Host Protein Biomarkers Identify Active Tuberculosis in HIV Uninfected and Co-infected Individuals

Highlights

• Active tuberculosis leads to the differential expression of serum proteins involved in associated host processes.

• Serum protein expression changes in tuberculosis involve the immune response, tissue repair, and lipid metabolism.

• Panels of 8–10 host proteins can distinguish active tuberculosis from latent infection, and other respiratory diseases.

Accurate biomarkers for active tuberculosis (TB) are urgently needed to improve rapid diagnosis. Current diagnostics for TB rely on microbiologic or molecular confirmation of M. tuberculosis, and are therefore dependent on a specimen from the site of disease which is not always accessible. This study demonstrates that human host proteins are differentially expressed in TB compared to latent M. tuberculosis infection, or respiratory diseases other than TB. Our data thus provide promise that host proteins have the potential to become the basis of rapid blood tests that do not require a sample from the site of disease.

Abstract

Biomarkers for active tuberculosis (TB) are urgently needed to improve rapid TB diagnosis. The objective of this study was to identify serum protein expression changes associated with TB but not latent Mycobacterium tuberculosis infection (LTBI), uninfected states, or respiratory diseases other than TB (ORD). Serum samples from 209 HIV uninfected (HIV⁻) and co-infected (HIV⁺) individuals were studied. In the discovery phase samples were analyzed via liquid chromatography and mass spectrometry, and in the verification phase biologically independent samples were analyzed via a multiplex multiple reaction monitoring mass spectrometry (MRM-MS) assay. Compared to LTBI and ORD, host proteins were significantly differentially expressed in TB, and involved in the immune response, tissue repair, and lipid metabolism. Biomarker panels whose composition differed according to HIV status, and consisted of 8 host proteins in HIV⁻ individuals (CD14, SEPP1, SELL, TNXB, LUM, PEPD, QSOX1, COMP, APOC1), or 10 host proteins in HIV⁺ individuals (CD14, SEPP1, PGLYRP2, PFN1, VASN, CPN2, TAGLN2, IGFBP6), respectively, distinguished TB from ORD with excellent accuracy (AUC = 0.96 for HIV⁻ TB, 0.95 for HIV⁺ TB). These results warrant validation in larger studies but provide promise that host protein biomarkers could be the basis for a rapid, blood-based test for TB.