Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, California, United States of America.
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
PLoS Pathog. 2018 May 10;14(5):e1007056. doi: 10.1371/journal.ppat.1007056. eCollection 2018 May.
Different pathogens share similar medical settings and rely on similar virulence strategies to cause infections. We have previously applied 3-D computational modeling and bioinformatics to discover novel antigens that target more than one human pathogen. Active and passive immunization with the recombinant N-terminus of Candida albicans Hyr1 (rHyr1p-N) protect mice against lethal candidemia. Here we determine that Hyr1p shares homology with cell surface proteins of the multidrug resistant Gram negative bacterium, Acinetobacter baumannii including hemagglutinin (FhaB) and outer membrane protein A (OmpA). The A. baumannii OmpA binds to C. albicans Hyr1p, leading to a mixed species biofilm. Deletion of HYR1, or blocking of Hyr1p using polyclonal antibodies, significantly reduce A. baumannii binding to C. albicans hyphae. Furthermore, active vaccination with rHyr1p-N or passive immunization with polyclonal antibodies raised against specific peptide motifs of rHyr1p-N markedly improve survival of diabetic or neutropenic mice infected with A. baumannii bacteremia or pneumonia. Antibody raised against one particular peptide of the rHyr1p-N sequence (peptide 5) confers majority of the protection through blocking A. baumannii invasion of host cells and inducing death of the bacterium by a putative iron starvation mechanism. Anti-Hyr1 peptide 5 antibodies also mitigate A. baumannii /C. albicans mixed biofilm formation in vitro. Consistent with our bioinformatic analysis and structural modeling of Hyr1p, anti-Hyr1p peptide 5 antibodies bound to A. baumannii FhaB, OmpA, and an outer membrane siderophore binding protein. Our studies highlight the concept of cross-kingdom vaccine protection against high priority human pathogens such as A. baumannii and C. albicans that share similar ecological niches in immunocompromised patients.
不同的病原体具有相似的医学环境，并依赖相似的毒力策略来引起感染。我们之前应用 3-D 计算建模和生物信息学来发现针对多种人类病原体的新型抗原。用重组白念珠菌 Hyr1 的 N 端（rHyr1p-N）进行主动和被动免疫可保护小鼠免受致命念珠菌血症的侵害。在这里，我们确定 Hyr1p 与多药耐药革兰氏阴性菌鲍曼不动杆菌的细胞表面蛋白具有同源性，包括血凝素（FhaB）和外膜蛋白 A（OmpA）。鲍曼不动杆菌 OmpA 与白念珠菌 Hyr1p 结合，导致混合物种生物膜形成。HYR1 的缺失，或使用多克隆抗体阻断 Hyr1p，可显著减少鲍曼不动杆菌与白念珠菌菌丝的结合。此外，用 rHyr1p-N 进行主动疫苗接种或用针对 rHyr1p-N 的特定肽段产生的多克隆抗体进行被动免疫，可显著提高糖尿病或中性粒细胞减少小鼠感染鲍曼不动杆菌菌血症或肺炎的存活率。针对 rHyr1p-N 序列的一个特定肽段（肽段 5）产生的抗体通过阻断鲍曼不动杆菌入侵宿主细胞并通过一种推测的铁饥饿机制诱导细菌死亡，从而赋予大部分保护作用。抗 Hyr1 肽段 5 抗体还可减轻鲍曼不动杆菌/白念珠菌混合生物膜在体外的形成。与我们对白念珠菌 Hyr1p 的生物信息学分析和结构建模一致，抗 Hyr1p 肽段 5 抗体与鲍曼不动杆菌 FhaB、OmpA 和外膜铁载体结合蛋白结合。我们的研究强调了针对高优先级人类病原体（如鲍曼不动杆菌和白念珠菌）的跨域疫苗保护概念，这些病原体在免疫功能低下的患者中具有相似的生态位。
