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

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....

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Autores principales:	Deniz Koyuncu, Muhammad Khalid Khan Niazi, Thomas Tavolara, Claudia Abeijon, Melanie L Ginese, Yanghui Liao, Carolyn Mark, Aubrey Specht, Adam C Gower, Blanca I Restrepo, Daniel M Gatti, Igor Kramnik, Metin Gurcan, Bülent Yener, Gillian Beamer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6791769b2d6943c1ae030343c587d806
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spelling	oai:doaj.org-article:6791769b2d6943c1ae030343c587d8062021-12-02T20:00:23ZCXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice.1553-73661553-737410.1371/journal.ppat.1009773https://doaj.org/article/6791769b2d6943c1ae030343c587d8062021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009773https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374More 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.Deniz KoyuncuMuhammad Khalid Khan NiaziThomas TavolaraClaudia AbeijonMelanie L GineseYanghui LiaoCarolyn MarkAubrey SpechtAdam C GowerBlanca I RestrepoDaniel M GattiIgor KramnikMetin GurcanBülent YenerGillian BeamerPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 8, p e1009773 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Deniz Koyuncu Muhammad Khalid Khan Niazi Thomas Tavolara Claudia Abeijon Melanie L Ginese Yanghui Liao Carolyn Mark Aubrey Specht Adam C Gower Blanca I Restrepo Daniel M Gatti Igor Kramnik Metin Gurcan Bülent Yener Gillian Beamer CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice.
description	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.
format	article
author	Deniz Koyuncu Muhammad Khalid Khan Niazi Thomas Tavolara Claudia Abeijon Melanie L Ginese Yanghui Liao Carolyn Mark Aubrey Specht Adam C Gower Blanca I Restrepo Daniel M Gatti Igor Kramnik Metin Gurcan Bülent Yener Gillian Beamer
author_facet	Deniz Koyuncu Muhammad Khalid Khan Niazi Thomas Tavolara Claudia Abeijon Melanie L Ginese Yanghui Liao Carolyn Mark Aubrey Specht Adam C Gower Blanca I Restrepo Daniel M Gatti Igor Kramnik Metin Gurcan Bülent Yener Gillian Beamer
author_sort	Deniz Koyuncu
title	CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice.
title_short	CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice.
title_full	CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice.
title_fullStr	CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice.
title_full_unstemmed	CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice.
title_sort	cxcl1: a new diagnostic biomarker for human tuberculosis discovered using diversity outbred mice.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/6791769b2d6943c1ae030343c587d806
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CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice.

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