Contribución del Interferón a la citopatogenicidad causada por el virus de la bursitis infecciosa (IBDV)

Abstract

Infectious bursal disease virus (IBDV) belongs to the Birnaviridae family, which includes nonenveloped viruses containing two double-stranded RNA (dsRNA) segments enclosed within a single icosahedral capsid. Their genome is structured into ribonucleoprotein (RNP) complexes, where the dsRNA is wrapped by the VP3 protein and complexed with the polymerase VP1. IBDV is the etiological agent of a highly contagious and immunosuppressive disease (IBD) that affects juvenile domestic chickens (Gallus gallus). IBD or Gumboro disease leads to high mortality of infected animals, and is responsible for major economic losses to the poultry industry world-wide. IBD is characterized by a massive loss of immature B lymphocytes and the destruction of the bursa of Fabricius, the main lymphoid organ in birds. The molecular bases of the IBDV pathogenicity are still poorly understood, nonetheless, there is a growing body of information indicating that an exacerbated cytokine immune response together with a B cell depletion due to apoptosis are the main factors contributing to the severity of the disease. In this work, we described the role of type I interferon (IFN) and, to a lesser degree, of type II IFN on IBDV infection in both, mammalian and chicken cells lines. While IFN pretreatment confers protection against subsequent IBDV infection, IFN addition to infected cell cultures early after infection drives to a massive apoptotic cell death, predominantly carried out through extrinsic pathway. Downregulation of PKR and TNF-α expression, or inhibition of nuclear factor-κB (NF-κB) reduces drastically the extent of apoptosis in HeLa cells, indicating that these are critical proteins in the apoptotic response induced by IBDV upon treatment with IFN-α. However, PKR plays a partial function in the apoptosis induction in chicken cell lines, and neither TNF-α nor TRAIL are responsible of triggering apoptosis in these cells. Silencing of MAVS expression indicates IFNB induction that occurs in infected cells upon IFN treatment could not be relevant in this apoptosis induction in the in vitro system, although it could be important in vivo. Our results indicate that IBDV genomic dsRNA is the viral factor contributing to apoptosis triggering. These findings provide novel insights into the potential mechanisms of IBDV-induced immunosuppression and pathogenesis in chickens.