Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Mekong Health Science Research Institute, Khon Kaen University, Khon Kaen, Thailand.
Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Front Immunol. 2018 Mar 20;9:484. doi: 10.3389/fimmu.2018.00484. eCollection 2018.
(Bp) is an environmental bacterial pathogen that causes potentially lethal sepsis in susceptible individuals and is considered a Category B, Tier-1 biothreat agent. As such, it is crucial to gain an improved understanding of protective immunity and potential vaccine candidates. The nature of immune correlates dictating why most exposed individuals in endemic regions undergo asymptomatic seroconversion while others succumb to life-threatening sepsis is largely uncharted. Bp seroreactive, immunogenic proteins have previously been identified by antigen microarray. We here set out to conduct an analysis of T-cell recognition of the Bp immunome using serodominant antigens represented in the original antigen microarray, examining immune correlates of disease in healthy seropositive individuals and those with acute disease or in convalescence. By screening a library of 739 overlapping peptides representing the sequences of 20 different Bp antigens, we aimed to define immune correlates of protection at the level of immunoprevalent T-cell epitopes. Responses to a large number of epitopes were common in healthy seropositive individuals: we found remarkably broad responsiveness to Bp epitopes, with 235 of 739 peptides recognized by ≥80% of all tested donors. The cumulative response to Bp epitopes in healthy, seropositive, donors from this endemic region were of the order of thousands of spot forming cells per million cells, making Bp recognition a significant component of the T-cell repertoire. Noteworthy among our findings, analysis revealed 10 highly immunoprevalent T-cell epitopes, able to induce Bp-specific IFNγ responses that were high in responding T-cell frequency within the repertoire, and also common across individuals with different human leukocyte antigen types. Acute melioidosis patients showed poor T-cell responses to the immunoprevalent epitopes, but acquired responsiveness following recovery from infection. Our findings suggest that a large repertoire of CD4 T cells, high in frequency and with broad coverage of antigens and epitopes, is important in controlling Bp infection. This offers an attractive potential strategy for subunit or epitope-based vaccines.
（Bp）是一种环境细菌病原体，可导致易感个体发生潜在致命性败血症，被认为是 B 类、1 级生物威胁剂。因此，深入了解保护性免疫和潜在疫苗候选物至关重要。决定为何大多数处于流行地区的暴露个体经历无症状血清转化，而其他个体则屈服于危及生命的败血症的免疫相关因素在很大程度上仍未被发现。以前通过抗原微阵列鉴定了 Bp 反应性、免疫原性蛋白。我们在此着手使用原始抗原微阵列中代表的血清优势抗原分析 Bp 免疫组的 T 细胞识别，检查健康血清阳性个体以及急性疾病或恢复期个体中疾病的免疫相关因素。通过筛选代表 20 种不同 Bp 抗原序列的 739 个重叠肽文库，我们旨在定义免疫优势 T 细胞表位的保护相关因素。大量表位的反应在健康血清阳性个体中很常见：我们发现对 Bp 表位的反应非常广泛，739 个肽中有 235 个被所有测试供体中的≥80%识别。来自该流行地区的健康血清阳性供体对 Bp 表位的累积反应数量达到了每百万细胞数千个斑点形成细胞，使 Bp 识别成为 T 细胞库的重要组成部分。在我们的发现中值得注意的是，分析揭示了 10 个高度免疫优势 T 细胞表位，能够诱导 Bp 特异性 IFNγ 反应，这些反应在反应 T 细胞频率内的反应频率很高，并且在不同人类白细胞抗原类型的个体中也很常见。急性类鼻疽病患者对免疫优势表位的 T 细胞反应较差，但在感染恢复后获得了反应性。我们的研究结果表明，高频率、广泛覆盖抗原和表位的大量 CD4 T 细胞对于控制 Bp 感染很重要。这为亚单位或表位疫苗提供了有吸引力的潜在策略。
