Cystic Fibrosis Therapy Vector HPIV3 Induces an Apoptotic Unfolded Protein Response

A recently created Parainfluenza viral vector (HPIV3) contains the wildtype CFTR protein as a therapy for Cystic Fibrosis. While leading to the increased production of wildtype CFTR protein for treatment of Cystic Fibrosis, the therapy correlates with increased apoptosis of lung cells. The Unfolded Protein Response (UPR) has been implicated in several aspects of viral replication, including that of the Influenza A virus, Herpes Simplex Virus-1, and Epstein-Barr virus, and may be implicated in apoptotic cellular responses to the engineered HPIV3 containing CFTR. This study compared gene transcripts of two UPR pathways in Human Airway Epithelial (HAE) cells infected with human parainfluenza virus 3 (HPIV3). Compared to a control, HPIV3 infection of both primary differentiated cultures of human airway epithelia and Calu-3 cell culture monolayers increased by several fold the expression of many downstream genes in the PERK pathway, including CHOP, a gene implicated in apoptotic cell responses to infection, inflammation, or stress. In addition, the IRE1 pathway, which leads to mRNA splicing (a proxy for activation) of the XBP-1 transcription factor, was also activated in HAE cells infected by HPIV3. The results of this study indicate that the IRE1 and PERK pathways of the UPR are greatly affected by HPIV3 infection. Therefore, future improvements to therapies using HPIV3 as a vector should include modifications that downregulate genes in the UPR pathways.