PPE18 and PepA Variations in Mycobacterium tuberculosis Clinical Isolates from Makassar, Indonesia: Challenges for Immune Recognition and Vaccine Development.

IF 1.6 Q4 INFECTIOUS DISEASES
International Journal of Mycobacteriology Pub Date : 2025-04-01 Epub Date: 2025-06-20 DOI:10.4103/ijmy.ijmy_70_25
Stephanie Cynthia Theorupun, Muhammad Nasrum Massi, Astutiati Nurhasanah, Fadhilah Syamsuri, Mochammad Hatta, Yoeke Dewi Rasita, Najdah Hidayah, Nihayatul Karimah, Doddy Irawan Setyo Utomo
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引用次数: 0

Abstract

Background: The M72/AS01E tuberculosis vaccine candidate, currently on trial in Indonesia, includes PPE18 (Rv1196) and PepA (Rv0125) as key antigens. Genetic variation in these proteins may affect immune recognition and vaccine efficacy. This study aims to analyse the genetic diversity of Rv1196 and Rv0125 in Mycobacterium tuberculosis clinical isolates from Indonesia and assess the structural and immunological implications using in silico methods.

Methods: Rv1196 and Rv0125 genes from clinical isolates were sequenced and analysed for polymorphisms. PPE18 variants were modelled using I-TASSER (Iterative Threading ASSEmbly Refinement), and structural stability and HLA (Human Leukocyte Antigen) binding predictions (HLA-I and HLA-II) were performed using IEDB (Immune Epitope Database) tools. Molecular docking with TLR2 (Toll-like Receptor 2) was conducted to evaluate receptor interactions.

Results: A novel non-synonymous mutation (T22G, Ser8Ala) was identified in Rv0125, which was otherwise conserved. Rv1196 showed high variability with 58 polymorphic sites, including 38 non-synonymous mutations, a frequent Arg287Gln substitution, and a ΔThr163-Ala164 deletion. Structural modelling indicated preserved PPE18 fold but altered epitope binding in an allele-specific manner. Docking showed stronger TLR2 interactions for variants 6S31 and 6S32, suggesting enhanced IL-10 induction and a Th2-skewed immune response.

Conclusions: PPE18 genetic variation may influence immune recognition and the effectiveness of M72/AS01E. Ongoing antigenic surveillance in endemic areas is essential to guide vaccine design and diagnostics.

印尼望加锡结核分枝杆菌临床分离株PPE18和PepA变异:免疫识别和疫苗开发的挑战
背景:目前正在印度尼西亚进行试验的M72/AS01E结核候选疫苗包括PPE18 (Rv1196)和PepA (Rv0125)作为关键抗原。这些蛋白的遗传变异可能影响免疫识别和疫苗效力。本研究旨在分析印度尼西亚结核分枝杆菌临床分离株Rv1196和Rv0125的遗传多样性,并利用计算机方法评估其结构和免疫学意义。方法:对临床分离的Rv1196和Rv0125基因进行测序和多态性分析。使用I-TASSER(迭代穿线装配精化)对PPE18变异进行建模,使用IEDB(免疫表位数据库)工具进行结构稳定性和HLA(人类白细胞抗原)结合预测(HLA- i和HLA- ii)。通过与TLR2 (toll样受体2)的分子对接来评估受体间的相互作用。结果:在Rv0125中发现了一个新的非同义突变(T22G, Ser8Ala),否则该突变是保守的。Rv1196具有58个多态性位点,包括38个非同义突变,一个频繁的Arg287Gln替换和一个ΔThr163-Ala164缺失。结构模型显示保留了PPE18折叠,但以等位基因特异性方式改变了表位结合。对接显示变异6S31和6S32的TLR2相互作用更强,表明IL-10诱导和th2偏斜免疫反应增强。结论:PPE18基因变异可能影响M72/AS01E的免疫识别和疗效。在流行地区持续进行抗原监测对于指导疫苗设计和诊断至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
2.20
自引率
25.00%
发文量
62
审稿时长
7 weeks
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