Laverde Diana, Wobser Dominique, Romero-Saavedra Felipe, Hogendorf Wouter, van der Marel Gijsbert, Berthold Martin, Kropec Andrea, Codee Jeroen, Huebner Johannes
Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany; EA4655 U2RM Stress/Virulence, University of Caen Lower-Normandy, Caen, France.
Division of Infectious Diseases, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany.
PLoS One. 2014 Oct 21;9(10):e110953. doi: 10.1371/journal.pone.0110953. eCollection 2014.
Lipoteichoic acids (LTA) are amphiphilic polymers that are important constituents of the cell wall of many Gram-positive bacteria. The chemical structures of LTA vary among organisms, albeit in the majority of Gram-positive bacteria the LTAs feature a common poly-1,3-(glycerolphosphate) backbone. Previously, the specificity of opsonic antibodies for this backbone present in some Gram-positive bacteria has been demonstrated, suggesting that this minimal structure may be sufficient for vaccine development. In the present work, we studied a well-defined synthetic LTA-fragment, which is able to inhibit opsonic killing of polyclonal rabbit sera raised against native LTA from Enterococcus faecalis 12030. This promising compound was conjugated with BSA and used to raise rabbit polyclonal antibodies. Subsequently, the opsonic activity of this serum was tested in an opsonophagocytic assay and specificity was confirmed by an opsonophagocytic inhibition assay. The conjugated LTA-fragment was able to induce specific opsonic antibodies that mediate killing of the clinical strains E. faecalis 12030, Enterococcus faecium E1162, and community-acquired Staphylococcus aureus strain MW2 (USA400). Prophylactic immunization with the teichoic acid conjugate and with the rabbit serum raised against this compound was evaluated in active and passive immunization studies in mice, and in an enterococcal endocarditis rat model. In all animal models, a statistically significant reduction of colony counts was observed indicating that the novel synthetic LTA-fragment conjugate is a promising vaccine candidate for active or passive immunotherapy against E. faecalis and other Gram-positive bacteria.
脂磷壁酸（LTA）是两亲性聚合物，是许多革兰氏阳性细菌细胞壁的重要组成成分。LTA的化学结构因生物体而异，尽管在大多数革兰氏阳性细菌中，LTA具有共同的聚-1,3-（甘油磷酸）主链。此前，已证明调理素抗体对某些革兰氏阳性细菌中这种主链具有特异性，这表明这种最小结构可能足以用于疫苗开发。在本研究中，我们研究了一种明确的合成LTA片段，它能够抑制针对粪肠球菌12030天然LTA产生的兔多克隆血清的调理杀伤作用。这种有前景的化合物与牛血清白蛋白（BSA）偶联，并用于制备兔多克隆抗体。随后，在调理吞噬试验中测试了该血清的调理活性，并通过调理吞噬抑制试验确认了其特异性。偶联的LTA片段能够诱导特异性调理素抗体，介导对临床菌株粪肠球菌12030、屎肠球菌E1162和社区获得性金黄色葡萄球菌菌株MW2（USA400）的杀伤作用。在小鼠的主动和被动免疫研究以及肠球菌性心内膜炎大鼠模型中，评估了用磷壁酸偶联物和针对该化合物产生的兔血清进行预防性免疫的效果。在所有动物模型中，均观察到菌落计数有统计学意义的减少，这表明新型合成LTA片段偶联物是用于针对粪肠球菌和其他革兰氏阳性细菌进行主动或被动免疫治疗的有前景的疫苗候选物。
