title: CCL2 responses to Mycobacterium tuberculosis are associated with disease severity in tuberculosis.
abstract: BACKGROUND
  Leucocyte activating chemokines such as CCL2, CCL3, and CXCL8 together with proinflammatory IFNgamma, TNFalpha and downmodulatory IL10 play a central role in the restriction of M. tuberculosis infections, but is unclear whether these markers are indicative of tuberculosis disease severity.
  
  
  METHODS
  We investigated live M. tuberculosis- and M. bovis BCG-induced peripheral blood mononuclear cell responses in patients with tuberculosis (TB) and healthy endemic controls (ECs, n = 36). TB patients comprised pulmonary (PTB, n = 34) and extrapulmonary groups, subdivided into those with less severe localized extrapulmonary TB (L-ETB, n = 16) or severe disseminated ETB (D-ETB, n = 16). Secretion of CCL2, IFNgamma, IL10 and CCL3, and mRNA expression of CCL2, TNFalpha, CCL3 and CXCL8 were determined.
  
  
  RESULTS
  M. tuberculosis- and BCG-induced CCL2 secretion was significantly increased in both PTB and D-ETB (p<0.05, p<0.01) as compared with L-ETB patients. CCL2 secretion in response to M. tuberculosis was significantly greater than to BCG in the PTB and D-ETB groups. M. tuberculosis-induced CCL2 mRNA transcription was greater in PTB than L-ETB (p = 0.023), while CCL2 was reduced in L-ETB as compared with D-ETB (p = 0.005) patients. M. tuberculosis-induced IFNgamma was greater in L-ETB than PTB (p = 0.04), while BCG-induced IFNgamma was greater in L-ETB as compared with D-ETB patients (p = 0.036). TNFalpha mRNA expression was raised in PTB as compared with L-ETB group in response to M. tuberculosis (p = 0.02) and BCG (p = 0.03). Mycobacterium-induced CCL3 and CXCL8 was comparable between TB groups.
  
  
  CONCLUSIONS
  The increased CCL2 and TNFalpha in PTB patients may support effective leucocyte recruitment and M. tuberculosis localization. CCL2 alone is associated with severity of TB, possibly due to increased systemic inflammation found in severe disseminated TB or due to increased monocyte infiltration to lung parenchyma in pulmonary disease.
authors.affiliation: The Aga Khan University, Karachi, Pakistan. zahra.hasan@aku.edu
authors.forename: Zahra
authors.initials: Z
authors.lastname: Hasan
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Cliff
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Dockrell
authors.forename: Bushra
authors.initials: B
authors.lastname: Jamil
authors.forename: Muhammad
authors.initials: M
authors.lastname: Irfan
authors.forename: Mussarat
authors.initials: M
authors.lastname: Ashraf
authors.forename: Rabia
authors.initials: R
authors.lastname: Hussain
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054405:Chemokine CCL3 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000382:microbiology; D008297:Male; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; C515429:CCL3 protein, human; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma