Abstract
Human T-cell lymphotropic virus type 1 (HTLV-1) can induce a neuroinflammatory condition that leads to myelopathy. Pentraxin 3 (PTX3) is an acute-phase protein that its plasma concentration increases during inflammation. We aimed to determine whether PTX3 serum level is elevated in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and HTLV-1 asymptomatic carriers (ACs) and evaluate its association with proviral load and clinical features. The serum level of PTX3 was measured using an enzyme-linked immunosorbent assay in 30 HAM patients, 30 HTLV-1 ACs, and 30 healthy controls. Also, the HTLV-1 proviral load was determined via real-time PCR technique. The findings showed that PTX3 serum level was significantly higher in HAM patients than in both asymptomatic carriers and healthy controls (p values < 0.0001). No correlation between PTX3 and the proviral load was observed in HAM patients and asymptomatic carriers (r = − 0.238, p = 0.205 and r = − 0.078, p = 0.681, respectively). The findings showed that there was no significant correlation between PTX3 and motor disability grading (MDG) (r = − 0.155, p = 0.41) nor urinary disturbance score (UDS) (r = − 0.238, p = 0.20). Higher levels of PTX3 are associated with HTLV-1-associated myelopathy compared to asymptomatic carriers. This finding may support the idea that PTX3 has the potential as a diagnostic biomarker.
Similar content being viewed by others
Data availability statement
The data generated or analyzed during this study are available from corresponding author on reasonable request.
References
Gessain A, Cassar O (2012) Epidemiological aspects and world distribution of HTLV-1 infection. Front Microbiol 15(3):388. https://doi.org/10.3389/fmicb.2012.00388
Rafatpanah H, Hedayati-Moghaddam MR, Fathimoghadam F, Bidkhori HR, Shamsian SK, Ahmadi S, Sohgandi L, Azarpazhooh MR, Rezaee SA, Farid R, Bazarbachi A (2011) High prevalence of HTLV-I infection in Mashhad, Northeast Iran: a population-based seroepidemiology survey. J Clin Virol 52(3):172–176. https://doi.org/10.1016/j.jcv.2011.07.004
Nozuma S, Kubota R, Jacobson S (2020) Human T-lymphotropic virus type 1 (HTLV-1) and cellular immune response in HTLV-1-associated myelopathy/tropical spastic paraparesis. J Neurovirol 26(5):652–663. https://doi.org/10.1007/s13365-020-00881-w
Mohammadi A, Fazeli B, Poursina Z, Tehranian F, Vakili V, Boostani R, Rafatpanah H (2019) HTLV-1-infected asymptomatic carriers compared to HAM/TSP patients over-express the apoptosis- and cytotoxicity-related molecules. Med Microbiol Immunol 208(6):835–844. https://doi.org/10.1007/s00430-019-00625-6
Gudo ES, Silva-Barbosa SD, Linhares-Lacerda L, Ribeiro-Alves M, Real SC, Bou-Habib DC, Savino W (2015) HAM/TSP-derived HTLV-1-infected T cell lines promote morphological and functional changes in human astrocytes cell lines: possible role in the enhanced T cells recruitment into central nervous system. Virol J 12(12):165. https://doi.org/10.1186/s12985-015-0398-x
Freitas NL, Gomes YCP, Souza FDS, Torres RC, Echevarria-Lima J, Leite ACCB, Lima MASD, Araújo AQC, Silva MTT, Espíndola OM (2022) Lessons from the cerebrospinal fluid analysis of HTLV-1-infected individuals: biomarkers of inflammation for HAM/TSP development. Viruses 14(10):2146. https://doi.org/10.3390/v14102146
Lopes Martins AL, Rios Grassi MF, de Aquino FA, Lacerda Araujo JP, Paixao TS, Galvão-Castro B, Boa-Sorte N (2018) Human T-lymphotropic virus-1-associated myelopathy/tropical spastic paraparesis is associated with sexual dysfunction in infected women of reproductive age. Sex Med 6(4):324–331. https://doi.org/10.1016/j.esxm.2018.07.002. (Epub 2018 Sep 1)
Hatatian N, Bosstani R, Mohammadi A, Mehraban S, Mahdifar M, Zemorshidi F, Mozhgani SH, Haji Ghadimi A, Foroughipour M, Rafatpanah H (2021) Evaluation of interleukin-32 and cyclooxygenase-2 expression in HAM/TSP patients and HTLV-1 asymptomatic carriers. Iran J Basic Med Sci 24(7):992–996. https://doi.org/10.22038/ijbms.2021.50821.11569
Guerra M, Luna T, Souza A, Amorim C, Carvalho NB, Carvalho L, Tanajura D, Cardoso LS, Carvalho EM, Santos S (2018) Local and systemic production of proinflammatory chemokines in the pathogenesis of HAM/TSP. Cell Immunol 334:70–77. https://doi.org/10.1016/j.cellimm.2018.09.009
Souza FDS, Freitas NL, Gomes YCP, Torres RC, Echevarria-Lima J, da Silva-Filho IL, Leite ACCB, de Lima MASD, da Silva MTT, Araújo AQC, Espíndola OM. Following the clues: usefulness of biomarkers of neuroinflammation and neurodegeneration in the investigation of HTLV-1-associated myelopathy progression. Front Immunol. 2021;12:737941. https://doi.org/10.3389/fimmu.2021.737941
Yi L, Tang J, Shi C, Zhang T, Li J, Guo F, Zhang W (2020) Pentraxin 3, TNF-α, and LDL-C are associated with carotid artery stenosis in patients with ischemic stroke. Front Neurol 10(10):1365. https://doi.org/10.3389/fneur.2019.01365
Qi S, Zhao F, Li Z, Liang F, Yu S (2020) Silencing of PTX3 alleviates LPS-induced inflammatory pain by regulating TLR4/NF-κB signaling pathway in mice. Biosci Rep 40(2):BSR20194208. https://doi.org/10.1042/BSR20194208
Ummenthum K, Peferoen LA, Finardi A, Baker D, Pryce G, Mantovani A, Bsibsi M, Bottazzi B, Peferoen-Baert R, van der Valk P, Garlanda C, Kipp M, Furlan R, van Noort JM, Amor S (2016) Pentraxin-3 is upregulated in the central nervous system during MS and EAE, but does not modulate experimental neurological disease. Eur J Immunol 46(3):701–711. https://doi.org/10.1002/eji.201545950
Moalli F, Paroni M, Véliz Rodriguez T, Riva F, Polentarutti N, Bottazzi B, Valentino S, Mantero S, Nebuloni M, Mantovani A, Bragonzi A, Garlanda C (2011) The therapeutic potential of the humoral pattern recognition molecule PTX3 in chronic lung infection caused by Pseudomonas aeruginosa. J Immunol 186(9):5425–5434. https://doi.org/10.4049/jimmunol.1002035
Rodriguez-Grande B, Varghese L, Molina-Holgado F, Rajkovic O, Garlanda C, Denes A, Pinteaux E (2015) Pentraxin 3 mediates neurogenesis and angiogenesis after cerebral ischaemia. J Neuroinflamm 24(12):15. https://doi.org/10.1186/s12974-014-0227-y
Polentarutti N, Bottazzi B, Di Santo E, Blasi E, Agnello D, Ghezzi P, Introna M, Bartfai T, Richards G, Mantovani A (2000) Inducible expression of the long pentraxin PTX3 in the central nervous system. J Neuroimmunol 106(1–2):87–94. https://doi.org/10.1016/s0165-5728(00)00214-9
Ravizza T, Moneta D, Bottazzi B, Peri G, Garlanda C, Hirsch E, Richards GJ, Mantovani A, Vezzani A (2001) Dynamic induction of the long pentraxin PTX3 in the CNS after limbic seizures: evidence for a protective role in seizure-induced neurodegeneration. Neuroscience 105(1):43–53. https://doi.org/10.1016/s0306-4522(01)00177-4
Lee HW, Choi J, Suk K (2011) Increases of pentraxin 3 plasma levels in patients with Parkinson’s disease. Mov Disord 26(13):2364–2370. https://doi.org/10.1002/mds.23871
Bourgeois MA, Denslow ND, Seino KS, Barber DS, Long MT (2011) Gene expression analysis in the thalamus and cerebrum of horses experimentally infected with West Nile virus. PLoS ONE 6(10):e24371. https://doi.org/10.1371/journal.pone.0024371
Zatta M, Di Bella S, Bottazzi B, Rossi F, D’Agaro P, Segat L, Fabbiani M, Mantovani A, Luzzati R (2020) Determination of pentraxin 3 levels in cerebrospinal fluid during central nervous system infections. Eur J Clin Microbiol Infect Dis 39(4):665–670. https://doi.org/10.1007/s10096-019-03767-w
Paternostro-Sluga T, Grim-Stieger M, Posch M, Schuhfried O, Vacariu G, Mittermaier C, Bittner C, Fialka-Moser V (2008) Reliability and validity of the Medical Research Council (MRC) scale and a modified scale for testing muscle strength in patients with radial palsy. J Rehabil Med 40(8):665–671. https://doi.org/10.2340/16501977-0235
Charalambous CP (2014) Interrater reliability of a modified Ashworth scale of muscle spasticity. Classic papers in orthopaedics. Springer, Berlin, pp 415–417
Izumo S, Usuku K, Osame M, Arimura K, Igata A (1988) Effect of alpha-interferon treatment on HTLV-I associated myelopathy (HAM). Neurology 39(Suppl 1):242
Ramezani S, Shirdel A, Rafatpanah H, Akbarin MM, Tarokhian H, Rahimi H, Bari A, Jahantigh HR, Rezaee SA (2017) Assessment of HTLV-1 proviral load, LAT, BIM, c-FOS and RAD51 gene expression in adult T cell leukemia/lymphoma. Med Microbiol Immunol 206(4):327–335. https://doi.org/10.1007/s00430-017-0506-1
Staubli SM, Schäfer J, Rosenthal R, Zeindler J, Oertli D, Nebiker CA (2019) The role of CRP and Pentraxin 3 in the prediction of systemic inflammatory response syndrome and death in acute pancreatitis. Sci Rep 9(1):18340. https://doi.org/10.1038/s41598-019-54910-8
Shoeibi A, Rafatpanah H, Azarpazhooh A, Mokhber N, Hedayati-Moghaddam MR, Amiri A, Hashemi P, Foroghipour M, Hoseini RF, Bazarbachi A, Azarpazhooh MR (2013) Clinical features of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in northeast Iran. Acta Neurol Belg 113(4):427–433. https://doi.org/10.1007/s13760-013-0194-6
Bozza S, Bistoni F, Gaziano R, Pitzurra L, Zelante T, Bonifazi P, Perruccio K, Bellocchio S, Neri M, Iorio AM, Salvatori G, De Santis R, Calvitti M, Doni A, Garlanda C, Mantovani A, Romani L (2006) Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation. Blood 108(10):3387–3396. https://doi.org/10.1182/blood-2006-03-009266
Porte R, Davoudian S, Asgari F, Parente R, Mantovani A, Garlanda C, Bottazzi B (2019) The long pentraxin PTX3 as a humoral innate immunity functional player and biomarker of infections and sepsis. Front Immunol 12(10):794. https://doi.org/10.3389/fimmu.2019.00794
Vengen IT, Enger TB, Videm V, Garred P (2017) Pentraxin 3, ficolin-2 and lectin pathway associated serine protease MASP-3 as early predictors of myocardial infarction—the HUNT2 study. Sci Rep 20(7):43045. https://doi.org/10.1038/srep43045
Oggioni M, Mercurio D, Minuta D, Fumagalli S, Popiolek-Barczyk K, Sironi M, Ciechanowska A, Ippati S, De Blasio D, Perego C, Mika J, Garlanda C, De Simoni MG (2021) Long pentraxin PTX3 is upregulated systemically and centrally after experimental neurotrauma, but its depletion leaves unaltered sensorimotor deficits or histopathology. Sci Rep 11(1):9616. https://doi.org/10.1038/s41598-021-89032-7
Wang H, Wang K, Wang C, Zhong X, Qiu W, Hu X (2013) Increased plasma levels of pentraxin 3 in patients with multiple sclerosis and neuromyelitis optica. Mult Scler 19(7):926–931. https://doi.org/10.1177/1352458512457845
Ryu WS, Kim CK, Kim BJ, Kim C, Lee SH, Yoon BW (2012) Pentraxin 3: a novel and independent prognostic marker in ischemic stroke. Atherosclerosis 220(2):581–586. https://doi.org/10.1016/j.atherosclerosis.2011.11.036
Mauri T, Bellani G, Patroniti N, Coppadoro A, Peri G, Cuccovillo I, Cugno M, Iapichino G, Gattinoni L, Pesenti A, Mantovani A (2010) Persisting high levels of plasma pentraxin 3 over the first days after severe sepsis and septic shock onset are associated with mortality. Intensive Care Med 36(4):621–629. https://doi.org/10.1007/s00134-010-1752-5
Ciancarella V, Lembo-Fazio L, Paciello I, Bruno AK, Jaillon S, Berardi S, Barbagallo M, Meron-Sudai S, Cohen D, Molinaro A, Rossi G, Garlanda C, Bernardini ML (2018) Role of a fluid-phase PRR in fighting an intracellular pathogen: PTX3 in Shigella infection. PLoS Pathog 14(12):e1007469. https://doi.org/10.1371/journal.ppat.1007469
Azzurri A, Sow OY, Amedei A, Bah B, Diallo S, Peri G, Benagiano M, D’Elios MM, Mantovani A, Del Prete G (2005) IFN-gamma-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. https://doi.org/10.1016/j.micinf.2004.09.004
Wagenaar JF, Goris MG, Gasem MH, Isbandrio B, Moalli F, Mantovani A, Boer KR, Hartskeerl RA, Garlanda C, van Gorp EC (2009) Long pentraxin PTX3 is associated with mortality and disease severity in severe Leptospirosis. J Infect 58(6):425–432. https://doi.org/10.1016/j.jinf.2009.04.004
Sprong T, Peri G, Neeleman C, Mantovani A, Signorini S, van der Meer JW, van Deuren M (2009) Pentraxin 3 and C-reactive protein in severe meningococcal disease. Shock 31(1):28–32. https://doi.org/10.1097/SHK.0b013e31817fd543
Mairuhu AT, Peri G, Setiati TE, Hack CE, Koraka P, Soemantri A, Osterhaus AD, Brandjes DP, van der Meer JW, Mantovani A, van Gorp EC (2005) Elevated plasma levels of the long pentraxin, pentraxin 3, in severe dengue virus infections. J Med Virol 76(4):547–552. https://doi.org/10.1002/jmv.20397
Kim HS, Won S, Lee EK, Chun YH, Yoon JS, Kim HH, Kim JT (2016) Pentraxin 3 as a clinical marker in children with lower respiratory tract infection. Pediatr Pulmonol 51(1):42–48. https://doi.org/10.1002/ppul.23199
Biagi E, Col M, Migliavacca M, Dell’Oro M, Silvestri D, Montanelli A, Peri G, Mantovani A, Biondi A, Rossi MR (2008) PTX3 as a potential novel tool for the diagnosis and monitoring of pulmonary fungal infections in immuno-compromised pediatric patients. J Pediatr Hematol Oncol 30(12):881–885. https://doi.org/10.1097/MPH.0b013e318180bc1d
Kao SJ, Yang HW, Tsao SM, Cheng CW, Bien MY, Yu MC, Bai KJ, Yang SF, Chien MH (2013) Plasma long pentraxin 3 (PTX3) concentration is a novel marker of disease activity in patients with community-acquired pneumonia. Clin Chem Lab Med 51(4):907–913. https://doi.org/10.1515/cclm-2012-0459
Jaillon S, Moalli F, Ragnarsdottir B, Bonavita E, Puthia M, Riva F, Barbati E, Nebuloni M, Cvetko Krajinovic L, Markotic A, Valentino S, Doni A, Tartari S, Graziani G, Montanelli A, Delneste Y, Svanborg C, Garlanda C, Mantovani A (2014) The humoral pattern recognition molecule PTX3 is a key component of innate immunity against urinary tract infection. Immunity 40(4):621–632. https://doi.org/10.1016/j.immuni.2014.02.015
Vakili R, Sabet F, Aahmadi S, Boostani R, Rafatpanah H, Shamsian A, Rezaee SA (2013) Human T-lymphotropic Virus Type I (HTLV-I) proviral load and clinical features in Iranian HAM/TSP patients: comparison of HTLV-I proviral load in HAM/TSP patients. Iran J Basic Med Sci 16(3):268–272
Jeffery KJ, Usuku K, Hall SE, Matsumoto W, Taylor GP, Procter J, Bunce M, Ogg GS, Welsh KI, Weber JN, Lloyd AL, Nowak MA, Nagai M, Kodama D, Izumo S, Osame M, Bangham CR (1999) HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. Proc Natl Acad Sci USA 96(7):3848–3853. https://doi.org/10.1073/pnas.96.7.3848
Reading PC, Bozza S, Gilbertson B, Tate M, Moretti S, Job ER, Crouch EC, Brooks AG, Brown LE, Bottazzi B, Romani L, Mantovani A (2008) Antiviral activity of the long chain pentraxin PTX3 against influenza viruses. J Immunol 180(5):3391–3398. https://doi.org/10.4049/jimmunol.180.5.3391
Foo SS, Chen W, Taylor A, Sheng KC, Yu X, Teng TS, Reading PC, Blanchard H, Garlanda C, Mantovani A, Ng LF, Herrero LJ, Mahalingam S (2015) Role of pentraxin 3 in shaping arthritogenic alphaviral disease: from enhanced viral replication to immunomodulation. PLoS Pathog. 11(2):e1004649. https://doi.org/10.1371/journal.ppat.1004649. (Erratum in: PLoS Pathog. 2015 Apr;11(4):e1004797)
Acknowledgements
This study was performed as the thesis for neurology specialty degree of the first author. The authors should appreciate the support of Vice-chancellor for research at Mashhad University of Medical Sciences (990557).
Funding
No funding was obtained for this study.
Author information
Authors and Affiliations
Contributions
MM, ZV, HR and FZ performed research; MKR Analyzed data; ZV and FZ conceived and designed research; RB supervised and coordinated the study; MM wrote the paper draft; FZ contributed to manuscript editing. The manuscript was approved by all the authors.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval and consent to participate
The study protocol was approved by the ethics committee of Mashhad University of Medical Sciences with approval code IR.MUMS.MEDICAL.REC.1399.44.7. All the participants were informed about the study procedure and provided written consent before they participated in the study.
Additional information
Edited by Matthias J. Reddehase.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Manzarinejad, M., Vahidi, Z., Boostani, R. et al. Pentraxin 3, a serum biomarker in human T-cell lymphotropic virus type-1-associated myelopathy patients and asymptomatic carriers. Med Microbiol Immunol 212, 271–278 (2023). https://doi.org/10.1007/s00430-023-00770-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00430-023-00770-z