Effect of innate and induced immunity on infectious bursal disease pathogenesis

Infectious bursal disease (IBD) is induced by a small non-enveloped virus, which is highly stable in the outer environment. The infectious bursal disease virus (IBDV) affects chicken’s immune system in a comprehensive and integrated manner thus destructing B-lymphocytes, attracting T-cells and activating macrophages. Being the RNA-virus, the agent is specified by high frequency of mutations, which result in the emergence of the strains with modified antigenicity and increased virulence. The molecular basis for the virus pathogenicity and exact cause of the clinical disease and death are still understudied as they are not clearly associated with the disease severity and degree of bursa of Fabricius lesions. Recent studies, however, demonstrated the role of the enhanced immune response at early stage of the infection along with increased production of cytokine storm-inducing promediators. In case of IBD, the immunosuppression is both direct consequence of specific target-cell infection and indirect consequence of the interactions occurring in the bird’s immune network. Infection with highly virulent virus strain or chicks’ infection at early age after recovery or subclinical infection results in immunosuppression with more severe consequences. Since immunosuppression induced by IBD agent is targeted mostly at B-lymphocytes, effect on the cell-mediated immunity was also demonstrated and it enhances the virus pressure on the immunocompetence of the chicks. The recent progress in avian immunology allowed for better understanding of the immunological mechanisms involved in the disease development. This review focuses on the role of the innate immunity in IBD pathogenesis as it is the first line of protection against the virus replication and can predetermine the disease outcome.

1. Mahgoub H. A. An overview of infectious bursal disease. Arch. Virol. 2012; 157 (11): 2047–2057. DOI: 10.1007/s00705-012-1377-9.

2. Ingrao F., Rauw F., Lambrecht B., van den Berg T. Infectious bursal disease: a complex host-pathogen interaction. Dev. Comp. Immunol. 2013; 41 (3): 429–438. DOI: 10.1016/j.dci.2013.03.017.

3. Wang W., He X., Zhang Y., Qiao Y., Shi J., Chen R., et al. Analysis of the global origin, evolution and transmission dynamics of the emerging novel variant IBDV (A2dB1b): the accumulation of critical aa-residue mutations and commercial trade contributes to the emergence and transmission of novel variants. Transbound. Emerg. Dis. 2022; 69 (5): e2832–e2851. DOI: 10.1111/tbed.14634.

4. Islam M. R., Nooruzzaman M., Rahman T., Mumu T. T., Rahman M. M., Chowdhury E. H., et al. A unified genotypic classification of infectious bursal disease virus based on both genome segments. Avian Pathol. 2021; 50 (2): 190–206. DOI: 10.1080/03079457.2021.1873245.

5. Nooruzzaman M., Hossain I., Rahman M. M., Uddin A. J., Mustari A., Parvin R., et al Comparative pathogenicity of infectious bursal disease viruses of three different genotypes. Microb. Pathog. 2022; 169:105641. DOI: 10.1016/j.micpath.2022.105641.

6. Fan L., WuT., WangY., Hussain A., Jiang N., Gao L., et al. Novel variants of infectious bursal disease virus can severely damage the bursa of Fabricius of immunized chickens. Vet. Microbiol. 2020; 240:108507. DOI: 10.1016/j.vetmic.2019.108507.

7. Shirokov D. A., Dubovoi A. S., ManuveraV. A., Samuseva G. N., Dmitrieva M. E., Lazarev V. N. Complete genome sequence of a novel very virulent strain of infectious bursal disease virus circulating in Russia. Microbiol. Resour. Announc. 2018; 7 (20):e01084-18. DOI: 10.1128/MRA.01084-18.

8. TakeuchiO., Akira S. Innate immunity to virusinfection. Immunol. Rev. 2009; 227 (1): 75–86. DOI: 10.1111/j.1600-065X.2008.00737.x.

9. Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007; 449 (7164): 819–826. DOI: 10.1038/nature06246.

10. Lombardo E., Maraver A., Espinosa I., Fernández-Arias A., Rodriguez J. F. VP5, the nonstructural polypeptide of infectious bursal disease virus, accumulates within the host plasma membrane and induces cell lysis. Virology. 2000; 277 (2): 345–357. DOI: 10.1006/viro.2000.0595.

11. Irigoyen N., Castón J. R., Rodríguez J. F. Host proteolytic activity is necessary for infectious bursal disease virus capsid protein assembly. J. Biol. Chem. 2012; 287 (29): 24473–24482. DOI: 10.1074/jbc.M112.356113.

12. Irigoyen N., Garriga D., Navarro A., Verdaguer N., Rodríguez J. F., Castón J. R. Autoproteolytic activity derived from the infectious bursal disease virus capsid protein. J. Biol. Chem. 2009; 284 (12): 8064–8072. DOI: 10.1074/jbc.M808942200.

13. QinY., Xu Z., WangY., Li X., Cao H., Zheng S. J. VP2 of infectious bursal disease virus induces apoptosis via triggering oral cancer overexpressed 1 (ORAOV1) protein degradation. Front. Microbiol. 2017; 8:1351. DOI: 10.3389/fmicb.2017.01351.

14. Li Z., Wang Y., Xue Y., Li X., Cao H., Zheng S. J. Critical role for voltage-dependent anion channel 2 in infectious bursal disease virus-induced apoptosis in host cells via interaction with VP5. J. Virol. 2012; 86 (3): 1328–1338. DOI: 10.1128/JVI.06104-11.

15. Lin W., Zhang Z., Xu Z., Wang B., Li X., Cao H., et al. The association of receptor of activated protein kinase C 1(RACK1) with infectious bursal disease virus viral protein VP5 and voltage-dependent anion channel 2 (VDAC2) inhibits apoptosis and enhances viral replication. J. Biol. Chem. 2015; 290 (13): 8500–8510. DOI: 10.1074/jbc.M114.585687.

16. Maraver A., Oña A., Abaitua F., González D., Clemente R., RuizDíaz J. A., et al. The oligomerization domain of VP3, the scaffolding protein of infectious bursal disease virus, plays a critical role in capsid assembly. J. Virol. 2003; 77 (11): 6438–6449. DOI: 10.1128/jvi.77.11.6438-6449.2003.

17. Kochan G., Gonzalez D., Rodriguez J. F. Characterization of the RNA-binding activity of VP3, a majorstructural protein of infectious bursal disease virus. Arch. Virol. 2003; 148 (4): 723–744. DOI: 10.1007/s00705-002- 0949-5.

18. DengT., Hu B., Wang X., YanY., Zhou J., Lin L., et al. DeSUMOylation of apoptosis inhibitor 5 by Avibirnavirus VP3 supports virus replication. mBio. 2021; 12 (4):e0198521. DOI: 10.1128/mBio.01985-21.

19. Shirokov D. A., Manuvera V. A., Miroshina O. A., Dubovoi A. S., Samuseva G. N., Dmitrieva M. E., Lazarev V. N. Generation of recombinant VP3 protein of infectious bursal disease virus in three different expression systems, antigenic analysis of the obtained polypeptides and development of an ELISA test. Arch. Virol. 2020; 165 (7): 1611–1620. DOI: 10.1007/s00705-020-04650-2.

20. Li Z., Wang Y., Li X., Li X., Cao H., Zheng S. J. Critical roles of glucocorticoid-induced leucine zipper in infectious bursal disease virus (IBDV)- induced suppression of type I interferon expression and enhancement of IBDV growth in host cells via interaction with VP4. J. Virol. 2013; 87 (2): 1221–1231. DOI: 10.1128/JVI.02421-12.

21. He Z., Chen X., Fu M., Tang J., Li X., Cao H., et al. Infectious bursal disease virus protein VP4 suppresses type I interferon expression via inhibiting K48-linked ubiquitylation of glucocorticoid-induced leucine zipper (GILZ). Immunobiology. 2018; 223 (4–5): 374–382. DOI: 10.1016/j.imbio.2017.10.048.

22. Dulwich K. L., Asfor A., Gray A., Giotis E. S., Skinner M. A., Broadbent A. J. The stronger downregulation of in vitro and in vivo innate antiviral responses by a very virulent strain of infectious bursal disease virus (IBDV), compared to a classicalstrain, is mediated, in part, by theVP4 protein. Front. Cell. Infect. Microbiol. 2020; 10:315. DOI: 10.3389/fcimb.2020.00315.

23. Nouën C. L., ToquinD., Müller H., Raue R., Kean K. M., Langlois P., et al. Different domains of the RNA polymerase of infectious bursal disease virus contribute to virulence. PLoSOne. 2012; 7 (1):e28064. DOI: 10.1371/journal.pone.0028064.

24. Palmquist J. M., Khatri M., Cha R. M., Goddeeris B. M., Walcheck B., Sharma J. M. In vivo activation of chicken macrophages by infectious bursal disease virus. Viral Immunol. 2006; 19 (2): 305–315. DOI: 10.1089/vim.2006.19.305.

25. EldaghayesI., Rothwell L., Williams A., Withers D., Balu S., Davison F., Kaiser P. Infectious bursal disease virus: strainsthat differ in virulence differentially modulate the innate immune response to infection in the chicken bursa. Viral Immunol. 2006; 19 (1): 83–91. DOI: 10.1089/vim.2006.19.83.

26. Rasoli M., Yeap S. K., Tan S. W., Roohani K., Kristeen-Teo Y. W., AlitheenN. B., et al. Differential modulation of immune response and cytokine profiles in the bursae and spleen of chickens infected with very virulent infectious bursal disease virus. BMC Vet. Res. 2015; 11:75. DOI: 10.1186/s12917-015-0377-x.

27. Liu A., Li H., Qi X., Wang Q., Yang B., Wu T., et al. Macrophage migration inhibitory factor triggersinflammatory responses during very virulent infectious bursal disease virus infection. Front. Microbiol. 2019; 10:2225. DOI: 10.3389/fmicb.2019.02225.

28. Asfor A. S., Nazki S., Reddy V. R. A. P., Campbell E., Dulwich K. L., Giotis E. S., et al. Transcriptomic analysis of inbred chicken lines reveals infectious bursal disease severity is associated with greater bursal inflammation in vivo and more rapid induction of pro-inflammatory responses in primary bursal cells stimulated ex vivo. Viruses. 2021; 13 (5):933. DOI: 10.3390/v13050933.

29. He Z., MaY., WuD., FengW., Xiao J. Protective effects of the NLRP3 inflammasome againstinfectious bursal disease virusreplication inDF-1 cells. Arch. Virol. 2021; 166 (7): 1943–1950. DOI: 10.1007/s00705-021-05099-7.

30. Xu Z. Y., YuY., LiuY., Ou C. B., ZhangY. H., Liu T. Y., et al. Differential expression of pro-inflammatory and anti-inflammatory genes of layer chicken bursa after experimental infection with infectious bursal disease virus. Poult. Sci. 2019; 98 (11): 5307–5314. DOI: 10.3382/ps/pez312.

31. Broto L., Romero N., Méndez F., Diaz-Beneitez E., Candelas-Rivera O., Fuentes D., et al. Type I interferon acts as a major barrier to the establishment of infectious bursal disease virus (IBDV) persistent infections. J. Virol. 2021; 95 (5): e02017-20. DOI: 10.1128/JVI.02017-20.

32. Lee C. C., Wu C. C., Lin T. L. Chicken melanoma differentiationassociated gene 5 (MDA5) recognizes infectious bursal disease virus infection and triggers MDA5-related innate immunity. Arch. Virol. 2014; 159 (7): 1671–1686. DOI: 10.1007/s00705-014-1983-9.

33. Chen R., Chen J., Xiang Y., Chen Y., Shen W., Wang W., et al. Differential modulation of innate antiviral profiles in the intestinal lamina propria cells of chickensinfected with infectious bursal disease viruses of different virulence. Viruses. 2022; 14 (2):393. DOI: 10.3390/v14020393.

34. Quan R., Zhu S., Wei L., Wang J., Yan X., Li Z., Liu J. Transcriptional profiles in bursal B-lymphoid DT40 cells infected with very virulent infectious bursal disease virus. Virol. J. 2017; 14 (1):7. DOI: 10.1186/s12985-016-0668-2.

35. HeX., ChenY., KangS., ChenG., WeiP. Differentialregulationof chTLR3 by infectious bursal disease viruses with different virulence in vitro and in vivo. Viral. Immunol. 2017; 30 (7): 490–499. DOI: 10.1089/vim.2016.0134.

36. Rauf A., Khatri M., Murgia M. V., Jung K., Saif Y. M. Differential modulation of cytokine, chemokine and Toll like receptor expression in chickens infected with classical and variant infectious bursal disease virus. Vet. Res. 2011; 42:85. DOI: 10.1186/1297-9716-42-85. 3

37. Lee C. C., Wu C. C., Lin T. L. Role of chicken melanoma differentiation-associated gene 5 in induction and activation of innate and adaptive immune responsesto infectious bursal disease virusin cultured macrophages. Arch. Virol. 2015; 160 (12): 3021–3035. DOI: 10.1007/s00705-015-2612-y.

38. Smith J., Sadeyen J. R., Butter C., Kaiser P., Burt D. W. Analysis of the early immune response to infection by infectious bursal disease virus in chickens differing in their resistance to the disease. J. Virol. 2015; 89 (5): 2469–2482. DOI: 10.1128/JVI.02828-14.

39. Gao X., Ding J., Liao C., Xu J., Liu X., Lu W. Defensins: the natural peptide antibiotic. Adv. Drug Deliv. Rev. 2021; 179:114008. DOI: 10.1016/j.addr.2021.114008.

40. ZhangH. H., Yang X. M., XieQ. M., Ma J. Y., LuoY. N., CaoY. C., et al. The potent adjuvant effects of chicken beta-defensin-1 when genetically fused with infectious bursal disease virusVP2 gene. Vet. Immunol. Immunopathol. 2010; 136 (1–2): 92–97. DOI: 10.1016/j.vetimm.2010.02.018.

41. Vasconcelos A. C., Lam K. M. Apoptosisinduced by infectious bursal disease virus. J. Gen. Virol. 1994; 75 (Pt 7): 1803–1806. DOI: 10.1099/0022-1317-75-7-1803.

42. Huang X., Liu W., Zhang J., Liu Z., Wang M., Wang L., et al. Very virulent infectious bursal disease virus-induced immune injury is involved in inflammation, apoptosis, and inflammatory cytokines imbalance in the bursa of fabricius. Dev. Comp. Immunol. 2021; 114:103839. DOI: 10.1016/j.dci.2020.103839.

43. Shah A. U., Li Y., Ouyang W., Wang Z., Zuo J., Shi S., et al. From nasal to basal: single-cellsequencing ofthe bursa of Fabricius highlightsthe IBDV infection mechanism in chickens. Cell Biosci. 2021; 11 (1):212. DOI: 10.1186/s13578-021-00728-9.

44. Aliyu H. B., Hamisu T. M., Hair Bejo M., Omar A. R., Ideris A. Comparative pathogenicity of Malaysian variant and very virulent infectious bursal disease virusesin chickens. Avian Pathol. 2022; 51 (1): 76–86. DOI: 10.1080/03079457.2021.2006604.

45. Kim I. J., You S. K., Kim H., Yeh H. Y., Sharma J. M. Characteristics of bursal T lymphocytes induced by infectious bursal disease virus. J. Virol. 2000; 74 (19): 8884–8892. DOI: 10.1128/jvi.74.19.8884-8892.2000.

46. Liu H., Zhang M., Han H., Yuan J., Li Z. Comparison of the expression of cytokine genesin the bursal tissues of the chickensfollowing challenge with infectious bursal disease viruses of varying virulence. Virol. J. 2010; 7:364. DOI: 10.1186/1743-422X-7-364.

47. Rautenschlein S., Yeh H. Y., Njenga M. K., Sharma J. M. Role of intrabursal T cells in infectious bursal disease virus (IBDV) infection: T cells promote viral clearance but delay follicular recovery. Arch. Virol. 2002; 147 (2): 285–304. DOI: 10.1007/s705-002-8320-2.

48. Viswanathan K., Früh K. Viral proteomics: global evaluation of viruses and their interaction with the host. Expert Rev. Proteomics. 2007; 4 (6): 815–829. DOI: 10.1586/14789450.4.6.815.

49. Abgarian S. R., Nikitina N. I., Semin A. N. Moleculary-biological diagnostics of respiratory diseases in birds. International Journal of Veterinary Medicine. 2019; (3): 11–15. DOI: 10.17238/issn2072-2419.2019.3.11. (in Russ.)

50. Gao L., Li K., Zhong L., Zhang L., Qi X., WangY., et al. Eukaryotic translational initiation factor 4AII reduces the replication of infectious bursal disease virus by inhibitingVP1 polymerase activity. Antiviral Res. 2017; 139: 102–111. DOI: 10.1016/j.antiviral.2016.11.022. DNA vaccine against IBDV in chickens. Viruses. 2019; 11 (5): 476. DOI: 10.3390/v11050476.

51. Wang S., Yu M., Liu A., Bao Y., Qi X., Gao L., et al. TRIM25 inhibits infectious bursal disease virus replication by targeting VP3 for ubiquitination and degradation. PLoS Pathog. 2021; 17 (9):e1009900. DOI: 10.1371/ journal.ppat.1009900.

52. Hu B., Zhang Y., Jia L., Wu H., Fan C., Sun Y., et al. Binding of the pathogen receptor HSP90AA1 to avibirnavirus VP2 induces autophagy by inactivating the AKT-MTOR pathway. Autophagy. 2015; 11 (3): 503–515. DOI: 10.1080/15548627.2015.1017184.

53. LiY., Hu B., Ji G., ZhangY., Xu C., LeiJ., et al. Cytoplasmic cargo receptor p62 inhibits avibirnavirus replication by mediating autophagic degradation of viral protein VP2. J. Virol. 2020; 94 (24):e01255-20. DOI: 10.1128/ JVI.01255-20.

54. Huo S., Zhang J., Fan J., Wang X., Wu F., Zuo Y., Zhong F. Co-expression of chicken IL-2 and IL-7 enhancesthe immunogenicity and protective efficacy of a VP2-expressing DNA vaccine against IBDV in chickens. Viruses. 2019; 11 (5): 476. DOI: 10.3390/v11050476.