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Synergism between chikungunya virus infection and rheumatoid arthritis on cytokine levels: Clinical implications?

  • Clinical Microbiology - Research Paper
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Abstract

Post-chikungunya virus (CHIKV) chronic arthritis shares several immunopathogenic mechanisms with rheumatoid arthritis (RA), which has led to discussions about the probable relationship between the two diseases. Indeed, some studies have suggested a role for CHIKV infection in RA development. However, to the best of our knowledge, the influence of CHIKV on previous RA has not yet been demonstrated. Herein, we analyzed the potential synergism between CHIKV infection and RA on cytokine and chemokine levels. For this, we compared the IL-1β, IL-6, IL-10, IL-17A, CCL2, CXCL8, CXCL9 and CXCL10 levels, in addition to rheumatoid factor (RF) and C-reactive protein (CRP), in patients with post-CHIKV chronic arthritis (named CHIKV group), patients with RA (RA group), and patients with previous RA who were later infected by CHIKV (RA-CHIKV). History of CHIKV infection was confirmed by serology (IgG, ELISA). Cytokines/chemokines were quantified by flow cytometry. RF, CRP, age and sex data were obtained from medical records. IL-1β, IL-6, IL-10 and IL-17A levels were significantly higher in RA-CHIKV compared to the other groups. CXCL8 levels were higher in the CHIKV group than in RA. CXCL9 was higher in CHIKV than in the RA-CHIKV group. CXCL10 was higher in CHIKV than in the other groups. FR levels were higher in RA than in the CHIKV group, and in RA-CHIKV than in CHIKV. No significant difference was observed in CCL2 and CRP, as well as in age and sex. Finally, our findings suggest an interplay between CHIKV infection and RA, which must be analyzed for its possible clinical impact.

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References

  1. Silva JVJ Jr, Ludwig-Begall LF, Oliveira-Filho EF, Oliveira RAS, Durães-Carvalho R, Lopes TRR, Silva DEA, Gil LHVG (2018) A sco** review of Chikungunya virus infection: epidemiology, clinical characteristics, viral co-circulation complications, and control. Acta Trop 188:213–224. https://doi.org/10.1016/j.actatropica.2018.09.003

    Article  PubMed  PubMed Central  Google Scholar 

  2. ICTV (2021) Virus Taxonomy, 2021. ICTV International Committee on Taxonomy of Viruses. https://ictv.global/taxonomy. Accessed 19 Nov 2022

  3. Staples JE, Susan LH, Ann MP (2020) Chapter 4: Travel-related Infectious Diseases. https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/chikungunya. Accessed 19 Nov 2022

  4. Mahendradas P, Avadhani K, Shetty R (2013) Chikungunya and the eye: a review. J Ophthalmic Inflamm Infect 3:35. https://doi.org/10.1186/1869-5760-3-35

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mehta R, Gerardin P, de Brito CAA, Soares CN, Ferreira MLB, Solomon T (2018) The neurological complications of chikungunya virus: A systematic review. Rev Med Virol 28:1978. https://doi.org/10.1002/rmv.1978

    Article  Google Scholar 

  6. Crosby L, Perreau C, Madeux B, Cossic J, Armand C, Herrmann-Storke C, Najioullah F, Valentino R, Thiéry G (2016) Severe manifestations of chikungunya virus in critically ill patients during the 2013–2014 Caribbean outbreak. Int J Infect Dis 48:78–80. https://doi.org/10.1016/j.ijid.2016.05.010

    Article  PubMed  Google Scholar 

  7. Calabrese LH (2008) Emerging viral infections and arthritis: the role of the rheumatologist. Nat Clin Pract Rheumatol 4:2–3. https://doi.org/10.1038/ncprheum0679

    Article  PubMed  Google Scholar 

  8. Hoarau JJ, Jaffar BMC, Krejbich TP, Das T, Li-Pat-Yuen G, Dassa B, Denizot M, Guichard E, Ribera A, Henni T, Tallet F, Moiton MP, Gauzère BA, Bruniquet S, Jaffar BZ, Morbidelli P, Martigny G, Jolivet M, Gay F, Grandadam M, Tolou H, Vieillard V, Debré P, Autran B, Gasque P (2010) Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol 184:5914–5927. https://doi.org/10.4049/jimmunol.0900255

    Article  CAS  PubMed  Google Scholar 

  9. Rodríguez-Morales AJ, Cardona-Ospina JA, Urbano-Garzón FS, Hurtado-Zapata SJ (2016) Prevalence of Post-Chikungunya Infection Chronic Inflammatory Arthritis: A Systematic Review and Meta-Analysis. Arthritis Care Res (Hoboken) 68:1849–1858. https://doi.org/10.1002/acr.22900

    Article  PubMed  Google Scholar 

  10. Goupil BA, Mores CN (2016) A Review of Chikungunya Virus-induced Arthralgia: Clinical Manifestations, Therapeutics, and Pathogenesis. Open Rheumatol J 30:129–140. https://doi.org/10.2174/1874312901610010129

    Article  Google Scholar 

  11. Amaral JK, Bilsborrow JB, Schoen RT (2020) Chronic Chikungunya Arthritis and Rheumatoid Arthritis: What They Have in Common. Am J Med 133:91–97. https://doi.org/10.1016/j.amjmed.2019.10.005

    Article  CAS  Google Scholar 

  12. Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff HL, Haines GK, Burdick MD, Pope RM, Strieter RM (1992) Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis 90:772–9. J Clin Invest. https://doi.org/10.1172/JCI115950

    Article  PubMed  PubMed Central  Google Scholar 

  13. Harigai M, Hara M, Yoshimura T, Leonard EJ, Inoue K, Kashiwazaki S (1993) Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium. Clin Immunol Immunopathol 69:83–91. https://doi.org/10.1006/clin.1993.1153

    Article  CAS  PubMed  Google Scholar 

  14. Chow A, Her Z, Ong EK, Chen JM, Dimatatac F, Kwek DJ, Barkham T, Yang H, Rénia L, Leo YS, Ng LF (2011) Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor. J Infect Dis 203:149–57. https://doi.org/10.1093/infdis/jiq042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219. https://doi.org/10.1056/NEJMra1004965

    Article  CAS  PubMed  Google Scholar 

  16. Ninla-Aesong P, Mitarnun W, Noipha K (2019) Proinflammatory Cytokines and Chemokines as Biomarkers of Persistent Arthralgia and Severe Disease After Chikungunya Virus Infection: A 5-Year Follow-Up Study in Southern Thailand. Viral Immunol 32:442–452. https://doi.org/10.1089/vim.2019.0064

    Article  CAS  PubMed  Google Scholar 

  17. Ferreira AS, Baldoni NR, Cardoso CS, Oliveira CDL (2021) Biomarkers of severity and chronification in chikungunya fever: a systematic review and meta-analysis. Rev Inst Med Trop Sao Paulo 63:16. https://doi.org/10.1590/S1678-9946202163016

    Article  Google Scholar 

  18. Nakaya HI, Gardner J, Poo YS, Major L, Pulendran B, Suhrbier A (2012) Gene profiling of Chikungunya virus arthritis in a mouse model reveals significant overlap with rheumatoid arthritis. Arthritis Rheum 64(11):3553–3563. https://doi.org/10.1002/art.34631

    Article  CAS  PubMed  Google Scholar 

  19. Fourie ED, Morrison JG (1979) Rheumatoid arthritic syndrome after chikungunya fever. S Afr Med J 56(4):130–132

    CAS  PubMed  Google Scholar 

  20. Bouquillard E, Combe B (2009) Rheumatoid arthritis after Chikungunya fever: a prospective follow-up study of 21 cases. Ann Rheum Dis 68:1505–1506. https://doi.org/10.1136/ard.2008.097626

    Article  CAS  PubMed  Google Scholar 

  21. Burt F, Chen W, Mahalingam S (2014) Chikungunya virus and arthritic disease. Lancet Infect Dis 9:789–790. https://doi.org/10.1016/S1473-3099(14)70869-2

    Article  Google Scholar 

  22. Katsikis PD, Chu CQ, Brennan FM, Maini RN, Feldmann M (1994) Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med 179:1517–1527. https://doi.org/10.1084/jem.179.5.1517

    Article  CAS  PubMed  Google Scholar 

  23. Lee EY, Lee ZH, Song YW (2012) The interaction between CXCL10 and cytokines in chronic inflammatory arthritis. Autoimmun Rev 12:554–557. https://doi.org/10.1016/j.autrev.2012.10.001

    Article  CAS  PubMed  Google Scholar 

  24. Domenicantonio DA (2014) Rheumatoid arthritis and the alpha-chemokine IP-10. Clin Ter 165:447–451. https://doi.org/10.7417/CT.2014.1791

    Article  Google Scholar 

  25. Magyari L, Varszegi D, Kovesdi E, Sarlos P, Farago B, Javorhazy A, Sumegi K, Banfai Z, Melegh B (2014) Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications. World J Orthop 5:516–536. https://doi.org/10.5312/wjo.v5.i4.516

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hernández-Bello J, Oregón-Romero E, Vázquez-Villamar M, García-Arellano S, Valle Y, Padilla-Gutiérrez JR, Román-Fernández IV, Palafox-Sánchez CA, Martínez-Bonilla GE, Muñoz-Valle JF (2017) Aberrant expression of interleukin-10 in rheumatoid arthritis: Relationship with IL10 haplotypes and autoantibodies. Cytokine 95:88–96. https://doi.org/10.1016/j.cyto.2017.02.022

    Article  CAS  PubMed  Google Scholar 

  27. Lee JH, Kim B, ** WJ, Kim HH, Ha H, Lee ZH (2017) Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis. Arthritis Res Ther 19:163. https://doi.org/10.1186/s13075-017-1353-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pandya JM, Lundell AC, Andersson K, Nordström I, Theander E, Rudin A (2017) Blood chemokine profile in untreated early rheumatoid arthritis: CXCL10 as a disease activity marker. Arthritis Res Ther 19:20. https://doi.org/10.1186/s13075-017-1224-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Paparo SR (2019) Rheumatoid arthritis and the Th1 chemokine MIG. Clin Ter 170:472–477. https://doi.org/10.7417/CT.2019.2178

    Article  Google Scholar 

  30. Lin T, Geng T, Harrison AG, Yang D, Vella AT, Fikrig E, Wang P (2020) CXCL10 Signaling Contributes to the Pathogenesis of Arthritogenic Alphaviruses. Viruse 12:1252. https://doi.org/10.3390/v12111252

    Article  CAS  Google Scholar 

  31. Jacob-Nascimento LC, Carvalho CX, Silva MMO, Kikuti M, Anjos RO, Fradico JRB, Campi-Azevedo AC, Tauro LB, Campos GS, Moreira PSDS, Portilho MM, Martins-Filho OA, Ribeiro GS, Reis MG (2021) Acute-Phase Levels of CXCL8 as Risk Factor for Chronic Arthralgia Following Chikungunya Virus Infection. Front Immunol 12:744183. https://doi.org/10.3389/fimmu.2021.744183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. NRAS (2022) What is Rheumatoid arthritis (RA). NRAS National Rheumatoid Arthritis Society. https://nras.org.uk/resource/what-is-ra/. Accessed 19 Nov 2022

  33. IBGE (2010) Synopsis of the 2010 Population Census (Pernambuco). IBGE Brazilian Institute of Geography and Statistics. https://censo2010.ibge.gov.br/sinopse/index.php?dados=210&uf=26. Accessed 19 Nov 2022

  34. Dhar SK, Vishnupriyan K, Damodar S, Gujar S, Das M (2021) IL-6 and IL-10 as predictors of disease severity in COVID-19 patients: results from meta-analysis and regression. Heliyon 7:06155. https://doi.org/10.1016/j.heliyon.2021.e06155

    Article  CAS  Google Scholar 

  35. Lu L, Zhang H, Dauphars DJ, He YW (2020) A Potential Role of Interleukin 10 in COVID-19 Pathogenesis. Trends Immunol 42:3–5. https://doi.org/10.1016/j.it.2020.10.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lohachanakul J, Phuklia W, Thannagith M, Thonsakulprasert T, Ubol S (2012) High concentrations of circulating interleukin-6 and monocyte chemotactic protein-1 with low concentrations of interleukin-8 were associated with severe chikungunya fever during the 2009–2010 outbreak in Thailand. Microbiol Immunol 56:134–138. https://doi.org/10.1111/j.1348-0421.2011.00417.x

    Article  CAS  PubMed  Google Scholar 

  37. Schilte C, Staikowsky F, Couderc T, Madec Y, Carpentier F, Kassab S, Albert ML, Lecuit M, Michault A (2013) Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study. PLoS Negl Trop Dis 7:2137. https://doi.org/10.1371/journal.pntd.0002137

    Article  Google Scholar 

  38. Pope JE, Choy EH (2021) C-reactive protein and implications in rheumatoid arthritis and associated comorbidities. Semin Arthritis Rheum 51:219–229. https://doi.org/10.1016/j.semarthrit.2020.11.005

    Article  CAS  PubMed  Google Scholar 

  39. Ingegnoli F, Castelli R, Gualtierotti R (2003) Rheumatoid factors: clinical applications. Dis Markers 35:727–734. https://doi.org/10.1155/2013/726598

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank the patients who agreed to participate and collaborate with the study.

Funding

LAB thanks the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (Brazil) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Brazil) for her scholarship. YCSB thanks the CNPq (Brazil) for her scholarship. JVJSJr was supported by Financiadora de Estudos e Projetos (FINEP) DTI-A-1. MRCDC was supported by CNPq research fellowship.

Author information

Author notes

  1. Luan Araújo Bezerra and Yan Charles da Silva Bastos contributed equally to this work

Authors and Affiliations

  1. Graduate Program in Tropical Medicine, Federal University of Pernambuco, Recife, Pernambuco, Brazil

    Luan Araújo Bezerra, Yan Charles da Silva Bastos & Maria Rosângela Cunha Duarte Coêlho

  2. Virology Sector, Keizo Asami Institute, Federal University of Pernambuco, Recife, Pernambuco, Brazil

    Luan Araújo Bezerra, Yan Charles da Silva Bastos, Juliana Prado Gonçales, José Valter Joaquim Silva Júnior & Maria Rosângela Cunha Duarte Coêlho

  3. SER Educational Group, Recife, Pernambuco, Brazil

    Juliana Prado Gonçales

  4. Virology Sector, Department of Preventive Veterinary Medicine, Center for Rural Sciences, Federal University of Santa Maria, Santa Maria, Rio Grande Do Sul, Brazil

    José Valter Joaquim Silva Júnior

  5. Department of Clinical Analysis, Health Sciences Center, Federal University of Santa Maria, Santa Maria, Rio Grande Do Sul, Brazil

    José Valter Joaquim Silva Júnior

  6. Immunoparasitology Laboratory, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Pernambuco, Brazil

    Virgínia Maria Barros de Lorena

  7. Rheumatology Service, Clinical Hospital, Federal University of Pernambuco, Recife, Pernambuco, Brazil

    Angela Luzia Branco Pinto Duarte & Claudia Diniz Lopes Marques

  8. Department of Physiology and Pharmacology, Biosciences Center, Federal University of Pernambuco, Recife, Pernambuco, Brazil

    Maria Rosângela Cunha Duarte Coêlho

  9. Setor de Virologia, Instituto Keizo Asami, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, S/N. Cidade Universitária, Recife, Pernambuco, 50.670-901, Brazil

    Maria Rosângela Cunha Duarte Coêlho

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  1. Luan Araújo Bezerra
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  2. Yan Charles da Silva Bastos
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Contributions

Conceptualization: LAB, YCSB, JPG, JVJSJr, ALBPD, CDLM and MRCDC; Data collection: LAB and YCSB; Experiments: LAB, YCSB, JPG and VMBL; Data analyses: LAB, YCSB, JPG, JVJSJr, VMBL, ALBPD, CDLM and MRCDC; Manuscript preparation: LAB, YCSB, JPG, JVJSJr and MRCDC; Supervision: MRCDC. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Maria Rosângela Cunha Duarte Coêlho.

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The study was approved by the Research Ethics Committee of the Health Sciences Center at UFPE (protocol 17712619.5.0000.5208).

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Bezerra, L.A., da Silva Bastos, Y.C., Gonçales, J.P. et al. Synergism between chikungunya virus infection and rheumatoid arthritis on cytokine levels: Clinical implications?. Braz J Microbiol 54, 885–890 (2023). https://doi.org/10.1007/s42770-023-00976-6

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