Genome-based prediction of cross-protective, HLA-DR-presented epitopes as putative vaccine antigens for multiple Bordetella species.
Genome-based prediction of cross-protective, HLA-DR-presented epitopes as putative vaccine antigens for multiple Bordetella species.
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DOI：
10.1128/spectrum.03527-23
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发表时间：
2024-01-11
影响因子：
3.7
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中科院分区：
文献类型：
--
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无细胞百日咳疫苗可预防严重百日咳，但疫苗诱导的免疫力会随着时间的推移而减弱。先前的动物研究表明，T 细胞反应是持久免疫力不可或缺的一部分。目前的百日咳疫苗也不能针对引起百日咳样疾病的其他物种（例如副百日咳博德特氏菌和霍姆斯博德特氏菌）提供相当大的保护。我们的目的是从保守的直系同源物中鉴定出潜在的疫苗抗原，这些抗原预计会与 CD4 T 细胞结合，并提供针对多种博德特氏菌病原体的交叉保护性免疫。先前收集了百日咳博德特氏菌、副百日咳博德特氏菌和霍姆斯博德特氏菌分离株的全基因组序列数据。使用免疫信息学和比较基因组学来预测一组博德特氏菌分离株的免疫原性、交叉反应蛋白和蛋白同源性。使用转录组和蛋白质组数据筛选同源免疫原性靶标的表达和生产水平，并通过逆转录定量PCR分析可检测基因。计算预测方法确定了假定的人类白细胞抗原 DR 结合表位。来自用全细胞百日咳疫苗免疫的个体的 T 细胞对靶标的识别在离体得到证实。在百日咳博德特氏菌基因组中，408 个基因与副百日咳博德特氏菌和霍姆斯博德特氏菌的直系同源物表现出高度序列保守性，并且选定的一组具有高免疫原性评分。可检测到的蛋白质的子集也是博德特氏菌特异性的且不发生交叉反应。表位作图预测了 36 个保守的、免疫原性的和自然加工的表位。在这 36 个靶标中，有 6 个表位上调了 T 细胞激活标记，另外 3 个表位引发了细胞因子的产生。我们的研究结果确定了一系列针对博德特氏菌呼吸道病原体的肽，这些肽可能会赋予持久的交叉保护性 T 细胞免疫力。百日咳由百日咳博德特氏菌引起，可引起令人衰弱的呼吸道症状，因此全细胞百日咳疫苗 (wPV) 在 20 世纪 40 年代推出。然而，wPV 的反应原性使得开发 20 世纪 90 年代推出的无细胞百日咳疫苗 (aPV) 成为必要。此后，直到 COVID-19 大流行开始，报告的百日咳发病率一直在增加，这表明 aPV 不能诱导持久的免疫力，也可能无法有效阻止传播。此外，aPV 不能针对爆发期间观察到的其他博德特氏菌物种提供保护。这项工作的意义在于确定多种博德特氏菌物种的潜在新疫苗抗原，这些抗原预计会引发长期免疫反应。基于基因组的方法有助于新型疫苗的开发；在这里，这些方法确定了可能具有交叉保护作用并预测会诱导强烈记忆反应的博德特氏菌候选疫苗。这些目标可以改进疫苗，使其具有很强的安全性，同时还能增强免疫反应的寿命。
Acellular pertussis vaccines protect against severe pertussis, but vaccine-induced immunity wanes over time. Prior animal studies showed that T-cell responses are integral to long-lasting immunity. Current pertussis vaccines also do not provide considerable protection against other species that cause pertussis-like illness, such as Bordetella parapertussis and Bordetella holmesii. We aimed to identify potential vaccine antigens from conserved orthologs that are predicted to engage CD4 T cells and provide cross-protective immunity against multiple Bordetella pathogens. Whole-genome sequence data were previously collected for Bordetella pertussis, B. parapertussis, and B. holmesii isolates. Immunoinformatics and comparative genomics were used to predict immunogenicity, cross-reactive proteins, and protein homology for a set of Bordetella isolates. Expression and production levels of homologous, immunogenic targets were screened using transcriptomic and proteomic data, and detectable genes were analyzed by reverse transcription quantitative PCR. Computational prediction methods identified putative human leukocyte antigen-DR-binding epitopes. Recognition of targets by T cells from individuals immunized with whole-cell pertussis vaccines was confirmed ex vivo. From the B. pertussis genome, 408 genes exhibited high sequence conservation with orthologs in B. parapertussis and B. holmesii, and a select group had high immunogenicity scores. A subset of detectable proteins were also Bordetella-specific and non-cross-reactive. Epitope mapping predicted 36 conserved, immunogenic, and naturally processed epitopes. Of these 36 targets, six epitopes upregulated markers of T-cell activation, and three elicited cytokine production. Our findings identified a list of peptides specific to Bordetella respiratory pathogens that may confer long-lasting, cross-protective T-cell immunity. Pertussis, caused by Bordetella pertussis, can cause debilitating respiratory symptoms, so whole-cell pertussis vaccines (wPVs) were introduced in the 1940s. However, reactogenicity of wPV necessitated the development of acellular pertussis vaccines (aPVs) that were introduced in the 1990s. Since then, until the COVID-19 pandemic began, reported pertussis incidence was increasing, suggesting that aPVs do not induce long-lasting immunity and may not effectively prevent transmission. Additionally, aPVs do not provide protection against other Bordetella species that are observed during outbreaks. The significance of this work is in determining potential new vaccine antigens for multiple Bordetella species that are predicted to elicit long-term immune responses. Genome-based approaches have aided the development of novel vaccines; here, these methods identified Bordetella vaccine candidates that may be cross-protective and predicted to induce strong memory responses. These targets can lead to an improved vaccine with a strong safety profile while also strengthening the longevity of the immune response.
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影响因子：
7.3
作者：
De Groot, Anne S.;Moise, Leonard;Martin, William D.
通讯作者：
Martin, William D.
影响因子：
15.9
作者：
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Sette, Alessandro
影响因子：
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作者：
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Pruden, Amy J.
成年人在中国北京的育龄前后成年人的百日咳血清阳性。
影响因子：
7.8
作者：
Chen, Zhiyun;Pang, Jie;Zhang, Yuxiao;Ding, Yiwei;Chen, Ning;Zhang, Nan;He, Qiushui
通讯作者：
He, Qiushui
影响因子：
3.1
作者：
KHELEF, N;DANVE, B;GUISO, N
通讯作者：
GUISO, N