Carrión-Nessi Fhabián S, Salazar-Alcalá Eva, Forero-Peña David A, Curiel Kellys A, Lopez-Perez Mary, Fernández-Mestre Mercedes
Immunogenetics Section, Laboratory of Pathophysiology, Centro de Medicina Experimental, Instituto Venezolano de Investigaciones Científicas, Altos de Pipe, Venezuela.
Biomedical Research and Therapeutic Vaccines Institute, Ciudad Bolívar, Venezuela.
PLoS Negl Trop Dis. 2025 Jun 30;19(6):e0013262. doi: 10.1371/journal.pntd.0013262. eCollection 2025 Jun.
Clinical immunity to malaria has been associated with humoral immune responses targeting asexual-stage parasite proteins. However, the variability in antibody-driven responses may be influenced by genetic factors in the human host. This study aimed to evaluate the frequency of SNPs in the TLR9 gene and their association with IgG antibody responses against PvCSP variants (VK247, VK210, and V-like) and PvMSP-119 among individuals presenting with symptomatic Plasmodium vivax infections in a malaria-endemic region of Venezuela.
METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was conducted in Bolívar state, Venezuela, involving 210 individuals infected with P. vivax. IgG reactivity against P. vivax recombinant antigens was assessed by ELISA, and three TLR9 gene SNPs (rs5743836, rs352140, and rs187084) were genotyped by PCR. The median age of individuals was 29 years, with the majority being male miners with a prior history of malaria. Over 90% of individuals exhibited IgG antibodies against the three PvCSP variants and PvMSP-119. High responders to the PvCSP variants reported fewer symptoms compared to medium (p < 0.001) and low (p < 0.001) responders. Among the analyzed SNPs, heterozygous genotypes were the most prevalent. Using an overdominant inheritance model, carrying the heterozygous genotype (T/C) for TLR9 gene SNP rs5743836 was associated with lower IgG antibody response against PvCSP VK247 (aOR = 0.26, 95% CI = 0.09 to 0.73, p = 0.0094) and PvCSP V-like (aOR = 0.37, 95% CI = 0.14 to 0.99, p = 0.047). No significant associations between inheritance models for the three SNPs and parasitemia were observed.
CONCLUSIONS/SIGNIFICANCE: These findings suggest that TLR9 gene variability, particularly the heterozygous genotype for SNP rs5743836, may influence the IgG antibody response against PvCSP VK247 and V-like. Identifying genetic traits that impact immune response development could be valuable for malaria vaccine design and implementation.
疟疾的临床免疫力与针对无性阶段寄生虫蛋白的体液免疫反应有关。然而，抗体驱动反应的变异性可能受到人类宿主遗传因素的影响。本研究旨在评估委内瑞拉疟疾流行地区有症状间日疟原虫感染个体中TLR9基因单核苷酸多态性（SNP）的频率及其与针对间日疟原虫环子孢子蛋白变异体（VK247、VK210和V样）和间日疟原虫裂殖子表面蛋白119（PvMSP-119）的IgG抗体反应的关联。
方法/主要发现：在委内瑞拉玻利瓦尔州进行了一项横断面研究，涉及210名感染间日疟原虫的个体。通过酶联免疫吸附测定（ELISA）评估针对间日疟原虫重组抗原的IgG反应性，并通过聚合酶链反应（PCR）对三个TLR9基因SNP（rs5743836、rs352140和rs187084）进行基因分型。个体的中位年龄为29岁，大多数为有疟疾既往史的男性矿工。超过90%的个体表现出针对三种间日疟原虫环子孢子蛋白变异体和间日疟原虫裂殖子表面蛋白119的IgG抗体。与中等反应者（p < 0.001）和低反应者（p < 0.001）相比，对间日疟原虫环子孢子蛋白变异体的高反应者报告的症状较少。在所分析的SNP中，杂合基因型最为普遍。使用超显性遗传模型，携带TLR9基因SNP rs5743836的杂合基因型（T/C）与针对间日疟原虫环子孢子蛋白VK247（调整后比值比[aOR]=0.26，95%置信区间[CI]=0.09至0.73，p = 0.0094）和间日疟原虫环子孢子蛋白V样（aOR = 0.37，95% CI = 0.14至0.99，p = 0.047）的较低IgG抗体反应相关。未观察到这三个SNP的遗传模型与寄生虫血症之间的显著关联。
结论/意义：这些发现表明，TLR9基因变异性，特别是SNP rs5743836的杂合基因型，可能影响针对间日疟原虫环子孢子蛋白VK247和V样的IgG抗体反应。识别影响免疫反应发展的遗传特征对于疟疾疫苗的设计和实施可能具有重要价值。
