Campylobacter jejuni (C. jejuni) is accountable for more than 400 million cases of gastroenteritis each year and is listed as a high-priority gut pathogen by the World Health Organization (WHO). Although the acute infection of C. jejuni (campylobacteriosis) is commonly treated with macrolides and fluoroquinolones, the emergence of antibiotic resistance among C. jejuni warrants the need for an alternative approach to control campylobacteriosis in humans. To this end, vaccines remain a safe, effective, and widely accepted strategy for controlling emerging and re-emerging infectious diseases. In search of a suitable vaccine against campylobacteriosis, recently, we demonstrated the potential of recombinant Haemolysin co-regulated protein (Hcp) of C. jejuni Type VI secretion system (T6SS) in imparting significant immune-protection against cecal colonization of C. jejuni; however, in the avian model. Since clinical features of human campylobacteriosis are more complicated than the avians, we explored the potential of Hcp as a T6SS targeted vaccine in a murine model as a more reliable and reproducible experimental host to study vaccine-induced immune-protection against C. jejuni. Because C. jejuni primarily utilizes the mucosal route for host pathogenesis, we analyzed the immunogenicity of a mucosally deliverable bioengineered Lactic acid bacteria (LAB), Lactococcus lactis (L. lactis), expressing Hcp. Considering the role of Hcp in both structural (membrane-bound) and functional (effector protein) exhibition of C. jejuni T6SS, a head-to-head comparison of two different forms of recombinant LAB vectors (cell wall anchored and secreted form of Hcp) were tested and assessed for the immune phenotypes of each modality in BALB/c mice. We show that regardless of the Hcp protein localization, mucosal delivery of bioengineered LAB vector expressing Hcp induced high-level production of antigen-specific neutralizing antibody (sIgA) in the gut with the potential to reduce the cecal load of C. jejuni in mice. Together with the non-commensal nature of L. lactis, short gut transit time in humans, and the ability to express the heterologous protein in the gut, the present study highlights the benefits of bioengineered LAB vectors based mucosal vaccine modality against C. jejuni without the risk of immunotolerance.

中文翻译：

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表达溶血素共调节蛋白 (Hcp) 的 LAB 载体的生物工程：控制小鼠模型中空肠弯曲杆菌肠道定植的战略方法

空肠弯曲杆菌 (C. jejuni) 每年造成超过 4 亿例胃肠炎，被世界卫生组织 (WHO) 列为高度优先的肠道病原体。虽然空肠弯曲杆菌（弯曲杆菌病）的急性感染通常用大环内酯类和氟喹诺酮类药物治疗，但空肠弯曲杆菌中抗生素耐药性的出现需要另一种方法来控制人类弯曲杆菌病。为此，疫苗仍然是控制新发和再发传染病的安全、有效和广泛接受的策略。为了寻找合适的抗弯曲杆菌病疫苗，最近，我们证明了重组溶血素共调节蛋白 (Hcp) 的潜力。空肠 VI 型分泌系统 (T6SS) 对 C. jejuni 的盲肠定植提供显着的免疫保护；然而，在鸟类模型中。由于人类弯曲杆菌病的临床特征比禽类更复杂，我们探索了 Hcp 作为小鼠模型中 T6SS 靶向疫苗的潜力，作为研究疫苗诱导的空肠弯曲杆菌免疫保护的更可靠和可重复的实验宿主。由于空肠弯曲杆菌主要利用粘膜途径进行宿主发病，因此我们分析了可通过粘膜递送的生物工程乳酸菌 (LAB)、乳酸乳球菌 (L. lactis) 表达 Hcp 的免疫原性。考虑到 Hcp 在空肠弯曲杆菌 T6SS 的结构（膜结合）和功能（效应蛋白）展示中的作用，测试和评估两种不同形式的重组 LAB 载体（细胞壁锚定和分泌形式的 Hcp）的头对头比较，以确定 BALB/c 小鼠中每种方式的免疫表型。我们表明，无论 Hcp 蛋白定位如何，表达 Hcp 的生物工程 LAB 载体的粘膜递送诱导肠道中抗原特异性中和抗体 (sIgA) 的高水平产生，并有可能减少小鼠空肠弯曲杆菌的盲肠负荷。连同乳酸乳球菌的非共生性质、人类肠道转运时间短以及在肠道中表达异源蛋白的能力，本研究强调了基于生物工程 LAB 载体的黏膜疫苗方式对空肠弯曲杆菌的益处，而无需免疫耐受的风险。