Transcriptomic Biomarkers for Tuberculosis: Evaluation ofDOCK9. EPHA4, andNPC2mRNA Expression in Peripheral Blood.
Lately, much effort has been made to find mRNA biomarkers for tuberculosis (TB) disease/infection with microarray-based approaches. In a pilot investigation, through RNA sequencing technology, we observed a prominent modulation ofDOCK9, EPHA4, andNPC2mRNA abundance in the blood of TB patients. To corroborate these findings, independent validations were performed in cohorts from different areas. Gene expression levels in blood were evaluated by quantitative real-time PCR (Brazil,n= 129) or reanalysis of public microarray data (UK:n= 96; South Africa:n= 51; Germany:n= 26; and UK/France:n= 63). In the Brazilian cohort, significant modulation of all target-genes was observed comparing TB vs. healthy recent close TB contacts (rCt). With a 92% specificity,NPC2mRNA high expression (NPC2high) showed the highest sensitivity (85%, 95% CI 65%-96%; area under the ROC curve [AUROC] = 0.88), followed byEPHA4(53%, 95% CI 33%-73%, AUROC = 0.73) andDOCK9(19%, 95% CI 7%-40%; AUROC = 0.66). All the other reanalyzed cohorts corroborated the potential ofNPC2highas a biomarker for TB (sensitivity: 82-100%; specificity: 94-97%). AnNPC2highprofile was also observed in 60% (29/48) of the tuberculin skin test positive rCt, and additional follow-up evaluation revealed changes in the expression levels ofNPC2during the different stages ofMycobacterium tuberculosisinfection, suggesting that further studies are needed to evaluate modulation of this gene during latent TB and/or progression to active disease. Considering its high specificity, our data indicate, for the first time, thatNPC2highmight serve as an accurate single-gene biomarker for TB.
Laboratório de Microbiologia Celular, Fundação Oswaldo Cruz, Instituto Oswaldo Cruz Rio de Janeiro, Brazil.
Leonardo S
LS
de Araujo
TWINCORE, Center for Experimental and Clinical Infection Research Hannover, Germany.
Lea A I
LA
Vaas
Laboratório de Pesquisa Clínica em DST-AIDS, Fundação Oswaldo Cruz, Instituto de Pesquisa Clínica Evandro Chagas Rio de Janeiro, Brazil.
Marcelo
M
Ribeiro-Alves
Helmholtz Centre for Infection Research Braunschweig, Germany.
Robert
R
Geffers
Thoracic Diseases Institute, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
Fernanda C Q
FC
Mello
Laboratório de Hanseníase, Fundação Oswaldo Cruz, Instituto Oswaldo Cruz Rio de Janeiro, Brazil.
Alexandre S
AS
de Almeida
Thoracic Diseases Institute, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
Adriana da S R
AD
Moreira
Thoracic Diseases Institute, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
Afrânio L
AL
Kritski
Thoracic Diseases Institute, Federal University of Rio de Janeiro Rio de Janeiro, Brazil.
José R
JR
Lapa E Silva
Laboratório de Hanseníase, Fundação Oswaldo Cruz, Instituto Oswaldo Cruz Rio de Janeiro, Brazil.
Milton O
MO
Moraes
TWINCORE, Center for Experimental and Clinical Infection ResearchHannover, Germany; Helmholtz Centre for Infection ResearchBraunschweig, Germany.
Frank
F
Pessler
Laboratório de Microbiologia Celular, Fundação Oswaldo Cruz, Instituto Oswaldo Cruz Rio de Janeiro, Brazil.
Maria H F
MH
Saad
LTBI; M. tuberculosis; biomarkers; messenger RNA; tuberculosis