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Infectious Bursal Disease Virus | 213

plays an important role in viral replication and pathogenicity of recombinant CD40L could be employed as an important strat-
vvIBDV. In contrast to VP1, VP2 seems to be more responsible egy to isolate pathogenic IBDV strains directly from the clinical
for the virulence of IBDV. Comparison of amino acid sequences samples. Although IBDV has a tropism for dividing B cells, it can
of VP2 variable region of three clinical IBDV isolates reveals that infect chicken fibroblasts (Somvanshi et al., 1992; Giotis et al.,
change of residue 284 (Thr to Ala) had a critical role in cell culture 2017), dendritic cells (Liang et al., 2015; Lin et al., 2016), and
infectivity, whereas the change in residue 279 (Asp to Asn) was macrophages (Palmquist et al., 2006; Khatri and Sharma, 2006,
associated with attenuation of the virus (Toroghi et al., 2001). In 2007). In addition, IBDV can infect and replicate in mammalian
addition, alteration of two specific amino acids (Q253H-A284T) cells such as Vero, HEK293T- and Hela cells (Fernández-Arias et
in VP2 HVR region of vvIBDV UK661 strain resulted in tissue al., 1997; Upadhyay et al., 2011). IBDV, like other non-enveloped
culture adaptation and attenuation of vvIBDV in chickens, viruses, is unable to utilize membrane fusion to enter the target
demonstrating that VP2 plays a decisive role in pathogenicity of cells. Endocytosis of receptor-bound viral particle by target cell
IBDV (van Loon et al., 2002). VP3 and VP5 are also related to seems to be the major means of IBDV infection (Yip et al., 2012).
the virulence of IBDV because exchange of the C-terminal part However, the exact mechanism underlying the invasion of IBDV
of VP3 from vvIBDV results in an attenuated virus with a unique is still not very clear.
antigenic structure(Boot et al., 2002) and exchange of the VP5
of serotype I with that of a serotype II strain reduced the viral Cell membrane receptors and the key elements
replication and cytotoxicity (Qin et al., 2009). Thus, the virulence associated with the entry of IBDV
of IBDV seems to be determined by multiple factors rather than The first step of IBDV infection is the attachment of virus to the
by VP2 only although the emergence of vvIBDV in infected flocks cell membrane specific receptors, followed by the endocytosis
is closely associated with the genetic variation of VP2. of the viral particle by target cells. Several cellular membrane
proteins, such as surface immunoglobulin M (sIgM), chicken
heat shock protein 90 (chHSP90), α4β1 integrin and Annexin
IBDV and host interaction II (Anx2), were proven to be the putative receptors for the entry
of IBDV, and were mostly discovered in the investigation of
Host and target cells host cellular proteins that bind to the viral particles or VP2, the
IBDV is highly host-specific. Serotype I IBDV mainly infects major component of the viral capsids. The sIgM of B lympho-
young chickens and causes clinical disease although it can be cyte was the first reported cellular receptor for IBDV because
easily isolated from adult chicken flocks with a history of IBD most of IBDV-infected cells were sIgM-positive B cells (Ogawa
occurrence. Cell-adapted strains of IBDV or vaccine could grow et al., 1998). Importantly, infection of DT40, a chicken bursal
well in mammalian cells (Vero cells, 293T-cells and BHK cells) in lymphoma-derived cell line, by IBDV was inhibited by monoclo-
vitro culture, but it has not been reported so far that IBDV could nal antibody against sIgM, and the λ light chain of sIgM can bind
cause disease in mammals. Inoculation of game/ornamental birds to the virus particle in a virulence-independent manner (Luo
(quails, partridges, pheasants and guinea fowls) with vvIBDV et al., 2010), suggesting that sIgM of B cell serves as the recep-
strains failed to induce disease (Ingrao et al., 2013). Serotype 1 tor for IBDV. However, the facts that cells without sIgM could
IBDV strains could be isolated from fowl and ducks, suggesting also be infected by IBDV indicate that sIgM is only one of the
that they might serve as the carriers for IBDV (McFerran et al., putative membrane receptors for IBDV that are required for the
1980). The developing B cells in the BF is generally regarded as viral infection. It was found that chHSP90 on the surface of DF-1
the target cells of IBDV (Müller, 1986; Rodenberg et al., 1994). cell membrane interacted with IBDV particle or VP2-subviral
Interestingly, the pathogenic serotype 1 virulent IBDV, non- particle (SVP), and that both chHSP90 and anti-chHSP90 could
cell-culture-adapted strains, can infect and grow very well in ex inhibit infection of DF-1 cell by IBDV (Lin et al., 2007), indicat-
vivo bursal primary cell culture stimulated with CD40 ligand ing chHSP90 as an IBDV receptor. Furthermore, capsid protein
(CD40L) (Dulwich et al., 2017). In principle, activation of mature VP2 of IBDV contains a functional ligand motif to α4β1 integrin
B cells not only requires engagement of B cell receptor (BCR) based on a multiple alignment (Delgui et al., 2009), and the α4β1
by thymus-dependent (TD) antigen but needs co-stimulation heterodimer is highly abundant in immature B lymphocytes and
via interaction of B cell membrane molecule CD40 with CD40L involved in their development (Rose et al., 2002), suggesting that
of activated CD4+T-cells. Signals delivered by the interaction of α4β1 integrin is involved in the selective tropism of IBDV.
CD40 with CD40L have crucial roles in the immune response The entry strategies employed by non-enveloped virus have
and are required for the development of germinal centres, not been fully understood so far. In general, the cellular mem-
maturation of T-dependent antibody response, and generation brane is breached by the lytic factors of virus, resulting in the
of B-cell memory, and these functions were also conserved in a transfer of the viral genome or nucleocapsid into the cytosol.
non-mammalian species (chicken) (Tregaskes et al., 2005). It was The cellular membrane perforation and conformational change
found that CD40L fusion proteins supported the proliferation were reported as the essential steps for non-enveloped virus
of B cells in cultures for up to 3 weeks and they differentiated to cross the membrane barrier (Moyer and Nemerow, 2011).
into plasma cell phenotype, secreting antibodies (Kothlow et In the case of IBDV infection, Pep46, a capsid-associated
al., 2008). As the proliferating B cells are permissive to vvIBDV peptide generated from the C-terminus of pVP2 by VP4 cleav-
(Dulwich et al., 2017), primary bursal cell culture stimulated with age, shows membrane perforating activity that deforms the