Oligopeptide Transporters of Nonencapsulated Streptococcus pneumoniae Regulate CbpAC and PspA Expression and Reduce Complement-Mediated Clearance.
Oligopeptide Transporters of Nonencapsulated Streptococcus pneumoniae Regulate CbpAC and PspA Expression and Reduce Complement-Mediated Clearance.
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肺炎链球菌在人的鼻咽部定植并引起几种疾病。肺炎球菌疫苗针对多糖胶囊并预防大多数严重疾病，但非胶囊化肺炎链球菌（NESp）的患病率有所增加。以前，人们认为需要一个胶囊来引起侵袭性疾病。从侵袭性疾病患者中分离到表达寡肽转运体AliC和AliD的NESp菌株。AliC和AliD寡肽转运体调节几种基因的表达，包括胆碱结合蛋白AC (CbpAC) （PspA的同源物），它有助于减少C3b的沉积。据推测，通过改变CbpAC表达，AliC和AliD通过减少c -反应蛋白（CRP）结合，为经典补体介导的清除提供保护。我们的研究表明，AliC和AliD调节了NESp中CbpAC的表达，并且在某些血清型被封装菌株中发现的AliD调节了PspA的表达。与野生型相比，NESp ΔaliD和封装突变体中的C3b沉积增加。与ΔaliC ΔaliD突变体相比，表达AliC和AliD的NESp菌株的C1q和CRP沉积显著减少。在小鼠模型中，补体蛋白C1q是NESp清除所必需的，并增加调理吞噬作用。通过调节CbpAC表达，NESp抑制CRP与细菌表面的结合，阻断经典补体激活，导致更大的系统存活和毒力。由于NESp患病率的增加，有必要更好地了解NESp的毒力机制，这有助于通过避免免疫系统的清除在宿主内建立疾病和持久性。
Streptococcus pneumoniae colonizes the human nasopharynx and causes several diseases. Pneumococcal vaccines target the polysaccharide capsule and prevent most serious disease, but there has been an increase in the prevalence of nonencapsulated S. pneumoniae (NESp). Previously, it was thought that a capsule was necessary to cause invasive disease. NESp strains expressing the oligopeptide transporters AliC and AliD have been isolated from patients with invasive disease. The AliC and AliD oligopeptide transporters regulate the expression of several genes, including choline binding protein AC (CbpAC) (a homolog of PspA), which aids in reducing C3b deposition. It is hypothesized that by altering CbpAC expression, AliC and AliD provide protection from classical complement-mediated clearance by reducing C-reactive protein (CRP) binding. Our study demonstrates that AliC and AliD regulate CbpAC expression in NESp and that AliD found in certain serotypes of encapsulated strains regulates PspA expression. C3b deposition was increased in the NESp ΔaliD and encapsulated mutants in comparison to the wild type. NESp strains expressing AliC and AliD have a significant decrease in C1q and CRP deposition in comparison to the ΔaliC ΔaliD mutant. The complement protein C1q is required for NESp clearance in a murine model and increases opsonophagocytosis. By regulating CbpAC expression, NESp inhibits CRP binding to the bacterial surface and blocks classical complement activation, leading to greater systemic survival and virulence. Due to the increase in the prevalence of NESp, it is important to gain a better understanding of NESp virulence mechanisms that aid in establishing disease and persistence within a host by avoiding clearance by the immune system.
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