Advertisement

Raised levels of Il-6, Il-17a, and Il-22 in fatal leptospirosis

  • Wan Shahriman Yushdie Wan Yusoff
  • Maha Abdullah
  • Zamberi Sekawi
  • Fairuz Amran
  • Muhammad Yazli Yuhana
  • Niazlin Mohd Taib
  • Ivan Kok Seng Yap
  • Leslie Thian Lung Than
  • Anim Md. Shah
  • Alex van Belkum
  • Syafinaz Amin NordinEmail author
Original Article
  • 109 Downloads

Abstract

Clinical manifestations of leptospirosis range from mild, common cold-like illness, to a life-threatening condition. The host immune response has been hypothesized to play a major role in leptospirosis outcome. Increased levels of inflammatory mediators, such as cytokines, may promote tissue damage that lead to increased disease severity. The question is whether cytokines levels may predict the outcome of leptospirosis and guide patient management. This study aimed to assess the association between Th1-, Th2-, and Th17-related cytokines with the clinical outcome of patients with leptospirosis. Different cytokine levels were measured in fifty-two plasma samples of hospitalized patients diagnosed with leptospirosis in Malaysia (January 2016–December 2017). Patients were divided into two separate categories: survived (n = 40) and fatal outcome (n = 12). Nineteen plasma samples from healthy individuals were obtained as controls. Cytokine quantification was performed using Simple Plex™ assays from ProteinSimple (San Jose, CA, USA). Measurements were done in triplicate and statistical analysis was performed using GraphPad software and SPSS v20. IL-6 (p = 0.033), IL-17A (p = 0.022), and IL-22 (p = 0.046) were significantly elevated in fatal cases. IL-17A concentration (OR 1.115; 95% CI 1.010–1.231) appeared to be an independent predictor of fatality of leptospirosis. Significantly higher levels of TNF-α (p ≤ 0.0001), IL-6 (p ≤ 0.0001), IL-10 (p ≤ 0.0001), IL-12 (p ≤ 0.0001), IL17A (p ≤ 0.0001), and IL-18 (p ≤ 0.0001) were observed among leptospirosis patients in comparison with healthy controls. Our study shows that certain cytokine levels may serve as possible prognostic biomarkers in leptospirosis patients.

Keywords

Cytokines Leptospirosis Clinical outcome Biomarkers T helper cell Malaysia 

Notes

Acknowledgments

A special thank-you to the Director General of Health Malaysia, Ministry of Health Malaysia, for his permission to publish this article and the Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, for the facilities and technical support provided.

Authors’ contributions

SAN, MA, and ZS were involved in the conception and design of the study. WSY performed the study, analyzed data, and drafted the manuscript. AvB substantially revised the analyses and manuscript. MYY, AMS, and NMT provided clinical data and sample. LT, IK, and FA contributed intellectual content to the study. All authors read and approved the final manuscript.

Funding information

This study was funded by the Ministry of Higher Education Malaysia through the Long-Term Research Grant Scheme (LRGS) (UPM/700-2/1/LRGS/5526402).

Compliance with ethical standards

Ethical approval and consent to participate

Samples were collected from study participants after they have given their written informed consent. Ethical approval for the study was obtained from the Medical Research and Ethics Committee, Ministry of Health Malaysia (NMRR (National Medical Research Register)-15-2148-27536 and NMRR-15-756-25320).

Informed consent

Written informed consent was obtained from the study participants for publication of their individual details in this manuscript.

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Cagliero J, Villanueva SYAM, Matsui M (2018) Leptospirosis pathophysiology: into the storm of cytokines. Front Cell Infect Microbiol 8:1–8.  https://doi.org/10.3389/fcimb.2018.00204 CrossRefGoogle Scholar
  2. 2.
    Chin V, Lee T, Lim W et al (2018) Leptospirosis in human: biomarkers in host immune responses. Microbiol Res 207:108–115.  https://doi.org/10.1016/j.micres.2017.11.015 CrossRefGoogle Scholar
  3. 3.
    Wang H, Wu Y, Ojcius DM et al (2012) Leptospiral hemolysins induce proinflammatory cytokines through toll-like receptor 2-and 4-mediated JNK and NF-κB signaling pathways. PLoS One 7.  https://doi.org/10.1371/journal.pone.0042266 CrossRefGoogle Scholar
  4. 4.
    Lee SH, Kim S, Park SC, Kim MJ (2002) Cytotoxic activities of Leptospira interrogans hemolysin SphH as a pore-forming protein on mammalian cells. Infect Immun 70:315–322.  https://doi.org/10.1128/IAI.70.1.315 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hoke DE, Egan S, Cullen PA, Adler B (2008) LipL32 is an extracellular matrix-interacting protein of Leptospira spp. and Pseudoalteromonas tunicata. Infect Immun 76:2063–2069.  https://doi.org/10.1128/IAI.01643-07 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nahori M-A, Fournié-Amazouz E, Que-Gewirth NS et al (2005) Differential TLR recognition of leptospiral lipid A and lipopolysaccharide in murine and human cells. J Immunol 175:6022–6031.  https://doi.org/10.4049/jimmunol.175.9.6022 CrossRefPubMedGoogle Scholar
  7. 7.
    Papa A, Kotrotsiou T (2015) Cytokines in human leptospirosis. Trans R Soc Trop Med Hyg 109:749–754.  https://doi.org/10.1093/trstmh/trv095 CrossRefPubMedGoogle Scholar
  8. 8.
    Mikulski M, Boisier P, Lacassin F et al (2015) Severity markers in severe leptospirosis: a cohort study. Eur J Clin Microbiol Infect Dis 34:687–695.  https://doi.org/10.1007/s10096-014-2275-8 CrossRefPubMedGoogle Scholar
  9. 9.
    Reis EAG, Hagan JE, Ribeiro GS et al (2013) Cytokine response signatures in disease progression and development of severe clinical outcomes for leptospirosis. PLoS Negl Trop Dis 7:e2457.  https://doi.org/10.1371/journal.pntd.0002457 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Kyriakidis I, Samara P, Papa A (2011) Serum TNF- alpha , sTNFR1, IL-6, IL-8 and IL-10 levels in Weil’s syndrome. Cytokine 54:117–120.  https://doi.org/10.1016/j.cyto.2011.01.014 CrossRefPubMedGoogle Scholar
  11. 11.
    Tajiki H, Salomao R (1996) Association of plasma levels of tumor necrosis factor alpha with severity of disease and mortality among patients with leptospirosis. Clin Infect Dis 23:1177–1178CrossRefGoogle Scholar
  12. 12.
    Estavoyer JM, Racadot E, Couetdic G et al (1991) Tumor necrosis factor in patients with leptospirosis. Rev Infect Dis 13:1245–1246CrossRefGoogle Scholar
  13. 13.
    Chirathaworn C, Supputtamongkol Y, Lertmaharit S, Poovorawan Y (2016) Cytokine levels as biomarkers for leptospirosis patients. Cytokine 85:80–82.  https://doi.org/10.1016/j.cyto.2016.06.007 CrossRefPubMedGoogle Scholar
  14. 14.
    Leptospirosis Burden Epidemiology Reference Group (LERG) (2011) Report of the Second Meeting of the Leptospirosis Burden Epidemiology Reference GroupGoogle Scholar
  15. 15.
    Aldo P, Marusov G, Svancara D et al (2016) Simple plexTM: a novel multi-analyte, automated microfluidic immunoassay platform for the detection of human and mouse cytokines and chemokines. Am J Reprod Immunol 75:678–693.  https://doi.org/10.1111/aji.12512 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bandara K, Gunasekara C, Weerasekera M et al (2018) Do the Th17 cells play a role in the pathogenesis of leptospirosis? Can J Infect Dis Med Microbiol 2018.  https://doi.org/10.1155/2018/9704532 CrossRefGoogle Scholar
  17. 17.
    Rizvi M, Azam M, Ajmal MR et al (2011) Prevalence of leptospira in acute hepatitis syndrome and assessment of IL-8 and TNF-alpha level in leptospiral hepatitis. Ann Trop Med Parasitol 105:499–506.  https://doi.org/10.1179/1364859411Y.0000000041 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Fernando N, De Silva R, Handunnetti SM et al (2018) Effect of antimicrobial agents on inflammatory cytokines in acute leptospirosis. Antimicrob Agents Chemother 62.  https://doi.org/10.1128/AAC.02312-17
  19. 19.
    Jumat MI, William T, John DV (2018) Cytokine profile of patients with leptospirosis in Sabah, Malaysia. Med J Malaysia 73:106–109Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Wan Shahriman Yushdie Wan Yusoff
    • 1
    • 2
  • Maha Abdullah
    • 3
  • Zamberi Sekawi
    • 2
  • Fairuz Amran
    • 4
  • Muhammad Yazli Yuhana
    • 5
  • Niazlin Mohd Taib
    • 2
  • Ivan Kok Seng Yap
    • 6
  • Leslie Thian Lung Than
    • 2
  • Anim Md. Shah
    • 7
  • Alex van Belkum
    • 8
  • Syafinaz Amin Nordin
    • 2
    Email author
  1. 1.Department of Medical Laboratory Technology, Faculty of Health SciencesUniversiti Teknologi MARA Cawangan SelangorBandar Puncak AlamMalaysia
  2. 2.Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health SciencesUniversiti Putra Malaysia (UPM)SerdangMalaysia
  3. 3.Department of Pathology, Faculty of Medicine and Health SciencesUniversiti Putra Malaysia (UPM)SerdangMalaysia
  4. 4.Infectious Disease Research Centre, Bacteriology UnitInstitute for Medical Research, Ministry of Health MalaysiaKuala LumpurMalaysia
  5. 5.Infectious Diseases Unit, Internal Medicine DepartmentUniversiti Teknologi MARASungai BulohMalaysia
  6. 6.Department of Life SciencesInternational Medical UniversityKuala LumpurMalaysia
  7. 7.Department of Medicine, Faculty of Medicine and Health SciencesUniversiti Putra MalaysiaSerdangMalaysia
  8. 8.Clinical UnitbioMérieuxLa Balme-les-GrottesFrance

Personalised recommendations