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

Achkar JM, Cortes L, Croteau P, Yanofsky C, Mentinova M, Rajotte I, Schirm M, Zhou Y, Junqueira-Kipnis AP, Kasprowicz VO, Larsen M, Allard R, Hunter J, Paramithiotis E - EBioMedicine (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA ; Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Differential expression of candidate TB biomarkers in sera. Protein expression ratios expressed as fold change in subjects with active tuberculosis (TB) relative to uninfected controls (NI) and latent M. tuberculosis infection (LI), or relative to subjects with other respiratory diseases (ORD), in HIV+ or HIV− infected groups. The numerators and denominators per comparison and the color scale are indicated. The ratio range was from 0.2 to 6.6. The HIV− and HIV+ panel members are indicated by * and † respectively.
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f0015: Differential expression of candidate TB biomarkers in sera. Protein expression ratios expressed as fold change in subjects with active tuberculosis (TB) relative to uninfected controls (NI) and latent M. tuberculosis infection (LI), or relative to subjects with other respiratory diseases (ORD), in HIV+ or HIV− infected groups. The numerators and denominators per comparison and the color scale are indicated. The ratio range was from 0.2 to 6.6. The HIV− and HIV+ panel members are indicated by * and † respectively.

Mentions: As anticipated, the comparison of TB to ORD resulted in different expression patterns than the comparison to LTBI (Fig. 3). The presence of an HIV co-infection reduced the overall magnitude of the host response, and induced other more subtle changes. The MRM-MS data was then split into training and test sets to derive biomarker panels able to distinguish TB from ORD (Fig. 1). In the HIV− and HIV+ groups the best single markers had a classification performance (AUC) of up to 0.80 and 0.77, respectively. When used in combinations, a subset of 10 candidates for the HIV− and 8 for the HIV+ groups, distinguished TB from ORD with excellent accuracy (AUC 0.96 and 0.95, respectively; Table 2 and Fig. 4). The AUC reported are average out of sample values and larger studies are needed to establish accurate confidence intervals. The composition of the panels differed according to HIV status but two of the candidates (CD14 and SEPP1) were present in both groups. Of note, we did neither observe significant differences in the biomarker protein expression between smear-positive and smear-negative TB, culture-positive and culture-negative TB, nor pulmonary and extrapulmonary TB, although these subgroup comparisons were limited by very small sample size. Furthermore, our spectrum of ORD included 5 nontuberculous mycobacterial (NTM) diseases in HIV+ patients (Table 1). Comparison of those 5 HIV+ NTM to the 10 HIV+ TB patients showed that 5/8 candidate proteins (SEPP1, PGLYRP2, VASN, CPN2, TAGLN2) were significantly differentially expressed between these two groups. Thus, there appears to be both a partial overlap as well as a TB specific signature of our protein biomarker candidates. Larger studies are needed to determine the accuracy of certain panel proteins to distinguish between TB and NTM disease.


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

Achkar JM, Cortes L, Croteau P, Yanofsky C, Mentinova M, Rajotte I, Schirm M, Zhou Y, Junqueira-Kipnis AP, Kasprowicz VO, Larsen M, Allard R, Hunter J, Paramithiotis E - EBioMedicine (2015)

Differential expression of candidate TB biomarkers in sera. Protein expression ratios expressed as fold change in subjects with active tuberculosis (TB) relative to uninfected controls (NI) and latent M. tuberculosis infection (LI), or relative to subjects with other respiratory diseases (ORD), in HIV+ or HIV− infected groups. The numerators and denominators per comparison and the color scale are indicated. The ratio range was from 0.2 to 6.6. The HIV− and HIV+ panel members are indicated by * and † respectively.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588417&req=5

f0015: Differential expression of candidate TB biomarkers in sera. Protein expression ratios expressed as fold change in subjects with active tuberculosis (TB) relative to uninfected controls (NI) and latent M. tuberculosis infection (LI), or relative to subjects with other respiratory diseases (ORD), in HIV+ or HIV− infected groups. The numerators and denominators per comparison and the color scale are indicated. The ratio range was from 0.2 to 6.6. The HIV− and HIV+ panel members are indicated by * and † respectively.
Mentions: As anticipated, the comparison of TB to ORD resulted in different expression patterns than the comparison to LTBI (Fig. 3). The presence of an HIV co-infection reduced the overall magnitude of the host response, and induced other more subtle changes. The MRM-MS data was then split into training and test sets to derive biomarker panels able to distinguish TB from ORD (Fig. 1). In the HIV− and HIV+ groups the best single markers had a classification performance (AUC) of up to 0.80 and 0.77, respectively. When used in combinations, a subset of 10 candidates for the HIV− and 8 for the HIV+ groups, distinguished TB from ORD with excellent accuracy (AUC 0.96 and 0.95, respectively; Table 2 and Fig. 4). The AUC reported are average out of sample values and larger studies are needed to establish accurate confidence intervals. The composition of the panels differed according to HIV status but two of the candidates (CD14 and SEPP1) were present in both groups. Of note, we did neither observe significant differences in the biomarker protein expression between smear-positive and smear-negative TB, culture-positive and culture-negative TB, nor pulmonary and extrapulmonary TB, although these subgroup comparisons were limited by very small sample size. Furthermore, our spectrum of ORD included 5 nontuberculous mycobacterial (NTM) diseases in HIV+ patients (Table 1). Comparison of those 5 HIV+ NTM to the 10 HIV+ TB patients showed that 5/8 candidate proteins (SEPP1, PGLYRP2, VASN, CPN2, TAGLN2) were significantly differentially expressed between these two groups. Thus, there appears to be both a partial overlap as well as a TB specific signature of our protein biomarker candidates. Larger studies are needed to determine the accuracy of certain panel proteins to distinguish between TB and NTM disease.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA ; Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.

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.

No MeSH data available.


Related in: MedlinePlus