Broadly Reactive Human Monoclonal Antibodies Targeting the Pneumococcal Histidine Triad Protein Protect against Fatal Pneumococcal Infection.
Broadly Reactive Human Monoclonal Antibodies Targeting the Pneumococcal Histidine Triad Protein Protect against Fatal Pneumococcal Infection.
复制标题
靶向肺炎球菌组氨酸三联体蛋白的广泛反应性人单克隆抗体可预防致命性肺炎球菌感染。
DOI：
10.1128/iai.00747-20
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发表时间：
2021-04-16
影响因子：
3.1
通讯作者：
Mousa JJ
中科院分区：
文献类型：
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作者：
Huang J;Gingerich AD;Royer F;Paschall AV;Pena-Briseno A;Avci FY;Mousa JJ
尽管疫苗的广泛使用，肺炎链球菌仍然是细菌性肺炎的主要原因。虽然疫苗可有效降低疫苗中所含大多数血清型的发病率，但由于非疫苗血清型导致的感染增加以及对某些疫苗血清型的中等疗效导致了高发病率。尽管疫苗的广泛使用，肺炎链球菌仍然是细菌性肺炎的主要原因。虽然疫苗可有效降低疫苗中所含大多数血清型的发病率，但由于非疫苗血清型导致的感染增加以及对某些疫苗血清型的中等疗效导致了高发病率。此外，许多S.肺炎是抗生素或多药耐药的。在大多数血清型中流行的几种保守的肺炎球菌蛋白已经在临床前和临床试验中检查了它们作为疫苗的潜力。另一种尚未开发的疾病预防和治疗工具是使用靶向保守肺炎球菌蛋白的人单克隆抗体（MAb）。在这里，我们分离的第一个人单克隆抗体（PhtD 3，PhtD 6，PhtD 7，PhtD 8，和PspA 16）对肺炎球菌组氨酸三联体蛋白（PhtD）和肺炎球菌表面蛋白A（PspA），两个保守和保护性抗原。针对PhtD的MAb靶向PhtD上的不同表位，MAb PspA 16靶向PspA的N-末端区段。PhtD特异性MAb结合多种血清型，而MAb PspA 16血清型宽度有限。单克隆抗体PhtD 3和PhtD 8延长了感染肺炎球菌血清型3的小鼠的存活时间。此外，单克隆抗体PhtD 3在肺炎球菌感染后24小时给药时，在肺炎球菌血清型4的鼻内和静脉内感染模型中以及在肺炎球菌血清型3感染的小鼠中，可延长小鼠的生存期。所有PhtD和PspA单克隆抗体均表现出调理吞噬活性，表明了潜在的保护机制。我们的研究结果确定了新的人单克隆抗体的肺炎球菌疾病的预防和治疗，并确定PhtD和PspA的表位识别的人B细胞。
Streptococcus pneumoniae remains a leading cause of bacterial pneumonia despite the widespread use of vaccines. While vaccines are effective at reducing the incidence of most serotypes included in vaccines, a rise in infection due to nonvaccine serotypes and moderate efficacy against some vaccine serotypes have contributed to high disease incidence. Streptococcus pneumoniae remains a leading cause of bacterial pneumonia despite the widespread use of vaccines. While vaccines are effective at reducing the incidence of most serotypes included in vaccines, a rise in infection due to nonvaccine serotypes and moderate efficacy against some vaccine serotypes have contributed to high disease incidence. Additionally, numerous isolates of S. pneumoniae are antibiotic or multidrug resistant. Several conserved pneumococcal proteins prevalent in the majority of serotypes have been examined for their potential as vaccines in preclinical and clinical trials. An additional, yet-unexplored tool for disease prevention and treatment is the use of human monoclonal antibodies (MAbs) targeting conserved pneumococcal proteins. Here, we isolated the first human MAbs (PhtD3, PhtD6, PhtD7, PhtD8, and PspA16) against the pneumococcal histidine triad protein (PhtD) and the pneumococcal surface protein A (PspA), two conserved and protective antigens. MAbs to PhtD target diverse epitopes on PhtD, and MAb PspA16 targets the N-terminal segment of PspA. The PhtD-specific MAbs bind to multiple serotypes, while MAb PspA16 serotype breadth is limited. MAbs PhtD3 and PhtD8 prolong the survival of mice infected with pneumococcal serotype 3. Furthermore, MAb PhtD3 prolongs the survival of mice in intranasal and intravenous infection models with pneumococcal serotype 4 and in mice infected with pneumococcal serotype 3 when administered 24 h after pneumococcal infection. All PhtD and PspA MAbs demonstrate opsonophagocytic activity, suggesting a potential mechanism of protection. Our results identify new human MAbs for pneumococcal disease prevention and treatment and identify epitopes on PhtD and PspA recognized by human B cells.