HLA-DRB1*1501 and VDR polymorphisms and survival of Mycobacterium tuberculosis in human macrophages exposed to inhalable microparticles

Author:

Singh Amit K1,Abhimanyu 2,Yadav Awadh B1,Sharma Sandeep1,Garg Rajiv3,Bose Mridula2,Misra Amit4

Affiliation:

1. CSIR-Central Drug Research Institute, Lucknow 226001, India

2. Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi-110007, Delhi, India

3. Department of Pulmonary Medicine, King George’s Medical University, Lucknow 226003, India

4. CSIR-Central Drug Research Institute, Lucknow 226001, India. .

Abstract

Aim: 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. Results: 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. Conclusion:S score predicts colonization of macrophages by Mtb, as does haplotype analysis. Drug-containing microparticles are superior to free drugs across diverse genetic backgrounds. Original submitted 12 June 2012; Revision submitted 4 January 2013

Publisher

Future Medicine Ltd

Subject

Pharmacology,Genetics,Molecular Medicine

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