title: Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases.
abstract: BACKGROUND
  Tuberculosis kills more than 1.5 million people per year, and standard treatment has remained unchanged for more than 30 years. Tuberculosis (TB) drives matrix metalloproteinase (MMP) activity to cause immunopathology. In advanced HIV infection, tissue destruction is reduced, but underlying mechanisms are poorly defined and no current antituberculous therapy reduces host tissue damage.
  
  
  OBJECTIVE
  To investigate MMP activity in patients with TB with and without HIV coinfection and to determine the potential of doxycycline to inhibit MMPs and decrease pathology.
  
  
  METHODS
  Concentrations of MMPs and cytokines were analyzed by Luminex array in a prospectively recruited cohort of patients. Modulation of MMP secretion and Mycobacterium tuberculosis growth by doxycycline was studied in primary human cells and TB-infected guinea pigs.
  
  
  RESULTS
  HIV coinfection decreased MMP concentrations in induced sputum of patients with TB. MMPs correlated with clinical markers of tissue damage, further implicating dysregulated protease activity in TB-driven pathology. In contrast, cytokine concentrations were no different. Doxycycline, a licensed MMP inhibitor, suppressed TB-dependent MMP-1 and -9 secretion from primary human macrophages and epithelial cells by inhibiting promoter activation. In the guinea pig model, doxycycline reduced lung TB colony forming units after 8 weeks in a dose-dependent manner compared with untreated animals, and in vitro doxycycline inhibited mycobacterial proliferation.
  
  
  CONCLUSIONS
  HIV coinfection in patients with TB reduces concentrations of immunopathogenic MMPs. Doxycycline decreases MMP activity in a cellular model and suppresses mycobacterial growth in vitro and in guinea pigs. Adjunctive doxycycline therapy may reduce morbidity and mortality in TB.
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Naomi F
authors.initials: NF
authors.lastname: Walker
authors.forename: Simon O
authors.initials: SO
authors.lastname: Clark
authors.forename: Tolu
authors.initials: T
authors.lastname: Oni
authors.forename: Nuria
authors.initials: N
authors.lastname: Andreu
authors.forename: Liku
authors.initials: L
authors.lastname: Tezera
authors.forename: Shivani
authors.initials: S
authors.lastname: Singh
authors.forename: Luísa
authors.initials: L
authors.lastname: Saraiva
authors.forename: Bernadette
authors.initials: B
authors.lastname: Pedersen
authors.forename: Dominic L
authors.initials: DL
authors.lastname: Kelly
authors.forename: Julia A
authors.initials: JA
authors.lastname: Tree
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: D'Armiento
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Mauri
authors.forename: Ann
authors.initials: A
authors.lastname: Williams
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
mesh_terms: D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D016207:Cytokines / Q000032:analysis; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D015658:HIV Infections / Q000150:complications* / Q000201:enzymology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013183:Sputum / Q000737:chemistry / Q000201:enzymology; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000201:enzymology*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020781:Matrix Metalloproteinase 1; D004318:Doxycycline