CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice.

Autor: Koyuncu D; Rensselaer Polytechnic Institute, Department of Electrical, Computer, and Systems Engineering, Troy, New York, United States of America., Niazi MKK; Wake Forest School of Medicine, Bowman Gray Center for Medical Education, Winston-Salem, North Carolina, United States of America., Tavolara T; Wake Forest School of Medicine, Bowman Gray Center for Medical Education, Winston-Salem, North Carolina, United States of America., Abeijon C; Tufts University, Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America., Ginese ML; Tufts University, Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America., Liao Y; Nanyang Technological University, Singapore., Mark C; Kansas State University, College of Veterinary Medicine, Manhattan, Kansas, United States of America., Specht A; Tufts University, Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America., Gower AC; Boston University Clinical and Translational Science Institute, Boston, Massachusetts, United States of America., Restrepo BI; The University of Texas Health Science Center at Houston School of Public Health in Brownsville, Texas, United States of America., Gatti DM; The Jackson Laboratory, Bar Harbor, Maine, United States of America., Kramnik I; Boston University, National Emerging Infectious Diseases Laboratories, Boston, Massachusetts, United States of America., Gurcan M; Wake Forest School of Medicine, Bowman Gray Center for Medical Education, Winston-Salem, North Carolina, United States of America., Yener B; Rensselaer Polytechnic Institute, Department of Computer Science, Troy, New York, United States of America., Beamer G; Tufts University, Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2021 Aug 17; Vol. 17 (8), pp. e1009773. Date of Electronic Publication: 2021 Aug 17 (Print Publication: 2021).
DOI: 10.1371/journal.ppat.1009773
Abstrakt: More humans have died of tuberculosis (TB) than any other infectious disease and millions still die each year. Experts advocate for blood-based, serum protein biomarkers to help diagnose TB, which afflicts millions of people in high-burden countries. However, the protein biomarker pipeline is small. Here, we used the Diversity Outbred (DO) mouse population to address this gap, identifying five protein biomarker candidates. One protein biomarker, serum CXCL1, met the World Health Organization's Targeted Product Profile for a triage test to diagnose active TB from latent M.tb infection (LTBI), non-TB lung disease, and normal sera in HIV-negative, adults from South Africa and Vietnam. To find the biomarker candidates, we quantified seven immune cytokines and four inflammatory proteins corresponding to highly expressed genes unique to progressor DO mice. Next, we applied statistical and machine learning methods to the data, i.e., 11 proteins in lungs from 453 infected and 29 non-infected mice. After searching all combinations of five algorithms and 239 protein subsets, validating, and testing the findings on independent data, two combinations accurately diagnosed progressor DO mice: Logistic Regression using MMP8; and Gradient Tree Boosting using a panel of 4: CXCL1, CXCL2, TNF, IL-10. Of those five protein biomarker candidates, two (MMP8 and CXCL1) were crucial for classifying DO mice; were above the limit of detection in most human serum samples; and had not been widely assessed for diagnostic performance in humans before. In patient sera, CXCL1 exceeded the triage diagnostic test criteria (>90% sensitivity; >70% specificity), while MMP8 did not. Using Area Under the Curve analyses, CXCL1 averaged 94.5% sensitivity and 88.8% specificity for active pulmonary TB (ATB) vs LTBI; 90.9% sensitivity and 71.4% specificity for ATB vs non-TB; and 100.0% sensitivity and 98.4% specificity for ATB vs normal sera. Our findings overall show that the DO mouse population can discover diagnostic-quality, serum protein biomarkers of human TB.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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