title: Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response.
abstract: BACKGROUND
  The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluation and detection of Mycobacterium tuberculosis (Mtb) in the patient's sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that immune activation markers on Mtb-specific CD4+ T cells would be associated with Mtb load in vivo and could thus provide a gauge of Mtb infection.
  
  
  METHODS
  Using polychromatic flow cytometry, we evaluated the expression of immune activation markers on Mtb-specific CD4+ T cells from individuals with asymptomatic latent Mtb infection (LTBI) and ATB as well as from ATB patients undergoing anti-TB treatment.
  
  
  RESULTS
  Frequencies of Mtb-specific IFN-γ+CD4+ T cells that expressed immune activation markers CD38 and HLA-DR as well as intracellular proliferation marker Ki-67 were substantially higher in subjects with ATB compared with those with LTBI. These markers accurately classified ATB and LTBI status, with cutoff values of 18%, 60%, and 5% for CD38+IFN-γ+, HLA-DR+IFN-γ+, and Ki-67+IFN-γ+, respectively, with 100% specificity and greater than 96% sensitivity. These markers also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment.
  
  
  CONCLUSIONS
  We have identified host blood-based biomarkers on Mtb-specific CD4+ T cells that discriminate between ATB and LTBI and provide a set of tools for monitoring treatment response and cure.
  
  
  BACKGROUND
  Registration is not required for observational studies.
  
  
  BACKGROUND
  This study was funded by Emory University, the NIH, and the Yerkes National Primate Center.
authors.forename: Toidi
authors.initials: T
authors.lastname: Adekambi
authors.forename: Chris C
authors.initials: CC
authors.lastname: Ibegbu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cagle
authors.forename: Ameeta S
authors.initials: AS
authors.lastname: Kalokhe
authors.forename: Yun F
authors.initials: YF
authors.lastname: Wang
authors.forename: Yijuan
authors.initials: Y
authors.lastname: Hu
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Day
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ray
authors.forename: Jyothi
authors.initials: J
authors.lastname: Rengarajan
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000097:blood*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000627:therapeutic use; D058070:Asymptomatic Diseases; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry*; D003937:Diagnosis, Differential; D016903:Drug Monitoring; D005260:Female; D005434:Flow Cytometry / Q000379:methods*; D005845:Georgia; D006684:HLA-DR Antigens / Q000097:blood*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood*; D019394:Ki-67 Antigen / Q000097:blood*; D055985:Latent Tuberculosis / Q000097:blood / Q000175:diagnosis / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000302:isolation & purification; D012680:Sensitivity and Specificity; D013019:South Africa; D013183:Sputum / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers; D006684:HLA-DR Antigens; D019394:Ki-67 Antigen; D008562:Membrane Glycoproteins; D007371:Interferon-gamma; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1
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