title: Monocyte unresponsiveness and impaired IL1β, TNFα and IL7 production are associated with a poor outcome in Malawian adults with pulmonary tuberculosis.
abstract: BACKGROUND
  Early death during TB treatment is associated with depressed TNFα response to antigenic stimulation and propensity to superadded bacterial infection. Hypothesising the role of monocyte unresponsiveness, we further compared the immunological profile between patients who died or suffered a life-threatening deterioration ('poor outcome') during the intensive phase of TB treatment with patients who had an uneventful clinical course ('good outcome') who had been recruited as part of a larger prospective cohort study of Malawian TB patients.
  
  
  METHODS
  Using Luminex, IL1β, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12, IL13, IL17, GCSF, GMCSF, MCP1, MIP1b, IFNγ and TNFα were measured in whole blood assay supernatants (stimulated with Mycobacterium tuberculosis H37Rv and LPS) and serum from 44 Malawian adult TB patients (22 of each outcome) immediately prior to commencing treatment, after 7 days and on day 56 of TB treatment. Monocyte surface expression of CD14, CD16, TLR2, TLR4, CD86 and HLADR, and intracellular TNFα were measured by flow cytometry as was intracellular TNFα response to purified TLR ligands.
  
  
  RESULTS
  Lower TB antigen-induced IL1β (p = 0.006), TNFα (p = 0.02) and IL7 (p = 0.009) were produced in the poor outcome group. TNFα was produced by 'classical' CD14(hi)CD16(lo) monocytes, with no correlation between this response and expression of monocyte surface markers. Response to TB antigens correlated with responses to the purified TLR 2, 3 and 4 ligands.
  
  
  CONCLUSIONS
  Dysregulated monocyte cytokine production was identified in TB patients with poor outcome. Lower TNFα responses to H37Rv paralleled lower responses to a panel of TLR ligands, suggesting an underlying perturbation in common TLR signalling pathways. Future work should explore the role of TLR polymorphisms in immune response and clinical outcome in TB patients.
authors.affiliation: Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, PO Box 30096, Chichiri, Blantyre, Malawi. cwaitt@liv.ac.uk.|Department of Molecular and Clinical Pharmacology, The University of Liverpool, Block A, The Waterhouse Buildings, 1-5 Brownlow Street, Liverpool, L69 3GL, United Kingdom. cwaitt@liv.ac.uk.
authors.forename: Catriona John
authors.initials: CJ
authors.lastname: Waitt
authors.affiliation: Department of Medicine, College of Medicine, University of Malawi, Blantyre, Malawi. npkbanda2000@yahoo.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Banda
authors.affiliation: Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, PO Box 30096, Chichiri, Blantyre, Malawi. sarahglennie1@gmail.com.|School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK. sarahglennie1@gmail.com.
authors.forename: Sarah
authors.initials: S
authors.lastname: Glennie
authors.affiliation: Imperial College London, London, UK. b.kampmann@imperial.ac.uk.|MRC Unit, The Gambia, Serrekunda, Gambia. b.kampmann@imperial.ac.uk.
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom. s.b.squire@liv.ac.uk.
authors.forename: S Bertel
authors.initials: SB
authors.lastname: Squire
authors.affiliation: Department of Molecular and Clinical Pharmacology, The University of Liverpool, Block A, The Waterhouse Buildings, 1-5 Brownlow Street, Liverpool, L69 3GL, United Kingdom. munirp@liv.ac.uk.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, PO Box 30096, Chichiri, Blantyre, Malawi. livrsh@liv.ac.uk.|Liverpool School of Tropical Medicine, Liverpool, United Kingdom. livrsh@liv.ac.uk.
authors.forename: Robert Simon
authors.initials: RS
authors.lastname: Heyderman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016207:Cytokines / Q000097:blood* / Q000378:metabolism; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000097:blood; D015851:Interleukin-7 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008295:Malawi / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity; D011446:Prospective Studies; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D055815:Young Adult
chemical_list: D016207:Cytokines; C508605:IL7 protein, human; D053583:Interleukin-1beta; D015851:Interleukin-7; D008070:Lipopolysaccharides; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha