Stromal Interaction Molecule 1 Promotes the Replication of vvIBDV by Mobilizing Ca²⁺ in the ER

Infectious bursal disease virus (IBDV) is one of the main threats to the poultry industry worldwide. Very virulent IBDV (vvIBDV) is a fatal virus strain that causes heavy mortality in young chicken flocks. Ca²⁺ is one of the most universal and versatile signalling molecules and is involved in almost every aspect of cellular processes. Clinical examination showed that one of the characteristics of vvIBDV-infected chickens was severe metabolic disorders, and the chemical examination showed that their serum Ca²⁺ level decreased significantly. However, there are limited studies on how vvIBDV infection modulates the cellular Ca²⁺ level and the effect of Ca²⁺ level changes on vvIBDV replication. In our study, we found Ca²⁺ levels in the endoplasmic reticulum (ER) of vvIBDV-infected B cells were higher than that of mock-infected cells, and the expression level of stromal interaction molecule 1 (STIM1), an ER Ca²⁺ sensor, was significantly upregulated due to vvIBDV infection. The knock-down expression of STIM1 led to decreased Ca²⁺ level in the ER and suppressed vvIBDV replication, while the over-expressed STIM1 led to ER Ca²⁺ upregulation and promoted vvIBDV replication. We also showed that the inhibition of Ca²⁺-release-activated-Ca²⁺ (CRAC) channels could reduce vvIBDV infection by blocking Ca²⁺ from entering the ER. This study suggests a new mechanism that STIM1 promotes the replication of vvIBDV by mobilizing Ca²⁺ in the ER.