Skip to main content
Top
Published in: BMC Infectious Diseases 1/2021

Open Access 01-12-2021 | Biomarkers | Research article

Low Annexin A1 level in HTLV-1 infected patients is a potential biomarker for the clinical progression and diagnosis of HAM/TSP

Authors: Bárbara Brasil Santana, Maria Alice Freitas Queiroz, Rodrigo Arcoverde Cerveira, Claudia Mendonça Rodrigues, Ednelza da Silva Graça Amoras, Carlos Araújo da Costa, Maisa Silva de Sousa, Ricardo Ishak, Luiz Ricardo Goulart, Antonio Carlos Rosário Vallinoto

Published in: BMC Infectious Diseases | Issue 1/2021

Login to get access

Abstract

Background

Human T-lymphotropic virus 1 (HTLV-1) is etiologically associated with the chronic inflammatory neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) Annexin A1 (AnxA1) is an anti-inflammatory protein with proposed neuroprotective and anti-neuroinflammatory functions. We hypothesized that ANXA1 gene expression may be dysregulated in HTLV-1-infected HAM/TSP patients.

Methods

This study involved 37 individuals infected with HTLV-1, including 21 asymptomatic (AS) carriers and 16 with HAM/TSP, and a control group of 30 individuals negative for HTLV-1 and HTLV-2. For AS HTLV-1-positive and HAM/TSP patients, ANXA1 and formyl peptide receptor (FPR1, FPR2 and FPR3) expression and HTLV-1 proviral load (PVL) in peripheral blood cells were evaluated by real-time quantitative PCR (qPCR), and plasma AnxA1 levels were determined by enzyme-linked immunosorbent assay (ELISA).

Results

ANXA1 gene expression was increased in the AS group compared with the HAM/TSP and control groups, but the differences were not statistically significant. FPR1 gene expression was higher in patients with HTLV-1 than in controls (AS, p = 0.0032; HAM/TSP, p < 0.0001). Plasma AnxA1 levels were higher in the AS group than in the HAM/TSP group (p = 0.0045), and PVL was higher in patients with HAM/TSP than in AS individuals (p = 0.0162). The use of a combined ROC curve using Annexin 1 levels and proviral load significantly increased the sensitivity and specificity to predict progression to HAM/TSP (AUC = 0.851 and AUC = 0.937, respectively, to AUC = 1000).

Conclusions

Our results suggest that AnxA1 may be dysregulated in HAM/TSP patients. Serological detection of AnxA1 in association with proviral load may provide a prognostic biomarker for HTLV-1-associated neurodegenerative disease.
Appendix
Available only for authorised users
Literature
2.
go back to reference Cassar O, Gessain A. Serological and molecular methods to study epidemiological aspects of human T-cell lymphotropi vírus type 1 infection. Methods Mol Biol. 2017;1582:3–24.CrossRef Cassar O, Gessain A. Serological and molecular methods to study epidemiological aspects of human T-cell lymphotropi vírus type 1 infection. Methods Mol Biol. 2017;1582:3–24.CrossRef
3.
go back to reference Hinuma Y, Komoda H, Chosa T, Kondo T, Kohakura M, Takenaka T, et al. Antibodies to adult T-cell leukemia-virus-associated antigens (ATLA) in sera from patients with ATL and controls in Japan: a nation-wide sero-epidemiologic study. Int J Cancer. 1982;29:631–5.CrossRef Hinuma Y, Komoda H, Chosa T, Kondo T, Kohakura M, Takenaka T, et al. Antibodies to adult T-cell leukemia-virus-associated antigens (ATLA) in sera from patients with ATL and controls in Japan: a nation-wide sero-epidemiologic study. Int J Cancer. 1982;29:631–5.CrossRef
4.
go back to reference Osame M, Usuku K, Izumo S. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986;1:1031–2.CrossRef Osame M, Usuku K, Izumo S. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986;1:1031–2.CrossRef
5.
go back to reference Ribas JGR, Melo GCN. Mielopatia associada ao vírus linfotrópico humano de células T do tipo 1 (HTLV-1). Rev Soc Bras Med Trop. 2002;35:377–84.CrossRef Ribas JGR, Melo GCN. Mielopatia associada ao vírus linfotrópico humano de células T do tipo 1 (HTLV-1). Rev Soc Bras Med Trop. 2002;35:377–84.CrossRef
6.
go back to reference Jacobson S, Gupta A, Mattson D, Mingioli E, McFarlin DE. Immunological studies in tropical spastic paraparesis. Ann Neurol. 1990;27:149–56.CrossRef Jacobson S, Gupta A, Mattson D, Mingioli E, McFarlin DE. Immunological studies in tropical spastic paraparesis. Ann Neurol. 1990;27:149–56.CrossRef
7.
go back to reference Kanagi M, Shida H, Igarashi H, Kuruma K, Murai H, Aono Y, et al. Target epitope in the tax protein of human T- cell leucemia vírus type I recognized by class I major histocompatiblity complex- restricted cytotoxic T cells. J Virol. 1992;66:2928–33.CrossRef Kanagi M, Shida H, Igarashi H, Kuruma K, Murai H, Aono Y, et al. Target epitope in the tax protein of human T- cell leucemia vírus type I recognized by class I major histocompatiblity complex- restricted cytotoxic T cells. J Virol. 1992;66:2928–33.CrossRef
8.
go back to reference Parker CE, Daenke SD, Nightingale S, Bangham CRM. Activated HTLV-I speci¢c cytotoxic Tcells are found in healthy seropositives as well as patients with tropical spastic paraparesis. Virology. 1992;188:628–36.CrossRef Parker CE, Daenke SD, Nightingale S, Bangham CRM. Activated HTLV-I speci¢c cytotoxic Tcells are found in healthy seropositives as well as patients with tropical spastic paraparesis. Virology. 1992;188:628–36.CrossRef
9.
go back to reference Goon PKC, Bangham CRM. Interference with immune function by HTLV-1. Clin Exp Immunol. 2004;137:234–6.CrossRef Goon PKC, Bangham CRM. Interference with immune function by HTLV-1. Clin Exp Immunol. 2004;137:234–6.CrossRef
10.
go back to reference Boxus M, Willems L. Mechanisms oh HTLV-1 persistence and transformation. Br J Cancer. 2009;101:1497–501.CrossRef Boxus M, Willems L. Mechanisms oh HTLV-1 persistence and transformation. Br J Cancer. 2009;101:1497–501.CrossRef
11.
go back to reference Barmak K, Harhaj EW, Wigdahl B. Mediators of central nervous system damage during the progression of human T-cell leukemia type I-associated myelopathy/tropical spastic paraparesis. J Neuro-Oncol. 2003;9:522–9. Barmak K, Harhaj EW, Wigdahl B. Mediators of central nervous system damage during the progression of human T-cell leukemia type I-associated myelopathy/tropical spastic paraparesis. J Neuro-Oncol. 2003;9:522–9.
12.
go back to reference Solito E, McArthur S, Christian H, Gavins F, Buckingham JC, Gillies GE. Annexin A1 in the brain - undiscovered roles? Trends Pharmacol Sci. 2008;29:135–42.CrossRef Solito E, McArthur S, Christian H, Gavins F, Buckingham JC, Gillies GE. Annexin A1 in the brain - undiscovered roles? Trends Pharmacol Sci. 2008;29:135–42.CrossRef
13.
go back to reference Pepinsky RB, Tizar D, Mattaliano RJ, Sinclair LK, Miller GT, Browning JL, et al. Five distinct calcium and phospholipid binding proteins share homology with lipocortin I. J Biol Chem. 1988;263:10799–811.CrossRef Pepinsky RB, Tizar D, Mattaliano RJ, Sinclair LK, Miller GT, Browning JL, et al. Five distinct calcium and phospholipid binding proteins share homology with lipocortin I. J Biol Chem. 1988;263:10799–811.CrossRef
14.
go back to reference Raynal P, Pollard H. Annexins: the problem of assessing the biological role for a gene family of multifunctional calcium- and phospholipid-binding proteins. Biochim Biophys Acta. 1994;1197:63–93.CrossRef Raynal P, Pollard H. Annexins: the problem of assessing the biological role for a gene family of multifunctional calcium- and phospholipid-binding proteins. Biochim Biophys Acta. 1994;1197:63–93.CrossRef
15.
go back to reference Flower RJ, Blackwell GJ. Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandina generation. Nature. 1997;278:456–9.CrossRef Flower RJ, Blackwell GJ. Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandina generation. Nature. 1997;278:456–9.CrossRef
16.
go back to reference Flower RJ. Lipocortin and the mechanism of action of the glucocorticoids. Br J Pharmacol. 1988;94:987–1015.CrossRef Flower RJ. Lipocortin and the mechanism of action of the glucocorticoids. Br J Pharmacol. 1988;94:987–1015.CrossRef
17.
go back to reference Buckingham JC, Flower RJ. Lipocortin 1: a second messenger of glucocorticoid action in the hypothalamo-pituitary-adrenocortical axis. Mol Med Today. 2997;3:296–302.CrossRef Buckingham JC, Flower RJ. Lipocortin 1: a second messenger of glucocorticoid action in the hypothalamo-pituitary-adrenocortical axis. Mol Med Today. 2997;3:296–302.CrossRef
18.
go back to reference Taylor AD, Philip JG, John CD. Annexin 1 (lipocortin 1) mediates the glucocorticoid inhibition of cyclic adenosine 3′,5′-monophosphate-stimulated prolactin secretion. Endocrinology. 2000;141:2209–19.CrossRef Taylor AD, Philip JG, John CD. Annexin 1 (lipocortin 1) mediates the glucocorticoid inhibition of cyclic adenosine 3′,5′-monophosphate-stimulated prolactin secretion. Endocrinology. 2000;141:2209–19.CrossRef
19.
go back to reference Yang Y, Hutchinson P, Morand EF. Inhibitory effect of annexin I on synovial inflammation in rat adjuvant arthritis. Arthritis Rheum. 1999;42:1538–44.CrossRef Yang Y, Hutchinson P, Morand EF. Inhibitory effect of annexin I on synovial inflammation in rat adjuvant arthritis. Arthritis Rheum. 1999;42:1538–44.CrossRef
20.
go back to reference Goulding NJ, Guyre PM. Regulation of inflammation by lipocortin 1. Immunol Today. 1992;13:295–7.CrossRef Goulding NJ, Guyre PM. Regulation of inflammation by lipocortin 1. Immunol Today. 1992;13:295–7.CrossRef
21.
go back to reference Goulding NJ, Pan L, Wardwell K, Guyre VC, Guyre PM. Evidence for specific annexin I-binding proteins on human monocytes. Biochem J. 1996;316:593–7.CrossRef Goulding NJ, Pan L, Wardwell K, Guyre VC, Guyre PM. Evidence for specific annexin I-binding proteins on human monocytes. Biochem J. 1996;316:593–7.CrossRef
22.
go back to reference Perretti M, Flower RJ. Measurement of lipocortin 1 levels in murine peripheral blood leukocytes by flow cytometry: modulation by glucocorticoids and inflammation. Br J Pharmacol. 1996;118:605–10.CrossRef Perretti M, Flower RJ. Measurement of lipocortin 1 levels in murine peripheral blood leukocytes by flow cytometry: modulation by glucocorticoids and inflammation. Br J Pharmacol. 1996;118:605–10.CrossRef
23.
go back to reference De Castro-Costa CM, Araújo AQ, Barreto MM, Takayanagui OM, Sohler MP, da Silva EL, et al. Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). AIDS Res Hum Retrovir. 2006;22:931–5.CrossRef De Castro-Costa CM, Araújo AQ, Barreto MM, Takayanagui OM, Sohler MP, da Silva EL, et al. Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). AIDS Res Hum Retrovir. 2006;22:931–5.CrossRef
24.
go back to reference Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 1992;25:402–8.CrossRef Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 1992;25:402–8.CrossRef
25.
go back to reference Tamegão-Lopes BP, Rezende PR, Maradei-Pereira LM, de Lemos JA. HTLV-1 and HTLV-2 proviral load: a simple method using quantitative real-time PCR. Rev Soc Bras Med Trop. 2006;39:548–52.CrossRef Tamegão-Lopes BP, Rezende PR, Maradei-Pereira LM, de Lemos JA. HTLV-1 and HTLV-2 proviral load: a simple method using quantitative real-time PCR. Rev Soc Bras Med Trop. 2006;39:548–52.CrossRef
26.
go back to reference Ayres M, Ayres JR, Ayres DL, Santos AS. BioEstat 5.3: aplicações estatísticas nas áreas das Ciências Biológicas e Médicas. Belém: Editora Sociedade Civil Mamirauá; 2011. p. 364p. Ayres M, Ayres JR, Ayres DL, Santos AS. BioEstat 5.3: aplicações estatísticas nas áreas das Ciências Biológicas e Médicas. Belém: Editora Sociedade Civil Mamirauá; 2011. p. 364p.
27.
go back to reference Jeffery KJ, Usuku K, Hall SE, Matsumoto W, Taylor GP, Procter J, et al. HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. Proc Natl Acad Sci U S A. 1999;96:3848–53.CrossRef Jeffery KJ, Usuku K, Hall SE, Matsumoto W, Taylor GP, Procter J, et al. HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. Proc Natl Acad Sci U S A. 1999;96:3848–53.CrossRef
28.
go back to reference Hanon E, Halls S, Taylor GP, Saito M, Davis R, Tanaka Y, et al. Abundant tax protein expression. InCD4+ T cells infected with human T-cell lymphotropic vírus type I (HTLV-I) is prevented by cytotoxic T lymphocytes. Blood. 2000;95:1386–92.CrossRef Hanon E, Halls S, Taylor GP, Saito M, Davis R, Tanaka Y, et al. Abundant tax protein expression. InCD4+ T cells infected with human T-cell lymphotropic vírus type I (HTLV-I) is prevented by cytotoxic T lymphocytes. Blood. 2000;95:1386–92.CrossRef
29.
go back to reference Ghezeldasht SA, Sadeghian H, Azarpazhooh MR, Shamsian SAA, Rafatpanah H, Mahmoodi M, Rezaee SA. Evaluation of T regulatory lymphocytes transcription factors in HTLV-1-associated myelopathy/tropical spastic Paraparesis (HAM/TSP) patients. Appl Biochem Biotechnol. 2017;182:1403–14.CrossRef Ghezeldasht SA, Sadeghian H, Azarpazhooh MR, Shamsian SAA, Rafatpanah H, Mahmoodi M, Rezaee SA. Evaluation of T regulatory lymphocytes transcription factors in HTLV-1-associated myelopathy/tropical spastic Paraparesis (HAM/TSP) patients. Appl Biochem Biotechnol. 2017;182:1403–14.CrossRef
30.
go back to reference Akbarin MM, Rahimi H, Hassannia T, Shoja Razavi G, Sabet F, Shirdel A. Comparison of HTLV-I Proviral load in adult T cell leukemia/lymphoma (ATL), HTLV-I-associated myelopathy (HAM-TSP) and healthy carriers. Iran J Basic Med Sci. 2013;16:208–12.PubMedPubMedCentral Akbarin MM, Rahimi H, Hassannia T, Shoja Razavi G, Sabet F, Shirdel A. Comparison of HTLV-I Proviral load in adult T cell leukemia/lymphoma (ATL), HTLV-I-associated myelopathy (HAM-TSP) and healthy carriers. Iran J Basic Med Sci. 2013;16:208–12.PubMedPubMedCentral
31.
go back to reference Nagai M, Usuku K, Matsumoto W, Kodama D, Takenouchi N, Moritoyo T, et al. Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: high prociral load strongly predisposes to HAM/TSP. J Neuro-Oncol. 1998;4:586–93. Nagai M, Usuku K, Matsumoto W, Kodama D, Takenouchi N, Moritoyo T, et al. Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: high prociral load strongly predisposes to HAM/TSP. J Neuro-Oncol. 1998;4:586–93.
32.
go back to reference Izumo S, Ijichi T, Higuchi I, Tashiro A, Takahashi K, Osame M. Neuropathology of HTLV-I-associated myelopathy--a report of two autopsy cases. Acta Paediatr Jpn. 1992;34:358–64.CrossRef Izumo S, Ijichi T, Higuchi I, Tashiro A, Takahashi K, Osame M. Neuropathology of HTLV-I-associated myelopathy--a report of two autopsy cases. Acta Paediatr Jpn. 1992;34:358–64.CrossRef
33.
go back to reference Goon PK, Hanon E, Igakura T, Tanaka Y, Weber JN, Taylor GP, Bangham CR. High frequencies of Th1-type CD4(+) T cells specific to HTLV-1 Env and tax proteins in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. Blood. 2002;99:3335–41.CrossRef Goon PK, Hanon E, Igakura T, Tanaka Y, Weber JN, Taylor GP, Bangham CR. High frequencies of Th1-type CD4(+) T cells specific to HTLV-1 Env and tax proteins in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. Blood. 2002;99:3335–41.CrossRef
34.
go back to reference Chen Z, Yoshihara E, Son A, Matsuo Y, Masutani H, Sugie K, et al. Differential roles of Annexin A1 (ANXA1/lipocortin-1/lipomodulin) and thioredoxin binding protein-2 (TBP-2/VDUP1/TXNIP) in glucocorticoid signaling of HTLV-I-transformed T cells. Immunol Lett. 2010;131:11–8.CrossRef Chen Z, Yoshihara E, Son A, Matsuo Y, Masutani H, Sugie K, et al. Differential roles of Annexin A1 (ANXA1/lipocortin-1/lipomodulin) and thioredoxin binding protein-2 (TBP-2/VDUP1/TXNIP) in glucocorticoid signaling of HTLV-I-transformed T cells. Immunol Lett. 2010;131:11–8.CrossRef
35.
go back to reference Gastardelo TS, Cunha BR, Raposo LS, Maniglia JV, Cury PM, Lisoni FC, et al. Inflammation and cancer: role of annexin A1 and FPR2/ALX in proliferation and metastasis in human laryngeal squamous cell carcinoma. PLoS One. 2014;9:e111317.CrossRef Gastardelo TS, Cunha BR, Raposo LS, Maniglia JV, Cury PM, Lisoni FC, et al. Inflammation and cancer: role of annexin A1 and FPR2/ALX in proliferation and metastasis in human laryngeal squamous cell carcinoma. PLoS One. 2014;9:e111317.CrossRef
36.
go back to reference Takaoka RTC, Sertório ND, Magalini LPJ, Dos Santos LM, Souza HR, Iyomasa-Pilon MM, et al. Expression profiles of Annexin A1, formylated peptide receptors and cyclooxigenase-2 in gastroesophageal inflammations and neoplasias. Pathol Res Pract. 2018;214:181–6.CrossRef Takaoka RTC, Sertório ND, Magalini LPJ, Dos Santos LM, Souza HR, Iyomasa-Pilon MM, et al. Expression profiles of Annexin A1, formylated peptide receptors and cyclooxigenase-2 in gastroesophageal inflammations and neoplasias. Pathol Res Pract. 2018;214:181–6.CrossRef
37.
go back to reference Kao W, Gu R, Jia Y, Wei X, Fan H, Harris J, et al. A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis. Br J Pharmacol. 2014;171:4087–96.CrossRef Kao W, Gu R, Jia Y, Wei X, Fan H, Harris J, et al. A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis. Br J Pharmacol. 2014;171:4087–96.CrossRef
38.
go back to reference Shimizu N, Tanaka A, Mori T, Hoque A, Jinno-Oue A, Apichartpiyakul C, et al. A formylpeptide receptor, FPRL1, acts as an efficient coreceptor for primary isolates of human immunodeficiency virus. Retrovirology. 2008;5:52.CrossRef Shimizu N, Tanaka A, Mori T, Hoque A, Jinno-Oue A, Apichartpiyakul C, et al. A formylpeptide receptor, FPRL1, acts as an efficient coreceptor for primary isolates of human immunodeficiency virus. Retrovirology. 2008;5:52.CrossRef
Metadata
Title
Low Annexin A1 level in HTLV-1 infected patients is a potential biomarker for the clinical progression and diagnosis of HAM/TSP
Authors
Bárbara Brasil Santana
Maria Alice Freitas Queiroz
Rodrigo Arcoverde Cerveira
Claudia Mendonça Rodrigues
Ednelza da Silva Graça Amoras
Carlos Araújo da Costa
Maisa Silva de Sousa
Ricardo Ishak
Luiz Ricardo Goulart
Antonio Carlos Rosário Vallinoto
Publication date
01-12-2021
Publisher
BioMed Central
Keyword
Biomarkers
Published in
BMC Infectious Diseases / Issue 1/2021
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/s12879-021-05917-y

Other articles of this Issue 1/2021

BMC Infectious Diseases 1/2021 Go to the issue