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TRANSCRIPTOMIC BIOMARKERS FOR TUBERCULOSIS: VALIDATION OF NPC2 AS A SINGLE MRNA BIOMARKER TO DIAGNOSE TB, PREDICT DISEASE PROGRESSION, AND MONITOR TREATMENT RESPONSE
NPC2
Niemann–Pick disease type C2
RNA
Biomarkers
Diagnosis
mRNA
Transcription
Treatment
Tuberculosis
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ, Brasil / TWINCORE Centre for Experimental and Clinical Infection Research. Research Group Biomarkers for Infectious Diseases. Hannover, Germany.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
Immunology Program, Memorial Sloan Kettering Cancer Center. New York, NY, USA / Weill Cornell Medicine. Clinical and Translational Science Center. New York, NY, USA.
Immunology Program, Memorial Sloan Kettering Cancer Center. New York, NY, USA / Stony Brook University. Division of Infectious Diseases, Renaissance School of Medicine. Stony Brook, NY, USA.
TWINCORE Centre for Experimental and Clinical Infection Research. Research Group Biomarkers for Infectious Diseases. Hannover, Germany / Centre for Individualised Infection Medicine. Hannover, Germany / Helmholtz Center for Infection Research. Braunschweig, Germany.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
Immunology Program, Memorial Sloan Kettering Cancer Center. New York, NY, USA / Weill Cornell Medicine. Clinical and Translational Science Center. New York, NY, USA.
Immunology Program, Memorial Sloan Kettering Cancer Center. New York, NY, USA / Stony Brook University. Division of Infectious Diseases, Renaissance School of Medicine. Stony Brook, NY, USA.
TWINCORE Centre for Experimental and Clinical Infection Research. Research Group Biomarkers for Infectious Diseases. Hannover, Germany / Centre for Individualised Infection Medicine. Hannover, Germany / Helmholtz Center for Infection Research. Braunschweig, Germany.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ, Brasil.
Abstract
External validation in different cohorts is a key step in the translational development of new biomarkers. We previously described three host mRNA whose expression in peripheral blood is significantly higher (NPC2) or lower (DOCK9 and EPHA4) in individuals with TB compared to latent TB infection (LTBI) and controls. We have now conducted an independent validation of these genes by re-analyzing publicly available transcriptomic datasets from Brazil, China, Haiti, India, South Africa, and the United Kingdom. Comparisons between TB and control/LTBI showed significant differential expression of all three genes (NPC2high p < 0.01, DOCK9low p < 0.01, and EPHA4low p < 0.05). NPC2high had the highest mean area under the ROC curve (AUROC) for the differentiation of TB vs. controls (0.95) and LTBI (0.94). In addition, NPC2 accurately distinguished TB from the clinically similar conditions pneumonia (AUROC, 0.88), non-active sarcoidosis (0.87), and lung cancer (0.86), but not from active sarcoidosis (0.66). Interestingly, individuals progressing from LTBI to TB showed a constant increase in NPC2 expression with time when compared to non-progressors (p < 0.05), with a significant change closer to manifestation of active disease (≤3 months, p = 0.003). Moreover, NPC2 expression normalized with completion of anti-TB treatment. Taken together, these results validate NPC2 mRNA as a diagnostic host biomarker for active TB independent of host genetic background. Moreover, they reveal its potential to predict progression from latent to active infection and to indicate a response to anti-TB treatment.
Keywords
Mycobacterium tuberculosisNPC2
Niemann–Pick disease type C2
RNA
Biomarkers
Diagnosis
mRNA
Transcription
Treatment
Tuberculosis
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