CSIR-Central Drug Research Institute, Lucknow 226001, India.
Pharmacogenomics. 2013 Apr;14(5):531-40. doi: 10.2217/pgs.13.12.
We examined whether HLA-DRB1*1501 and four VDR SNPs influence the macrophage response to infection with Mycobacterium tuberculosis (Mtb) via innate immune versus drug treatment or drug delivery mechanisms.
MATERIALS & METHODS: Monocyte-derived macrophages from 24 healthy donors were infected with Mtb in vitro. Survival of intracellular bacilli and secretion of cytokines and nitric oxide by the infected cells were monitored with and without exposure to isoniazid and rifabutin.
Haplotype analysis was conducted, and an arbitrary score of genetic 'susceptibility' (S ) score ranging from -3 to +3 was assigned to donors based on the presence or absence of genetic markers. S scores correlated more strongly with Mtb survival (r = 0.68) than TNF and nitric oxide (NO; r = ∼0.01-0.11). A specific haplotype was significantly associated with decreased Mtb survival (p < 0.05), increased NO and decreased IL-10/IL-4. Macrophages with S scores ≥ 2 secreted significantly (p < 0.05) more IL-10 and IL-4, and less NO upon infection, and supported Mtb survival. Microparticulate drugs showed higher bactericidal activity than free drugs, irrespective of S score.
S score predicts colonization of macrophages by Mtb, as does haplotype analysis. Drug-containing microparticles are superior to free drugs across diverse genetic backgrounds.
我们通过先天免疫与药物治疗或药物递送机制，研究了 HLA-DRB1*1501 和四个 VDR SNP 是否影响巨噬细胞对结核分枝杆菌（Mtb）感染的反应。
体外感染 24 名健康供体的单核细胞衍生的巨噬细胞。在有无异烟肼和利福布汀暴露的情况下，监测细胞内细菌的存活情况以及受感染细胞分泌的细胞因子和一氧化氮。
进行了单倍型分析，并根据遗传标记的存在与否，为供体分配了遗传“易感性”（S）评分，范围为-3 至+3。S 评分与 Mtb 存活率的相关性（r = 0.68）强于 TNF 和一氧化氮（NO；r = 0.01-0.11）。特定的单倍型与 Mtb 存活率降低显著相关（p < 0.05），NO 增加，IL-10/IL-4 减少。S 评分≥2 的巨噬细胞在感染后分泌明显更多的 IL-10 和 IL-4，而 NO 减少，并支持 Mtb 的存活。含药微粒比游离药物具有更高的杀菌活性，而与 S 评分无关。
S 评分可预测 Mtb 对巨噬细胞的定植，单倍型分析也是如此。含药微粒在不同遗传背景下均优于游离药物。
