Medical Microbiology and Immunology

, Volume 207, Issue 2, pp 105–115 | Cite as

Blocking of opioid receptors in experimental formaline-inactivated respiratory syncytial virus (FI-RSV) immunopathogenesis: from beneficial to harmful impacts

  • Vahid Salimi
  • Habib Mirzaei
  • Ali Ramezani
  • Alireza Tahamtan
  • Abbas Jamali
  • Shahram Shahabi
  • Maryam Golaram
  • Bagher Minaei
  • Mohammad Javad Gharagozlou
  • Mahmood Mahmoodi
  • Louis Bont
  • Fazel Shokri
  • Talat Mokhtari-Azad
Original Investigation

Abstract

Opioid system plays a significant role in pathophysiological processes, such as immune response and impacts on disease severity. Here, we investigated the effect of opioid system on the immunopathogenesis of respiratory syncytial virus (RSV) vaccine (FI-RSV)-mediated illness in a widely used mouse model. Female Balb/c mice were immunized at days 0 and 21 with FI-RSV (2 × 106 pfu, i.m.) and challenged with RSV-A2 (3 × 106 pfu, i.n.) at day 42. Nalmefene as a universal opioid receptors blocker administered at a dose of 1 mg/kg in combination with FI-RSV (FI-RSV + NL), and daily after live virus challenge (RSV + NL). Mice were sacrificed at day 5 after challenge and bronchoalveolar lavage (BAL) fluid and lungs were harvested to measure airway immune cells influx, T lymphocyte subtypes, cytokines/chemokines secretion, lung histopathology, and viral load. Administration of nalmefene in combination with FI-RSV (FI-RSV + NL-RSV) resulted in the reduction of the immune cells infiltration to the BAL fluid, the ratio of CD4/CD8 T lymphocyte, the level of IL-5, IL-10, MIP-1α, lung pathology, and restored weight loss after RSV infection. Blocking of opioid receptors during RSV infection in vaccinated mice (FI-RSV-RSV + NL) had no significant effects on RSV immunopathogenesis. Moreover, administration of nalmefene in combination with FI-RSV and blocking opioid receptors during RSV infection (FI-RSV + NL-RSV + NL) resulted in an increased influx of the immune cells to the BAL fluid, increases the level of IFN-γ, lung pathology, and weight loss in compared to control condition. Although nalmefene administration within FI-RSV vaccine decreases vaccine-enhanced infection during subsequent exposure to the virus, opioid receptor blocking during RSV infection aggravates the host inflammatory response to RSV infection. Thus, caution is required due to beneficial/harmful functions of opioid systems while targeting as potentially therapies.

Keywords

Respiratory syncytial virus Formalin-inactivated RSV Immunopathogenesis Opioids Nalmefene 

Abbreviations

RSV

Respiratory syncytial virus

FI-RSV

Formalin-inactivated RSV

Th

T-helper

MORs

µ-Opioid receptors

DORs

δ-Opioid receptors

KORs

κ-Opioid receptors

PBS

Phosphate buffer saline

NL

Nalmefene

BAL

Bronchoalveolar lavage

BALF

BAL fluid

BE

Beta-endorphin

SP

Substance P

Notes

Acknowledgements

This work was supported by Iran National Science Foundation (No.88000497).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

References

  1. 1.
    Borchers AT, Chang C, Gershwin ME, Gershwin LJ (2013) Respiratory syncytial virus—a comprehensive review. Clin Rev Allergy Immunol 45:331–379CrossRefPubMedGoogle Scholar
  2. 2.
    Shi T, McAllister DA, O’Brien KL, Simoes EAF, Madhi SA, Gessner BD et al (2017) Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 390:946–958CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Salimi V, Tavakoli-Yaraki M, Yavarian J, Bont L, Mokhtari-Azad T (2015) Prevalence of human respiratory syncytial virus circulating in Iran. J Infect Public Health 9:125–135CrossRefPubMedGoogle Scholar
  4. 4.
    Openshaw PJ, Chiu C, Culley FJ, Johansson C (2017) Protective and harmful immunity to RSV infection. Annu Rev Immunol 26:501–532CrossRefGoogle Scholar
  5. 5.
    Fauroux B, Simoes EA, Checchia PA, Paes B, Figueras-Aloy J, Manzoni P et al (2017) The burden and long-term respiratory morbidity associated with respiratory syncytial virus infection in early childhood. Infect Dis Ther 6:173–197CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Graham BS (2017) Vaccine development for respiratory syncytial virus. Current Opin Virol 23:107–112CrossRefGoogle Scholar
  7. 7.
    Broadbent L, Groves H, Shields MD, Power UF (2015) Respiratory syncytial virus, an ongoing medical dilemma: an expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials. Influenza Other Respir Viruses 9:169–178CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tahamtan A, Inchley CS, Marzban M, Tavakoli-Yaraki M, Teymoori-Rad M, Nakstad B et al (2016) The role of microRNAs in respiratory viral infection: friend or foe? Rev Med Virol 26:389–407CrossRefPubMedGoogle Scholar
  9. 9.
    Mazur NI, Martinón-Torres F, Baraldi E, Fauroux B, Greenough A, Heikkinen T et al (2015) Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics. Lancet Respir Med 3:888–900CrossRefPubMedGoogle Scholar
  10. 10.
    Openshaw PJ, Tregoning JS (2005) Immune responses and disease enhancement during respiratory syncytial virus infection. Clin Microbiol Rev 18:541–555CrossRefGoogle Scholar
  11. 11.
    Waris ME, Tsou C, Erdman DD, Zaki SR, Anderson LJ (1996) Respiratory synctial virus infection in BALB/c mice previously immunized with formalin-inactivated virus induces enhanced pulmonary inflammatory response with a predominant Th2-like cytokine pattern. J Virol 70:2852–2860PubMedPubMedCentralGoogle Scholar
  12. 12.
    Blanco JC, Boukhvalova MS, Shirey KA, Prince GA, Vogel SN (2010) New insights for development of a safe and protective RSV vaccine. Hum Vaccines 6:482–492CrossRefGoogle Scholar
  13. 13.
    Stein C (2015) Opioid receptors. Annu Rev Med 67:433–51Google Scholar
  14. 14.
    Bidlack JM (2000) Detection and function of opioid receptors on cells from the immune system. Clin Diagn Lab Immunol 7:719–723Google Scholar
  15. 15.
    Tahamtan A, Tavakoli-Yaraki M, Mokhtari-Azad T, Teymuri-Rad M, Bont L, Shokri F et al (2016) Opioids and viral infections: a double-edged sword. Front Microbiol 7:970CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Salimi V, Hennus MP, Mokhtari-Azad T, Shokri F, Janssen R, Hodemaekers HM et al (2013) Opioid receptors control viral replication in the airways. Crit Care Med 41:205–214CrossRefPubMedGoogle Scholar
  17. 17.
    Osborn MD, Lowery JJ, Skorput AG, Giuvelis D, Bilsky EJ (2010) In vivo characterization of the opioid antagonist nalmefene in mice. Life Sci 86:624–630CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K et al (1969) Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 89:422–434CrossRefGoogle Scholar
  19. 19.
    Salimi V, Ramezani A, Mirzaei H, Tahamtan A, Faghihloo E, Rezaei F et al (2017) Evaluation of the expression level of 12/15 lipoxygenase and the related inflammatory factors (CCL5, CCL3) in respiratory syncytial virus infection in mice model. Microb Pathog 109:209–213CrossRefPubMedGoogle Scholar
  20. 20.
    Jazani NH, Sohrabpour M, Mazloomi E, Shahabi S (2011) A novel adjuvant, a mixture of alum and the general opioid antagonist naloxone, elicits both humoral and cellular immune responses for heat-killed Salmonella typhimurium vaccine. FEMS Immunol Med Microbiol 61:54–62CrossRefPubMedGoogle Scholar
  21. 21.
    Shahabi S, Azizi H, Mazloomi E, Tappeh KH, Seyedi S, Mohammadzadeh H (2014) A novel adjuvant, the mixture of alum and naltrexone, augments vaccine-induced immunity against Plasmodium berghei. Immunol Investig 43:653–666CrossRefGoogle Scholar
  22. 22.
    Khorshidvand Z, Shahabi S, Mohamadzade H, Daryani A, Tappeh KH (2016) Mixture of Alum–Naloxone and Alum–Naltrexone as a novel adjuvant elicits immune responses for Toxoplasma gondii lysate Antigen in BALB/c mice. Exp Parasitol 162:28–34CrossRefPubMedGoogle Scholar
  23. 23.
    Jamali A, Mahdavi M, Hassan ZM, Sabahi F, Farsani MJ, Bamdad T et al (2009) A novel adjuvant, the general opioid antagonist naloxone, elicits a robust cellular immune response for a DNA vaccine. Int Immunol 21:217–225CrossRefPubMedGoogle Scholar
  24. 24.
    Bart G, Schluger JH, Borg L, Ho A, Bidlack JM, Kreek MJ (2005) Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity? Neuropsychopharmacol: Off Public Am Coll Neuropsychopharmacol 30:2254–2262CrossRefGoogle Scholar
  25. 25.
    Panerai AE, Sacerdote P (1997) Beta-endorphin in the immune system: a role at last? Immunol Today 18:317–319CrossRefPubMedGoogle Scholar
  26. 26.
    Johnson TR, Rao S, Seder RA, Chen M, Graham BS (2009) TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity. Vaccine 27:3045–3052CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kaneider NC, Kaser A, Dunzendorfer S, Tilg H, Patsch JR, Wiedermann CJ (2005) Neurokinin-1 receptor interacts with PrP 106–126-induced dendritic cell migration and maturation. J Neuroimmunol 158:153–158CrossRefPubMedGoogle Scholar
  28. 28.
    Grimm MC, Ben-Baruch A, Taub DD, Howard OM, Resau JH, Wang JM et al (1998) Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization. J Exp Med 188:317–325CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hassan ATM, Hassan ZM, Moazzeni SM, Mostafaie A, Shahabi S, Ebtekar M et al (2009) Naloxone can improve the anti-tumor immunity by reducing the CD4 + CD25 + Foxp3 + regulatory T cells in BALB/c mice. Int Immunopharmacol 9:1381–1386CrossRefPubMedGoogle Scholar
  30. 30.
    Karaji AG, Hamzavi Y (2012) The opioid antagonist naloxone inhibits Leishmania major infection in BALB/c mice. Exp Parasitol 130:73–77CrossRefPubMedGoogle Scholar
  31. 31.
    Tahamtan A, Tavakoli-Yaraki M, Rygiel TP, Mokhtari-Azad T, Salimi V (2015) Effects of cannabinoids and their receptors on viral infections. J Med Virol 88:1–12CrossRefPubMedGoogle Scholar
  32. 32.
    Rios C, Gomes I, Devi LA (2006) mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol 148:387–395CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tahamtan A, Samieipoor Y, Nayeri FS, Rahbarimanesh AA, Izadi A, Rashidi-Nezhad A et al (2017) Effects of cannabinoid receptor type 2 in respiratory syncytial virus infection in human subjects and mice. Virulence.  https://doi.org/10.1080/21505594.2017.1389369

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Vahid Salimi
    • 1
  • Habib Mirzaei
    • 1
  • Ali Ramezani
    • 1
  • Alireza Tahamtan
    • 1
    • 2
  • Abbas Jamali
    • 3
  • Shahram Shahabi
    • 4
  • Maryam Golaram
    • 5
  • Bagher Minaei
    • 6
  • Mohammad Javad Gharagozlou
    • 7
  • Mahmood Mahmoodi
    • 8
  • Louis Bont
    • 9
  • Fazel Shokri
    • 5
  • Talat Mokhtari-Azad
    • 1
  1. 1.Department of Virology, School of Public HealthTehran University of Medical SciencesTehranIran
  2. 2.Department of Microbiology, School of MedicineGolestan University of Medical SciencesGorganIran
  3. 3.Influenza and Other Respiratory Viruses DepartmentPasteur Institute of IranTehranIran
  4. 4.Cellular and Molecular Research CenterUrmia University of Medical SciencesUrmiaIran
  5. 5.Department of Immunology, School of Public HealthTehran University of Medical SciencesTehranIran
  6. 6.Department of Anatomy, Faculty of MedicineTehran University of Medical SciencesTehranIran
  7. 7.Department of Pathology, Faculty of Veterinary MedicineUniversity of TehranTehranIran
  8. 8.Epidemiology and Biostatistics Department, School of Public HealthTehran University of Medical SciencesTehranIran
  9. 9.Department of Paediatrics, Wilhelmina Children’s HospitalUniversity Medical Centre UtrechtUtrechtThe Netherlands

Personalised recommendations