Resolution of Staphylococcus aureus Biofilm Infection Using Vaccination and Antibiotic Treatment
Resolution of Staphylococcus aureus Biofilm Infection Using Vaccination and Antibiotic Treatment
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DOI：
10.1128/iai.00451-10
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发表时间：
2011-04-01
影响因子：
3.1
通讯作者：
Shirtliff, Mark E.
中科院分区：
文献类型：
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作者：
Brady, Rebecca A.;O'May, Graeme A.;Shirtliff, Mark E.
金黄色葡萄球菌感染，特别是来自耐甲氧西林菌株的感染（即，MRSA），正在达到流行病的程度，没有有效的疫苗。在该病原体的感染过程中毒力因子的大量和瞬时表达使得保护性抗原的发现特别困难。此外，不同的增殖和生物膜生长模式及其伴随的蛋白质组学变化也证明了疫苗开发的重大障碍。在这项研究中，评估了多组分疫苗清除葡萄球菌生物膜感染的能力。选择抗原（氨基葡萄糖苷酶、ABC转运蛋白脂蛋白、保守的假设蛋白和保守的脂蛋白），因为在先前的研究中发现它们在体外和体内的生物膜中具有上调和持续的表达。针对这些抗原的抗体首先用于显微镜研究，以定位它们在体外生物膜中的表达。四种抗原中的每一种在生物膜中的复杂生物膜群落内的各个位置显示出异质性产生。基于这些研究，四种抗原作为四价疫苗同时递送，以补偿这种不同的生产。此外，由于疫苗抗原可能是生物膜特异性的，因此还施用抗生素治疗以清除剩余的未附着的增殖细胞。结果表明，当在兔慢性骨髓炎生物膜模型中接种疫苗与万古霉素治疗相结合时，与用万古霉素治疗或不治疗的感染动物相比，感染的临床和放射学体征分别显著减少67%和82%。相比之下，与未接种疫苗或万古霉素治疗的动物组相比，单独接种疫苗导致感染的临床（减少34%）和放射学体征（减少9%）适度且不显著减少。最后，MRSA生物膜感染在87.5%的接种疫苗和抗生素治疗的动物中被显著清除，而与对照组相比，单独使用抗生素或疫苗不能显著清除感染（清除率分别为55.6%、22.2%和33.3%）。这种疫苗开发方法可能会导致针对其他病原性生物膜细菌的疫苗的产生。
Staphylococcus aureus infections, particularly those from methicillin-resistant strains (i.e., MRSA), are reaching epidemic proportions, with no effective vaccine available. The vast number and transient expression of virulence factors in the infectious course of this pathogen have made the discovery of protective antigens particularly difficult. In addition, the divergent planktonic and biofilm modes of growth with their accompanying proteomic changes also demonstrate significant hindrances to vaccine development. In this study, a multicomponent vaccine was evaluated for its ability to clear a staphylococcal biofilm infection. Antigens (glucosaminidase, an ABC transporter lipoprotein, a conserved hypothetical protein, and a conserved lipoprotein) were chosen since they were found in previous studies to have upregulated and sustained expression in a biofilm, both in vitro and in vivo. Antibodies against these antigens were first used in microscopy studies to localize their expression in in vitro biofilms. Each of the four antigens showed heterogeneous production in various locations within the complex biofilm community in the biofilm. Based upon these studies, the four antigens were delivered simultaneously as a quadrivalent vaccine in order to compensate for this varied production. In addition, antibiotic treatment was also administered to clear the remaining nonattached planktonic cells since the vaccine antigens may have been biofilm specific. The results demonstrated that when vaccination was coupled with vancomycin treatment in a biofilm model of chronic osteomyelitis in rabbits, clinical and radiographic signs of infection significantly reduced by 67 and 82%, respectively, compared to infected animals that were either treated with vancomycin or left untreated. In contrast, vaccination alone resulted in a modest, and nonsignificant, decrease in clinical (34% reduction) and radiographic signs (9% reduction) of infection, compared to nonvaccinated animal groups untreated or treated with vancomycin. Lastly, MRSA biofilm infections were significantly cleared in 87.5% of vaccinated and antibiotic-treated animals, while antibiotics or vaccine alone could not significantly clear infection compared to controls (55.6, 22.2, and 33.3% clearance rates, respectively). This approach to vaccine development may lead to the generation of vaccines against other pathogenic biofilm bacteria.