Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Scientific Reports
  • View all journals
  • Search
  • My Account Login
  • Content Explore content
  • About the journal
  • Publish with us
  • Sign up for alerts
  • RSS feed
  1. nature
  2. scientific reports
  3. articles
  4. article
The value of the monocyte-to-lymphocyte ratio and osteopontin (SPP1) in tuberculosis treatment response monitoring
Download PDF
Download PDF
  • Article
  • Open access
  • Published: 01 April 2026

The value of the monocyte-to-lymphocyte ratio and osteopontin (SPP1) in tuberculosis treatment response monitoring

  • Bongani Motaung1 na1,
  • Anne-Rika Holtzhausen1 na1,
  • Kim Stanley2,
  • Ilana van Rensburg2,
  • Candice I. Snyders2 &
  • …
  • Andre G. Loxton1 

Scientific Reports , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cytokines
  • Tuberculosis

Abstract

There is an urgent need to rapidly diagnose tuberculosis (TB) disease and effectively monitor anti-TB treatment responses. Host-directed therapy (HDT) is a promising platform to mitigate challenges in TB diagnosis and anti-TB treatment response monitoring. Identifying changes in systemic proteins and immune cell distributions during the disease is an integral aspect of developing targeted therapies. Here, samples were collected from healthy individuals (CTRL) [n = 32 plasma, n = 9 bronchoalveolar lavage (BAL)] and newly diagnosed TB patients (TB treatment group) [n = 82 plasma, n = 28 BAL] to analyze full blood count, secreted levels of full-length osteopontin (OPN), and inflammatory markers. Peripheral blood and BAL samples were collected at a single time-point from CTRL, while in TB participants, they were collected at TB diagnosis (TBDx), week 1 (TBW1), month 2 (TBM2), and month 6 (TBM6). We observed a significantly increased monocyte-to-lymphocyte ratio (MLR) and plasma OPN in TB group at TBDx compared to the CTRL group. Inflammatory markers including IL-6, VEGF-A, and sFasL showed significant increase at TBDx when compared to CTRL, but these significantly declined by TBM6. Plasma OPN significantly declined at TBW1 and TBM2 when compared to TBDx but significantly increased at TBM6. BAL OPN showed no significant differences between CTRL and TB patients at TBDx, whereas a significant increase was observed in TB group between TBDx and TBM6. Given the study limitations, these findings should be considered preliminary and exploratory. Our results add to literature and identify MLR and plasma OPN as potential targets for early TB diagnosis and treatment monitoring.

Similar content being viewed by others

Identification of host biomarkers from dried blood spots for monitoring treatment response in extrapulmonary tuberculosis

Article Open access 12 January 2023

Tuberculosis after allogeneic hematopoietic stem cell transplantation: a decade nationwide case-control retrospective study in low-incidence country

Article 10 March 2026

Host response biomarkers of tuberculosis recurrence and treatment failure

Article Open access 14 February 2026

Data availability

Data are contained within the article.

References

  1. Global tuberculosis report 2025. Geneva: World Health Organization [Internet]. Geneva. (2025). Available from: https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global-tuberculosis-report-2025

  2. Dheda, K. et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med. 5 (4), 291–360 (2017).

    Google Scholar 

  3. Geneva & World Health Organization. ; Practical manual on tuberculosis laboratory strengthening, 2022 update [Internet]. (2022). Available from: https://iris.who.int/server/api/core/bitstreams/6ed85122-48a2-437e-a47c-e4a0709728d9/content

  4. Parrish, N. M. & Carroll, K. C. Role of the Clinical Mycobacteriology Laboratory in Diagnosis and Management of Tuberculosis in Low-Prevalence Settings. J. Clin. Microbiol. 49 (3), 772–776 (2011).

    Google Scholar 

  5. Lawn, S. D. et al. Advances in tuberculosis diagnostics: The Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect. Dis. 13(4), 349–61 (2013).

    Google Scholar 

  6. Naranbhai, V. et al. Ratio of Monocytes to Lymphocytes in Peripheral Blood Identifies Adults at Risk of Incident Tuberculosis Among HIV-Infected Adults Initiating Antiretroviral Therapy. J. Infect. Dis. 209 (4), 500–509 (2014).

    Google Scholar 

  7. La Manna, M. P. et al. Quantitative and qualitative profiles of circulating monocytes may help identifying tuberculosis infection and disease stages. Wilkinson KA, editor. PLOS ONE. 12(2): e0171358. (2017).

  8. Estévez, O. et al. Multi-parameter flow cytometry immunophenotyping distinguishes different stages of tuberculosis infection. J. Infect. 81(1), 57–71 (2020).

    Google Scholar 

  9. Grassi, G. et al. PMN-MDSC frequency discriminates active versus latent tuberculosis and could play a role in counteracting the immune-mediated lung damage in active disease. Front. Immunol. 12, 594376 (2021).

    Google Scholar 

  10. Denhardt, D. T., Noda, M., O’Regan, A. W., Pavlin, D. & Berman, J. S. Osteopontin as a means to cope with environmental insults: Regulation of inflammation, tissue remodeling, and cell survival. J. Clin. Invest. 107(9), 7 (2001).

    Google Scholar 

  11. Nyström, T., Dunér, P. & Hultgårdh-Nilsson, A. A constitutive endogenous osteopontin production is important for macrophage function and differentiation. Exp. Cell Res. 313(6), 1149–1160 (2007).

    Google Scholar 

  12. Koh, A. et al. Role of osteopontin in neutrophil function. Immunology 122 (4), 466–475 (2007).

    Google Scholar 

  13. Nishimichi, N. et al. Osteopontin Undergoes Polymerization in Vivo and Gains Chemotactic Activity for Neutrophils Mediated by Integrin α9β1. J. Biol. Chem. 286 (13), 11170–11178 (2011).

    Google Scholar 

  14. Xiang, J. et al. Preoperative monocyte-to-lymphocyte ratio in peripheral blood predicts stages, metastasis, and histological grades in patients with ovarian cancer. Transl. Oncol. 10(1), 33–9 (2017).

    Google Scholar 

  15. Huang, Y. et al. Relationship between monocytes to lymphocytes ratio and axial spondyloarthritis. Int. Immunopharmacol. 57, 43–6 (2018).

    Google Scholar 

  16. Domingo-Gonzalez, R., Prince, O., Cooper, A. & Khader, S. A. Cytokines and Chemokines in Mycobacterium tuberculosis Infection. Microbiol. Spectr. 4(5), TBTB2-0018-2016. https://doi.org/10.1128/microbiolspec.TBTB2-0018-2016 (2016).

    Google Scholar 

  17. Giachelli, C. M., Lombardi, D., Johnson, R. J. & Almeida, M. Evidence for a Role of Osteopontin in Macrophage Infiltration in Response to Pathological Stimuli in vivo. Am. J. Pathol. 152(2), 353–358 (1998).

  18. Weber, G. F. et al. Phosphorylation-dependent interaction of osteopontin with its receptors regulates macrophage migration and activation. J. Leukoc. Biol. 72(4), 752–761. https://doi.org/10.1189/jlb.72.4.752 (2002).

    Google Scholar 

  19. Crawford, H. C., Matrisian, L. M. & Liaw, L. Distinct Roles of Osteopontin in Host Defense Activity and Tumor Survival during Squamous Cell Carcinoma Progression in vivo. Cancer Res. 58(22), 5206–5215 (1998).

  20. Scatena, M., Liaw, L. & Giachelli, C. M. Osteopontin: A multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler. Thromb. Vasc. Biol. 27(11), 2302–2309 (2007).

    Google Scholar 

  21. Inoue, M. & Shinohara, M. L. Intracellular osteopontin (iOPN) and immunity. Immunol. Res. 49(1–3), 160–72 (2011).

    Google Scholar 

  22. Masuda, K., Takahashi, N., Tsukamoto, Y., Honma, H. & Kohri, K. N-glycan structures of an osteopontin from human bone. Biochem. Biophys. Res. Commun. 268(3), 814–817 (2000).

    Google Scholar 

  23. Cho, E. H., Cho, K. H., Lee, H. A. & Kim, S. W. High serum osteopontin levels are associated with low bone mineral density in postmenopausal women. J. Korean Med. Sci. 28(10), 1496 (2013).

    Google Scholar 

  24. Koguchi, Y. et al. High plasma osteopontin level and its relationship with interleukin-12-mediated type 1 T helper cell response in tuberculosis. Am. J. Respir Crit. Care Med. 167 (10), 1355–1359 (2003).

    Google Scholar 

  25. Nau, G. J. et al. A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proc. Natl. Acad. Sci. 94 (12), 6414–6419 (1997).

    Google Scholar 

  26. Liaw, L. et al. Altered Wound Healing in Mice Lacking a Functional Osteopontin Gene (spp1). J Clin Invest https://doi.org/10.1172/JCI1122 (1998).

    Google Scholar 

  27. Ragno, S. et al. Changes in gene expression in macrophages infected with Mycobacterium tuberculosis: A combined transcriptomic and proteomic approach. Immunology 104(1), 99–108 (2001).

    Google Scholar 

  28. Kanayama, M. et al. Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin. Nat Immunol 18(9), 973–84 (2017).

    Google Scholar 

  29. Denhardt, D. T. & Guo, X. Osteopontin: A protein with diverse functions. FASEB J. 7(15), 1475–82 (1993).

    Google Scholar 

  30. O’Regan, A. W., Hayden, J. M. & Berman, J. S. Osteopontin augments CD3-mediated interferon-gamma and CD40 ligand expression by T cells, which results in IL-12 production from peripheral blood mononuclear cells. J Leukoc Biol https://doi.org/10.1189/jlb.68.4.495 (2000).

  31. Patarca, R. et al. Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection. J. Exp. Med. 170 (1), 145–161 (1989).

    Google Scholar 

  32. Uede, T. Osteopontin, intrinsic tissue regulator of intractable inflammatory diseases: Osteopontin, cytokine or matrix protein? Pathol. Int. 61 (5), 265–280 (2011).

    Google Scholar 

  33. Shete, A. et al. Elevated Levels of Galectin-9 but Not Osteopontin in HIV and Tuberculosis Infections Indicate Their Roles in Detecting MTB Infection in HIV Infected Individuals. Front. Microbiol. 11, 1685 (2020).

    Google Scholar 

  34. Shiratori, B. et al. Elevated OPN, IP-10, and Neutrophilia in Loop-Mediated Isothermal Amplification Confirmed Tuberculosis Patients. Mediators Inflamm. 2014, 1–8 (2014).

    Google Scholar 

  35. Zhu, Y. et al. Decreased Osteopontin Expression as a Reliable Prognostic Indicator of Improvement in Pulmonary Tuberculosis: Impact of the Level of Interferon-γ-Inducible Protein 10. Cell. Physiol. Biochem. 37 (5), 1983–1996 (2015).

    Google Scholar 

  36. Hasibuan, F. M. et al. Evaluation of matricellular proteins in systemic and local immune response to Mycobacterium tuberculosis infection: Matricellular proteins in tuberculosis. Microbiol. Immunol. 59 (10), 623–632 (2015).

    Google Scholar 

  37. Shiratori, B. et al. Immunological Roles of Elevated Plasma Levels of Matricellular Proteins in Japanese Patients with Pulmonary Tuberculosis. Int. J. Mol. Sci. 18 (1), 19 (2016).

    Google Scholar 

  38. Wang, D. et al. The association between osteopontin and tuberculosis: A systematic review and meta-analysis. Rottenberg ME, editor. PLOS ONE. 15(12):e0242702. (2020).

  39. Heilmann, K. et al. Osteopontin as two-sided mediator of intestinal inflammation. J. Cell. Mol. Med. 13 (6), 1162–1174 (2009).

    Google Scholar 

  40. Kourepini, E. et al. Osteopontin expression by CD103 – dendritic cells drives intestinal inflammation. Proc. Natl. Acad. Sci. 111 (9), E856–E865 (2014).

    Google Scholar 

  41. Toyonaga, T. et al. Osteopontin Deficiency Accelerates Spontaneous Colitis in Mice with Disrupted Gut Microbiota and Macrophage Phagocytic Activity. Bamias G, editor. PLOS ONE. 10(8):e0135552. (2015).

  42. Gupte, A. N. et al. Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: A multisite discovery and validation study. Eur. Respir. J. 59(4), 2100905 (2022).

    Google Scholar 

  43. Djoba Siawaya, J. F., Beyers, N., van Helden, P. & Walzl, G. Differential cytokine secretion and early treatment response in patients with pulmonary tuberculosis. Clin. Exp. Immunol. 156 (1), 69–77 (2009).

    Google Scholar 

  44. Gao, K. et al. Diagnostic value of the blood monocyte–lymphocyte ratio in knee osteoarthritis. J. Int. Med. Res. 47(9), 4413–21 (2019).

    Google Scholar 

  45. Wang, J. et al. Ratio of monocytes to lymphocytes in peripheral blood in patients diagnosed with active tuberculosis. Braz. J. Infect. Dis. 19(2), 125–31 (2015).

    Google Scholar 

  46. Naranbhai, V. et al. Distinct transcriptional and anti-mycobacterial profiles of peripheral blood monocytes dependent on the ratio of monocytes: Lymphocytes. EBioMedicine 2(11), 1619–26 (2015).

    Google Scholar 

  47. Zhou, Q., Shao, X., Xu, L., Zou, H. & Chen, W. Association between monocyte-to-lymphocyte ratio and inflammation in chronic kidney disease: A cross-sectional study. Kidney Blood Press. Res. 49(1), 1066–1074 (2024).

    Google Scholar 

  48. Li, X. et al. Association between monocyte-to-lymphocyte ratio and cardiovascular diseases: Insights from NHANES data. Diabetol. Metab. Syndr. 17(1), 98 (2025).

    Google Scholar 

  49. Kösehasanoğulları, M., Bilecik, N. A., Şen, S. B. & Koçyiğit, B. F. Elevated Monocyte-to-Lymphocyte and Platelet-to-Lymphocyte Ratios Are Associated with Disease Activity and Pain in Fibromyalgia: A Cross-Sectional Study. J. Clin. Med. 15 (1), 155 (2025).

    Google Scholar 

  50. Bot, F. J., van Eijk, L., Broeders, L., Aarden, L. A. & Löwenberg, B. Interleukin-6 synergizes with M-CSF in the formation of macrophage colonies from purified human marrow progenitor cells. Blood 73(2), 435–7 (1989).

    Google Scholar 

  51. Maeda, K. et al. Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals. Blood 113 (19), 4534–4540 (2009).

    Google Scholar 

  52. Kethireddy, S. et al. Mycobacterium tuberculosis septic shock. Chest 144(2), 474–82 (2013).

    Google Scholar 

  53. Shamaei, M. et al. Tuberculosis-Associated Secondary Pneumothorax: A Retrospective Study of 53 Patients. Respir Care. 56 (3), 298–302 (2011).

    Google Scholar 

  54. Jordan, T. S., Spencer, E. M. & Davies, P. Tuberculosis, bronchiectasis and chronic airflow obstruction: Tuberculosis, Bronchiectasis and CAO. Respirology 15 (4), 623–628 (2010).

    Google Scholar 

  55. Kuo, S. C. et al. Association between tuberculosis infections and non-pulmonary malignancies: A nationwide population-based study. Br. J. Cancer 109(1), 229–34 (2013).

    Google Scholar 

  56. Chen, Y. Y. et al. Increased risk of incident osteoporosis and osteoporotic fracture in tuberculosis patients: A population-based study in a tuberculosis-endemic area. Osteoporos. Int. 28(5), 1711–21 (2017).

    Google Scholar 

  57. Azzurri, A. et al. IFN-γ-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in Mycobacterium tuberculosis infection. Microbes Infect. 7(1), 1–8 (2005).

    Google Scholar 

  58. Su, W. L. et al. Association of reduced tumor necrosis factor alpha, gamma interferon, and interleukin-1β (IL-1β) but increased IL-10 expression with improved chest radiography in patients with pulmonary tuberculosis. Clin. Vaccine Immunol. 17(2), 223–231 (2010).

    Google Scholar 

  59. Ronacher, K. et al. Distinct serum biosignatures are associated with different tuberculosis treatment outcomes. Tuberculosis 118, 101859 (2019).

    Google Scholar 

  60. Hong, J. Y. et al. Efficacy of IP-10 as a biomarker for monitoring tuberculosis treatment. J. Infect. 68(3), 252–8 (2014).

    Google Scholar 

  61. Kumar, N. P. et al. Plasma chemokines are baseline predictors of unfavorable treatment outcomes in pulmonary tuberculosis. Clin. Infect. Dis. ;ciaa1104. (2020).

  62. de Oliveira, L. R. C. et al. da, Analysis of Toll-Like Receptors, iNOS and Cytokine Profiles in Patients with Pulmonary Tuberculosis during Anti-Tuberculosis Treatment. Torrelles JB, editor. PLoS ONE. 9(2): e88572. (2014).

  63. Jacobs, A. J., Mongkolsapaya, J., Screaton, G. R., McShane, H. & Wilkinson, R. J. Antibodies and tuberculosis. Tuberculosis 101, 102–13 (2016).

    Google Scholar 

Download references

Acknowledgements

The authors thank the participants and members of the Immunology Research Group for providing the samples.

Funding

AGL and BM is funded by the Centre for Tuberculosis Research (CTR) of the South African Medical Research Council (SAMRC). AGL is supported by the National Research Foundation (NRF) [CSUR Grant number 60502163639] and by the Trails of Excellence in Southern Africa (TESA) III of the European Development and Clinical Trails Partnership (EDCTP) [Grant number CSA2020NoE-3104].

Author information

Author notes
  1. These authors contributed equally to this work: Bongani Motaung and Anne-Rika Holtzhausen.

Authors and Affiliations

  1. DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape, South Africa

    Bongani Motaung, Anne-Rika Holtzhausen & Andre G. Loxton

  2. DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Immunology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    Kim Stanley, Ilana van Rensburg & Candice I. Snyders

Authors
  1. Bongani Motaung
    View author publications

    Search author on:PubMed Google Scholar

  2. Anne-Rika Holtzhausen
    View author publications

    Search author on:PubMed Google Scholar

  3. Kim Stanley
    View author publications

    Search author on:PubMed Google Scholar

  4. Ilana van Rensburg
    View author publications

    Search author on:PubMed Google Scholar

  5. Candice I. Snyders
    View author publications

    Search author on:PubMed Google Scholar

  6. Andre G. Loxton
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Conceptualization, A.G.L.; methodology, B.M., A.H., C.I.S., and I.R.; formal analysis, K.S.; writing—original draft preparation, B.M. and A.H.; writing—review and editing, K.S., I.R., C.I.S; supervision, A.G.L.; funding acquisition, A.G.L. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Andre G. Loxton.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Motaung, B., Holtzhausen, AR., Stanley, K. et al. The value of the monocyte-to-lymphocyte ratio and osteopontin (SPP1) in tuberculosis treatment response monitoring. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46176-8

Download citation

  • Received: 11 April 2025

  • Accepted: 24 March 2026

  • Published: 01 April 2026

  • DOI: https://doi.org/10.1038/s41598-026-46176-8

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Keywords

  • OPN
  • Cytokines
  • MLR
  • Tuberculosis
  • Biomarker
  • Treatment response
Download PDF

Advertisement

Explore content

  • Research articles
  • News & Comment
  • Collections
  • Subjects
  • Follow us on Facebook
  • Follow us on X
  • Sign up for alerts
  • RSS feed

About the journal

  • About Scientific Reports
  • Contact
  • Journal policies
  • Guide to referees
  • Calls for Papers
  • Editor's Choice
  • Journal highlights
  • Open Access Fees and Funding

Publish with us

  • For authors
  • Language editing services
  • Open access funding
  • Submit manuscript

Search

Advanced search

Quick links

  • Explore articles by subject
  • Find a job
  • Guide to authors
  • Editorial policies

Scientific Reports (Sci Rep)

ISSN 2045-2322 (online)

nature.com footer links

About Nature Portfolio

  • About us
  • Press releases
  • Press office
  • Contact us

Discover content

  • Journals A-Z
  • Articles by subject
  • protocols.io
  • Nature Index

Publishing policies

  • Nature portfolio policies
  • Open access

Author & Researcher services

  • Reprints & permissions
  • Research data
  • Language editing
  • Scientific editing
  • Nature Masterclasses
  • Research Solutions

Libraries & institutions

  • Librarian service & tools
  • Librarian portal
  • Open research
  • Recommend to library

Advertising & partnerships

  • Advertising
  • Partnerships & Services
  • Media kits
  • Branded content

Professional development

  • Nature Awards
  • Nature Careers
  • Nature Conferences

Regional websites

  • Nature Africa
  • Nature China
  • Nature India
  • Nature Japan
  • Nature Middle East
  • Privacy Policy
  • Use of cookies
  • Legal notice
  • Accessibility statement
  • Terms & Conditions
  • Your US state privacy rights
Springer Nature

© 2026 Springer Nature Limited

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing