Chand Yamini, Jain Tanvi, Singh Sachidanand
Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Lucknow-Deva Road, Barabanki, 225003, Uttar Pradesh, India.
Department of Biotechnology, School of Energy and Technology, Pandit Deendayal Energy University, Gandhinagar, 382426, Gujarat, India.
Cell Biochem Biophys. 2024 Sep;82(3):2901-2936. doi: 10.1007/s12013-024-01407-5. Epub 2024 Jul 17.
Salmonella subsp. enterica (SE) presents a significant global health challenge in both developed and developing countries. Current SE vaccines have limitations, targeting specific strains and demonstrating moderate efficacy in adults, while also being unsuitable for young children and often unaffordable in regions with lower income levels where the disease is prevalent. To address these challenges, this study employed a computational approach integrating core proteomics, subtractive proteomics, and immunoinformatics to develop a universal SE vaccine and identify potential drug targets. Analysis of the core proteome of 185 SE strains revealed 1964 conserved proteins. Subtractive proteomics identified 9 proteins as potential vaccine candidates and 41 as novel drug targets. Using reverse vaccinology-based immunoinformatics, four multi-epitope-based subunit vaccine constructs (MESVCs) were designed, aiming to stimulate cytotoxic T lymphocyte, helper T lymphocyte, and linear B lymphocyte responses. These constructs underwent comprehensive evaluations for antigenicity, immunogenicity, toxicity, hydropathicity, and physicochemical properties. Predictive modeling, refinement, and validation were conducted to determine the secondary and tertiary structures of the SE-MESVCs, followed by docking studies with MHC-I, MHC-II, and TLR4 receptors. Molecular docking assessments showed favorable binding with all three receptors, with SE-MESVC-4 exhibiting the most promising binding energy. Molecular dynamics simulations confirmed the binding affinity and stability of SE-MESVC-4 with the TLR4/MD2 complex. Additionally, codon optimization and in silico cloning verified the efficient translation and successful expression of SE-MESVC-4 in Escherichia coli (E. coli) str. K12. Subsequent in silico immune simulation evaluated the efficacy of SE-MESVC-4 in triggering an effective immune response. These results suggest that SE-MESVC-4 may induce both humoral and cellular immune responses, making it a potential candidate for an effective SE vaccine. However, further experimental investigations are necessary to validate the immunogenicity and efficacy of SE-MESVC-4, bringing us closer to effectively combating SE infections.
肠炎沙门氏菌亚种（SE）在发达国家和发展中国家都构成了重大的全球健康挑战。当前的SE疫苗存在局限性，仅针对特定菌株，在成年人中显示出中等疗效，同时不适用于幼儿，并且在该疾病流行的低收入地区往往价格昂贵。为应对这些挑战，本研究采用了一种整合核心蛋白质组学、消减蛋白质组学和免疫信息学的计算方法来开发通用的SE疫苗并确定潜在的药物靶点。对185株SE菌株的核心蛋白质组分析揭示了1964种保守蛋白质。消减蛋白质组学确定了9种蛋白质作为潜在的疫苗候选物，41种作为新型药物靶点。使用基于反向疫苗学的免疫信息学，设计了四种基于多表位的亚单位疫苗构建体（MESVCs），旨在刺激细胞毒性T淋巴细胞、辅助性T淋巴细胞和线性B淋巴细胞反应。对这些构建体进行了抗原性、免疫原性、毒性、亲水性和物理化学性质的综合评估。进行了预测建模、优化和验证，以确定SE-MESVCs的二级和三级结构，随后与MHC-I、MHC-II和TLR4受体进行对接研究。分子对接评估显示与所有三种受体都有良好的结合，其中SE-MESVC-4表现出最有前景的结合能。分子动力学模拟证实了SE-MESVC-4与TLR4/MD2复合物的结合亲和力和稳定性。此外，密码子优化和电子克隆验证了SE-MESVC-4在大肠杆菌（E. coli）菌株K12中的高效翻译和成功表达。随后的电子免疫模拟评估了SE-MESVC-4引发有效免疫反应的功效。这些结果表明，SE-MESVC-4可能诱导体液免疫和细胞免疫反应，使其成为有效SE疫苗的潜在候选物。然而，需要进一步的实验研究来验证SE-MESVC-4的免疫原性和疗效，从而使我们更接近有效对抗SE感染。
