Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples

Wenshu Zheng; Sylvia M. LaCourse; Bofan Song; Dhiraj Kumar Singh; Mayank Khanna; Juan Olivo; Joshua Stern; Jaclyn N. Escudero; Carlos Vergara; Fangfang Zhang; Shaobai Li; Shu Wang; Lisa M. Cranmer; Zhen Huang; Christine M. Bojanowski; Duran Bao; Irene Njuguna; Yating Xiao; Dalton C. Wamalwa; Duc T. Nguyen; Li Yang; Elizabeth Maleche-Obimbo; Nhung Nguyen; Lili Zhang; Ha Phan; Jia Fan; Bo Ning; Chenzhong Li; Christopher J. Lyon; Edward A. Graviss; Grace John-Stewart; Charles D. Mitchell; Alistair J. Ramsay; Deepak Kaushal; Rongguang Liang; Eddy Pérez-Then; Tony Y. Hu

doi:10.1038/s41551-022-00922-1

Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples

Wenshu Zheng, Sylvia M. LaCourse, Bofan Song, Dhiraj Kumar Singh, Mayank Khanna, Juan Olivo, Joshua Stern, Jaclyn N. Escudero, Carlos Vergara, Fangfang Zhang, Shaobai Li, Shu Wang, Lisa M. Cranmer, Zhen Huang, Christine M. Bojanowski, Duran Bao, Irene Njuguna, Yating Xiao, Dalton C. Wamalwa, Duc T. NguyenLi Yang, Elizabeth Maleche-Obimbo, Nhung Nguyen, Lili Zhang, Ha Phan, Jia Fan, Bo Ning, Chenzhong Li, Christopher J. Lyon, Edward A. Graviss, Grace John-Stewart, Charles D. Mitchell, Alistair J. Ramsay, Deepak Kaushal, Rongguang Liang, Eddy Pérez-Then, Tony Y. Hu

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53 Scopus citations

Abstract

Sensitive and specific blood-based assays for the detection of pulmonary and extrapulmonary tuberculosis would reduce mortality associated with missed diagnoses, particularly in children. Here we report a nanoparticle-enhanced immunoassay read by dark-field microscopy that detects two Mycobacterium tuberculosis virulence factors (the glycolipid lipoarabinomannan and its carrier protein) on the surface of circulating extracellular vesicles. In a cohort study of 147 hospitalized and severely immunosuppressed children living with HIV, the assay detected 58 of the 78 (74%) cases of paediatric tuberculosis, 48 of the 66 (73%) cases that were missed by microbiological assays, and 8 out of 10 (80%) cases undiagnosed during the study. It also distinguished tuberculosis from latent-tuberculosis infections in non-human primates. We adapted the assay to make it portable and operable by a smartphone. With further development, the assay may facilitate the detection of tuberculosis at the point of care, particularly in resource-limited settings.

Original language	English (US)
Pages (from-to)	979-991
Number of pages	13
Journal	Nature Biomedical Engineering
Volume	6
Issue number	8
DOIs	https://doi.org/10.1038/s41551-022-00922-1
State	Published - Aug 2022

Keywords

Animals
Cohort Studies
Extracellular Vesicles
Humans
Mycobacterium tuberculosis
Tuberculosis/diagnosis
Virulence Factors

ASJC Scopus subject areas

Bioengineering
Biotechnology
Biomedical Engineering
Medicine (miscellaneous)
Computer Science Applications

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10.1038/s41551-022-00922-1

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Zheng, W., LaCourse, S. M., Song, B., Singh, D. K., Khanna, M., Olivo, J., Stern, J., Escudero, J. N., Vergara, C., Zhang, F., Li, S., Wang, S., Cranmer, L. M., Huang, Z., Bojanowski, C. M., Bao, D., Njuguna, I., Xiao, Y., Wamalwa, D. C., ... Hu, T. Y. (2022). Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples. Nature Biomedical Engineering, 6(8), 979-991. https://doi.org/10.1038/s41551-022-00922-1

Zheng, W, LaCourse, SM, Song, B, Singh, DK, Khanna, M, Olivo, J, Stern, J, Escudero, JN, Vergara, C, Zhang, F, Li, S, Wang, S, Cranmer, LM, Huang, Z, Bojanowski, CM, Bao, D, Njuguna, I, Xiao, Y, Wamalwa, DC, Nguyen, DT, Yang, L, Maleche-Obimbo, E, Nguyen, N, Zhang, L, Phan, H, Fan, J, Ning, B, Li, C, Lyon, CJ, Graviss, EA, John-Stewart, G, Mitchell, CD, Ramsay, AJ, Kaushal, D, Liang, R, Pérez-Then, E & Hu, TY 2022, 'Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples', Nature Biomedical Engineering, vol. 6, no. 8, pp. 979-991. https://doi.org/10.1038/s41551-022-00922-1

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title = "Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples",

abstract = "Sensitive and specific blood-based assays for the detection of pulmonary and extrapulmonary tuberculosis would reduce mortality associated with missed diagnoses, particularly in children. Here we report a nanoparticle-enhanced immunoassay read by dark-field microscopy that detects two Mycobacterium tuberculosis virulence factors (the glycolipid lipoarabinomannan and its carrier protein) on the surface of circulating extracellular vesicles. In a cohort study of 147 hospitalized and severely immunosuppressed children living with HIV, the assay detected 58 of the 78 (74%) cases of paediatric tuberculosis, 48 of the 66 (73%) cases that were missed by microbiological assays, and 8 out of 10 (80%) cases undiagnosed during the study. It also distinguished tuberculosis from latent-tuberculosis infections in non-human primates. We adapted the assay to make it portable and operable by a smartphone. With further development, the assay may facilitate the detection of tuberculosis at the point of care, particularly in resource-limited settings.",

keywords = "Animals, Cohort Studies, Extracellular Vesicles, Humans, Mycobacterium tuberculosis, Tuberculosis/diagnosis, Virulence Factors",

author = "Wenshu Zheng and LaCourse, {Sylvia M.} and Bofan Song and Singh, {Dhiraj Kumar} and Mayank Khanna and Juan Olivo and Joshua Stern and Escudero, {Jaclyn N.} and Carlos Vergara and Fangfang Zhang and Shaobai Li and Shu Wang and Cranmer, {Lisa M.} and Zhen Huang and Bojanowski, {Christine M.} and Duran Bao and Irene Njuguna and Yating Xiao and Wamalwa, {Dalton C.} and Nguyen, {Duc T.} and Li Yang and Elizabeth Maleche-Obimbo and Nhung Nguyen and Lili Zhang and Ha Phan and Jia Fan and Bo Ning and Chenzhong Li and Lyon, {Christopher J.} and Graviss, {Edward A.} and Grace John-Stewart and Mitchell, {Charles D.} and Ramsay, {Alistair J.} and Deepak Kaushal and Rongguang Liang and Eddy P{\'e}rez-Then and Hu, {Tony Y.}",

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year = "2022",

month = aug,

doi = "10.1038/s41551-022-00922-1",

language = "English (US)",

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AU - Zheng, Wenshu

AU - LaCourse, Sylvia M.

AU - Song, Bofan

AU - Singh, Dhiraj Kumar

AU - Khanna, Mayank

AU - Olivo, Juan

AU - Stern, Joshua

AU - Escudero, Jaclyn N.

AU - Vergara, Carlos

AU - Zhang, Fangfang

AU - Li, Shaobai

AU - Wang, Shu

AU - Cranmer, Lisa M.

AU - Huang, Zhen

AU - Bojanowski, Christine M.

AU - Bao, Duran

AU - Njuguna, Irene

AU - Xiao, Yating

AU - Wamalwa, Dalton C.

AU - Nguyen, Duc T.

AU - Yang, Li

AU - Maleche-Obimbo, Elizabeth

AU - Nguyen, Nhung

AU - Zhang, Lili

AU - Phan, Ha

AU - Fan, Jia

AU - Ning, Bo

AU - Li, Chenzhong

AU - Lyon, Christopher J.

AU - Graviss, Edward A.

AU - John-Stewart, Grace

AU - Mitchell, Charles D.

AU - Ramsay, Alistair J.

AU - Kaushal, Deepak

AU - Liang, Rongguang

AU - Pérez-Then, Eddy

AU - Hu, Tony Y.

PY - 2022/8

Y1 - 2022/8

N2 - Sensitive and specific blood-based assays for the detection of pulmonary and extrapulmonary tuberculosis would reduce mortality associated with missed diagnoses, particularly in children. Here we report a nanoparticle-enhanced immunoassay read by dark-field microscopy that detects two Mycobacterium tuberculosis virulence factors (the glycolipid lipoarabinomannan and its carrier protein) on the surface of circulating extracellular vesicles. In a cohort study of 147 hospitalized and severely immunosuppressed children living with HIV, the assay detected 58 of the 78 (74%) cases of paediatric tuberculosis, 48 of the 66 (73%) cases that were missed by microbiological assays, and 8 out of 10 (80%) cases undiagnosed during the study. It also distinguished tuberculosis from latent-tuberculosis infections in non-human primates. We adapted the assay to make it portable and operable by a smartphone. With further development, the assay may facilitate the detection of tuberculosis at the point of care, particularly in resource-limited settings.

AB - Sensitive and specific blood-based assays for the detection of pulmonary and extrapulmonary tuberculosis would reduce mortality associated with missed diagnoses, particularly in children. Here we report a nanoparticle-enhanced immunoassay read by dark-field microscopy that detects two Mycobacterium tuberculosis virulence factors (the glycolipid lipoarabinomannan and its carrier protein) on the surface of circulating extracellular vesicles. In a cohort study of 147 hospitalized and severely immunosuppressed children living with HIV, the assay detected 58 of the 78 (74%) cases of paediatric tuberculosis, 48 of the 66 (73%) cases that were missed by microbiological assays, and 8 out of 10 (80%) cases undiagnosed during the study. It also distinguished tuberculosis from latent-tuberculosis infections in non-human primates. We adapted the assay to make it portable and operable by a smartphone. With further development, the assay may facilitate the detection of tuberculosis at the point of care, particularly in resource-limited settings.

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KW - Cohort Studies

KW - Extracellular Vesicles

KW - Humans

KW - Mycobacterium tuberculosis

KW - Tuberculosis/diagnosis

KW - Virulence Factors

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JO - Nature Biomedical Engineering

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Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples

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