Respiratory syncytial virus infection in mice inducing airway disfunction associated with lung tissue inflammation as a model of human pathology

Abstract

Abstract. Human respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in children. RSV infection, characterized by high morbidity and mortality, is a serious public health problem. There are no licensed vaccines available for the prevention of this disease. Save and affordable medications for RSV treatment were not developed yet. One of the main difficulties to study RSV pathogenesis and to develop new approaches for its therapy is the lack universal animal model that recapitulates all aspects of human pathology. There are exist animal models of RSV infection in mice, rats, ferrets, calves, sheeps, chimpanzees, etc. Most often, mice are used for RSV modeling, since their use is most economically feasible. However, RSV is not a natural pathogen for mice, therefore its replication in the mouse respiratory tract is not significant, and pathological features are poorly expressed. That is the main reason why all aspects of human RSV pathology could not be reproduced in mice simultaneously. In this study, we created the BALB/c mouse infection protocol with purified and concentrated RSV (strain A2), which allows induce such clinically significant manifestations of human pathology as bronchial hyperreactivity, pneumonia, respiratory tract infiltration by pro-inflammatory cells, etc. A study showed that RSV infection activates mainly Th1 immune response in mice, which is consistent with clinical observations in humans. Model of RSV infection in mice developed in this study can be used both to clarify the pathogenesis of the disease and to test new approaches for anti-RSV therapy.

Keywords:respiratory syncytial virus; murine model; immune response

For citation: Shilovskiy I.P, Nikolskii A.A., Nikonova A.A., Gaisina A.R., Vishniakova L.I., Barvinskaya E.D., Kovchina VI., Bolotova S.I., Yumashev K.V., Brylina V.E., Khaitov M.R. Respiratory syncytial virus infection in mice inducing airway disfunction associated with lung tissue inflammation as a model of human pathology. Immunologiya. 2019. 40 (5): 72-83. doi: 10.24411/0206-4952-2019-15008.

Funding. The study was supported by RSF No 18-74-10002.

Conflict of interests. The authors declare no conflict of interests.

References

1. Shi T., Denouel A., Tietjen A.K., Campbell I., et al. Global disease burden estimates of respiratory syncytial virus-associated acute respiratory infection in older adults in 2015: a systematic review and meta-analysis. J. Infect. Dis. 2019.

URL: https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiz059/5382266

doi: 10.1093/infdis/jiz059

2. Allakhverdiyeva L.I., Humbatova U.M. Immune disturbances in children with virus-induced bronchial asthma. Immunologiya. 2013; 34 (4): 217-20. (in Russian)

3. Troeger C., Blacker B., Khalil I.A., Rao P.C., et al. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect. Dis. 2018; 18 (11): 1191-210.

URL: https://www.ncbi.nlm.nih.gov/pubmed/30243584

doi: 10.1016/S1473-3099(18)30310-4

4. Geoghegan S., Erviti A., Caballero M.T., Vallone F., et al. Mortality due to respiratory syncytial virus burden and risk factors. Am. J. Respir. Crit. Care. Med. 2017; 195 (1): 96-103.

URL: https://www.ncbi.nlm.nih.gov/pubmed/27331632

doi: 10.1164/rccm.201603-0658OC

5. Halasa N.B., Williams J.V., Wilson G.J., Walsh W.F., et al. Medical and economic impact of a respiratory syncytial virus outbreak in a neonatal intensive care unit. Pediatr. Infect. Dis. J. 2005; 24 (12): 1040-4.

URL: https://www.ncbi.nlm.nih.gov/pubmed/16371862

doi: 10.1097/01.inf.0000190027.59795.ac

6. Muralidharan A., Li C., Wang L., Li X. Immunopathogenesis associated with formaldehyde-inactivated RSV vaccine in preclinical and clinical studies. Expert Rev. Vaccines. 2017; 16 (4): 351-60.

URL: https://www.ncbi.nlm.nih.gov/pubmed/27841687

doi: 10.1080/14760584.2017.1260452

7. Janai H.K., Marks M.I., Zaleska M., Stutman H.R. Ribavirin: adverse drug reactions, 1986 to 1988. Pediatr. Infect. Dis. J. 1990; 9 (3): 209-11.

URL: https://www.ncbi.nlm.nih.gov/pubmed/2139930

doi: 10.1097/00006454-199003000-00013

8. Wang D., Cummins C., Bayliss S., Sandercock J., et al. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: A systematic review and economic evaluation. Health Technol. Assess. (Rockv.). 2008; 12 (36): 1-86.

URL: https://openaccess.city.ac.uk/id/eprint/3377/1/Immunoprophylaxis_against_respiratory.pdf

doi: 10.3310/hta12360

9. Khaitov M.R., Litvin L.S., Shilovsky I.P., Bashkatova Y.N., et al. RNA interference. New approaches to the development of antiviral agents. Immunologiya. 2010; 31 (2): 69-76. (in Russian)

10. Osminkina L.A., Timoshenko V.Y., Shilovsky I.P., Kornilaeva G.V., et al. Porous silicon nanoparticles as scavengers of hazardous viruses. J. Nanoparticle Res. 2014; 16 (6): 2430.

URL: https://www.researchgate.net/publication/262486489

doi: 10.1007/s11051-014-2430-2

11. Shilovskiy I.P., Andreev S.M., Kozhikhova K.V. Nikolskii A.A., et al. Prospects for the use of peptides against respiratory syncytial virus. Molekulyarnaya biologiya. 2019; 53 (4): 484-500. (in Russian)

URL: https://link.springer.com/article/10.1134%2FS0026893319040125

doi: 10.1134/s0026893319040125

12. Pinegin B.V., Pashchenkov M.V. Immunostimulators of muramylpeptide nature in the treatment and prevention of infectious-inflammatory processes. Immunologiya. 2019; 40 (3): 65-71. (in Russian)

13. Budikhina A.S. The role of antimicrobial peptides in the pathology of diseases of the upper respiratory tract. Immunologiya. 2017; 38 (4): 234-8. (in Russian)

URL: https://cyberleninka.ru/article/n/rol-antimikrobnyh-peptidov-v-patologii-zabolevaniy-verhnih-dyhatelnyh-putey/viewer

14. Krivitskaya V.Z., Aleksandrova N.A., Orlov A.V., Pokhodzey I.V. IGA response to respiratory-syncytial virus infection in children and adults with various forms of acute and chronic bronchitis. Immunologiya. 1999; 2: 51-5. (in Russian)

15. Griffiths C., Drews S.J., Marchant D.J. Respiratory syncytial virus: Infection, detection, and new options for prevention and treatment. Clin. Microbiol. Rev. 2017; 30 (1): 277-319.

URL: https://www.ncbi.nlm.nih.gov/pubmed/27903593

doi: 10.1128/CMR.00010-16

16. Plekhova N.G., Kodrashova N.M., Geltser B.I., Kotelnikov V.N. Cellular and molecular factors of innate defense and its role in the pathogenesis of pneumonia. Immunologiya. 2017; 38 (2): 124-9. (in Russian)

17. Russell C.D., Unger S.A., Walton M., Schwarze J. The human immune response to respiratory syncytial virus infection. Clin. Microbiol. Rev. 2017; 30 (2): 481-502.

URL: https://www.ncbi.nlm.nih.gov/pubmed/28179378

doi: 10.1128/CMR.00090-16

18. Taylor G. Animal models of respiratory syncytial virus infection. Vaccine. 2017; 35 (3): 469-80.

URL: https://www.ncbi.nlm.nih.gov/pubmed/27908639

doi: 10.1016/j.vaccine.2016.11.054

19. Altamirano-Lagos M.J., Díaz F.E., Mansilla M.A., Rivera-Pérezet D., et al. Current animal models for understanding the pathology caused by the respiratory syncytial virus. Front. Microbiol. 2019; 10: 1-18.

URL: https://www.ncbi.nlm.nih.gov/pubmed/31130923

doi: 10.3389/fmicb.2019.00873

20. Zschaler J., Schlorke D., Arnhold J. Differences in innate immune response between man and mouse. Crit. Rev. Immunol. 2014; 34 (5): 433-54.

21. Mejías A., Chávez-Bueno S., Ríos A.M., Aten M.F., et al. Comparative effects of two neutralizing anti-respiratory syncytial virus (RSV) monoclonal antibodies in the RSV murine model: time versus potency. Antimicrob. Agents Chemother. 2005; 49 (11): 4700-7.

URL: https://www.ncbi.nlm.nih.gov/pubmed/16251314

doi: 10.1128/AAC.49.11.4700-4707.2005

22. Khaitov M.R., Shilovskiy I.P., Nikonova A.A., Shershakova N.N., et al. Small interfering RNAs targeted to interleukin-4 and respiratory syncytial virus reduce airway inflammation in a mouse model of virus-induced asthma exacerbation. Hum. Gene Ther. 2014; 25 (7): 642-50.

URL: https://www.ncbi.nlm.nih.gov/pubmed/24655063

doi: 10.1089/hum.2013.142

23. Bitko V., Musiyenko A., Shulyayeva O., Barik S. Inhibition of respiratory viruses by nasally administered siRNA. Nat. Med. 2005; 11 (1): 50-5.

URL: https://www.ncbi.nlm.nih.gov/pubmed/15619632

doi: 10.1038/nm1164

24. Ueba O. Respiratory syncytial virus concentration and purification of the infectious virus. Acta Med. Okayama. 1978; 32 (4): 265-72.

25. Ennis D.P., Cassidy J.P., Mahon B.P. Acellular pertussis vaccine protects against exacerbation of allergic asthma due to Bordetella pertussis in a murine model. Clin. Diagn. Lab. Immunol. 2005; 12 (3): 409-17.

URL: https://www.ncbi.nlm.nih.gov/pubmed/15753254

doi: 10.1128/CDLI.12.3.409-417.2005

26. Stokes K.L., Chi M.H., Sakamoto K., Newcomb D.C., et al. Differential pathogenesis of respiratory syncytial virus clinical isolates in BALB/C mice. J. Virol. 2011; 85 (12): 5782-93.

URL: https://www.ncbi.nlm.nih.gov/pubmed/21471228

doi: 10.1128/jvi.01693-10

27. Johnson J.E., Gonzales R.A., Olson S.J., Wright P.F. The histopathology of fatal untreated human respiratory syncytial virus infection. Mod. Pathol. 2007; 20 (1): 108-19.

URL: https://pubmed.ncbi.nlm.nih.gov/17143259-the-histopathology-of-fatal-untreated-human-respiratory-syncytial-virus-infection/

doi: 10.1038/modpathol.3800725

28. Hashimoto K, Durbin JE, Zhou W, Collins R.D., et al. Respiratory syncytial virus infection in the absence of STAT1 results in airway dysfunction, airway mucus, and augmented IL-17 levels. J. Allergy Clin. Immunol. 2005; 116 (3): 550-7.

URL: https://pubmed.ncbi.nlm.nih.gov/16159623-respiratory-syncytial-virus-infection-in-the-absence-of-stat-1-results-in-airway-dysfunction-airway-mucus-and-augmented-il-17-levels/

doi: 10.1016/j.jaci.2005.03.051

29. Lukacs N.W., Moore M.L., Rudd B.D., Berlin A.A., et al. Differential immune responses and pulmonary pathophysiology are induced by two different strains of respiratory syncytial virus. Am. J. Pathol. 2006; 169 (3): 977-86.

URL: https://pubmed.ncbi.nlm.nih.gov/16936271-differential-immune-responses-and-pulmonary-pathophysiology-are-induced-by-two-different-strains-of-respiratory-syncytial-virus/

doi: 10.2353/ajpath.2006.051055

30. Rameix-Welti M.A., Le Goffic R., Hervé P.L., Sourimant J., et al. Visualizing the replication of respiratory syncytial virus in cells and in living mice. Nat. Commun. 2014; 5: 1-10.

URL: https://www.nature.com/articles/ncomms6104

doi: 10.1038/ncomms6104

31. Jafri H.S., Chávez-Bueno S., Mejías A., Gomez A.M., et al. Respiratory syncytial virus induces pneumonia, cytokine response, airway obstruction, and chronic inflammatory infiltrates associated with long‐term airway hyperresponsiveness in mice. J. Infect. Dis. 2004; 189 (10): 1856-65.

URL: https://pubmed.ncbi.nlm.nih.gov/15122522-respiratory-syncytial-virus-induces-pneumonia-cytokine-response-airway-obstruction-and-chronic-inflammatory-infiltrates-associated-with-long-term-airway-hyperresponsiveness-in-mice/

doi: 10.1086/386372

32. Zou Y., Huang H., Xu J. Primary respiratory syncytial virus infection in mice. Chin. J. Tuberc. Respir. Dis. 2001; 24 (8): 484-6.

33. Moore M.L., Chi M.H., Luongo C., Lukacs N.W., et al. A chimeric A2 strain of respiratory syncytial virus (RSV) with the fusion protein of RSV strain line 19 exhibits enhanced viral load, mucus, and airway dysfunction. J. Virol. 2009; 83 (9): 4185-94.

URL: https://pubmed.ncbi.nlm.nih.gov/19211758-a-chimeric-a2-strain-of-respiratory-syncytial-virus-rsv-with-the-fusion-protein-of-rsv-strain-line-19-exhibits-enhanced-viral-load-mucus-and-airway-dysfunction/

doi: 10.1128/jvi.01853-08

34. Smith P.K., Wang S.Z., Dowling K.D., Forsyth K.D. Leucocyte populations in respiratory syncytial virus-induced bronchiolitis. J. Paediatr. Child Health. 2001; 37 (2): 146-51.

URL: https://pubmed.ncbi.nlm.nih.gov/11328469-leucocyte-populations-in-respiratory-syncytial-virus-induced-bronchiolitis/

doi: 10.1046/j.1440-1754.2001.00618.x

35. Tripp R.A., Moore D., Barskey A. 4th, Jones L., et al. Peripheral blood mononuclear cells from infants hospitalized because of respiratory syncytial virus infection express T helper-1 and T helper-2 cytokines and CC chemokine messenger RNA. J. Infect. Dis. 2002; 185 (10): 1388-94.

URL: https://www.jstor.org/stable/30138142?seq=1

doi: 10.1086/340505

36. Elser B., Lohoff M., Kock S., Giaisi M., et al. IFN-γrepresses IL-4 expression via IRF-1 and IRF-2. Immunity. 2002; 17 (6): 703-12.

URL: https://www.cell.com/immunity/fulltext/S1074-7613(02)00471-5?

doi: 10.1016/S1074-7613(02)00471-5

37. Geevarghese B., Weinberg A. Cell-mediated immune responses to respiratory syncytial virus infection: magnitude, kinetics, and correlates with morbidity and age. Hum. Vaccines Immunother. 2014; 10 (4): 1047-56.

URL: https://pubmed.ncbi.nlm.nih.gov/24513666-cell-mediated-immune-responses-to-respiratory-syncytial-virus-infection-magnitude-kinetics-and-correlates-with-morbidity-and-age/

doi: 10.4161/hv.27908

38. Rosenberg H.F., Domachowske J.B. Inflammatory responses to respiratory syncytial virus (RSV) infection and the development of immunomodulatory pharmacotherapeutics. Curr. Med. Chem. 2012; 19 (10): 1424-31.

39. Puthothu B., Bierbaum S., Kopp M.V., Forster J., et al. Association of TNF-α with severe respiratory syncytial virus infection and bronchial asthma. Pediatr. Allergy Immunol. 2009; 20 (2): 157-63.

URL: https://pubmed.ncbi.nlm.nih.gov/18811622-association-of-tnf-alpha-with-severe-respiratory-syncytial-virus-infection-and-bronchial-asthma/

doi: 10.1111/j.1399-3038.2008.00751.x

40. Roufosse F. Targeting the interleukin-5 pathway for treatment of eosinophilic conditions other than asthma. Front. Med. 2018; 5: 1-27.

URL: https://pubmed.ncbi.nlm.nih.gov/29682504-targeting-the-interleukin-5-pathway-for-treatment-of-eosinophilic-conditions-other-than-asthma/

doi: 10.3389/fmed.2018.00049

41. Monin L., Gaffen S.L. Interleukin 17 family cytokines: Signaling mechanisms, biological activities, and therapeutic implications. Cold Spring Harb. Perspect. Biol. 2018; 10 (4): 1-19.

URL: https://pubmed.ncbi.nlm.nih.gov/28620097-interleukin-17-family-cytokines-signaling-mechanisms-biological-activities-and-therapeutic-implications/

doi: 10.1101/cshperspect.a028522

42. Lora J.M., Zhang D.M., Liao S.M., Burwell T., et al. Tumor necrosis factor-α triggers mucus production in airway epithelium through an IκB kinase β-dependent mechanism. J. Biol. Chem. 2005; 280 (43): 36 510-7.

URL: https://pubmed.ncbi.nlm.nih.gov/16123045-tumor-necrosis-factor-alpha-triggers-mucus-production-in-airway-epithelium-through-an-ikappab-kinase-beta-dependent-mechanism/

doi: 10.1074/jbc.M507977200

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)


JOURNALS of «GEOTAR-Media»