for combatting zinc chelation by calprotectin and establishing invasive disease.
机译：B组链球菌（GBS）渐近地殖民雌性生殖道，但是脑膜炎的常见致病因子。 GBS脑膜炎的特征在于携带高浓度CalProtectin的中性粒细胞的大量浸润，金属螯合剂。为了持续存在于炎症性遗址并引起侵袭性疾病，GBS必须规避宿主饥饿的尝试。在这里，我们确定了在CalProtectin挑战期间GBS存活的全球要求，包括参与金属离子运输的已知和推定系统。我们以锌进口在体外和小鼠感染模型中耐受钙保护菌素应激的作用。我们观察到，全球锌摄取突变体比亲本GBS菌株较低，并且发现CalProtectin敲除小鼠同样易受野生型（WT）和突变菌株感染的影响。这些研究结果表明，感染部位的CalProtectin产生导致锌有限的环境，并揭示了GBS金属稳态对侵入性疾病的重要性。摘要营养免疫是一种优雅的宿主机制，用于终止侵入必要的营养金属的病原体。 CalProtectin，一种金属结合蛋白，由中性粒细胞大量产生，并且在感染期间以高浓度的炎性部位内发现。 B组链球菌（GBS）对胃肠和雌性生殖束进行殖民，通常与新生儿，肺炎，败血症和脑膜炎等重症侵袭性感染有关。虽然GBS感染诱导强大的中性粒细胞招生和炎症，但GBS和CALPROTECIN相互作用的动态仍然未知。在此，我们证明疾病和殖民化分离株菌株对CALPRotectin的金属饥饿表现出易感性。我们在GBS中构建了一个水土母牛转座（KRMIT）突变体文库，并确定了258个基因，有助于存活的CalProtectin胁迫。在用CalProtectin治疗后近20％的突变突变体是预测的金属转运蛋白，包括已知的锌系统。由于CalProtectin用Picomolar亲和力结合锌，我们调查了GBS锌摄取对克服CalProtectin施加的饥饿的贡献。定量逆转录酶PCR（QRT-PCR）揭示了在CalProtectin暴露之后编码锌结合蛋白，Adca，Adcaii和LMB的基因的显着上调，而CalProtectin的生长揭示了全局锌获取突变体的显着缺陷（ΔAdcaδ与GBS野生型（WT）菌株的生长相比，Adcaiiδ1MB。此外，与δAdcaδAdcaiiδ1MB突变体攻击的小鼠表现出降低的死亡率，与用WT GBS感染的小鼠相比，大脑中的细菌负担显着降低; CalProtectin敲除小鼠中的这种差异出现了。总的来说，这些数据表明，GBS锌运输机制对于通过CalProtectin和建立侵入性疾病来对抗锌螯合性很重要。

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