title: HLA-DRB1*1501 and VDR polymorphisms and survival of Mycobacterium tuberculosis in human macrophages exposed to inhalable microparticles.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  S score predicts colonization of macrophages by Mtb, as does haplotype analysis. Drug-containing microparticles are superior to free drugs across diverse genetic backgrounds.
authors.affiliation: CSIR-Central Drug Research Institute, Lucknow 226001, India.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Singh
authors.lastname: Abhimanyu
authors.forename: Awadh B
authors.initials: AB
authors.lastname: Yadav
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sharma
authors.forename: Rajiv
authors.initials: R
authors.lastname: Garg
authors.forename: Mridula
authors.initials: M
authors.lastname: Bose
authors.forename: Amit
authors.initials: A
authors.lastname: Misra
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007538:Isoniazid / Q000008:administration & dosage*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D009569:Nitric Oxide / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D017828:Rifabutin / Q000008:administration & dosage*; D014376:Tuberculosis / Q000188:drug therapy / Q000235:genetics* / Q000382:microbiology
chemical_list: D059811:HLA-DRB1 Chains; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D017828:Rifabutin; D009569:Nitric Oxide; D007538:Isoniazid