Contribution of PB1-F2 to transmission in the guinea pig model

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): The PB1-F2 protein is the most recently discovered influenza A virus protein. The protein is translated from the +1 reading frame of the PB1 gene of the influenza A virus genome. This small protein of 87 amino acids has been shown to cause apoptosis in infected cells. PB1-F2 interacts with the mitochondrial membrane proteins adenine nucleotide translocator 3 (ANT3) and voltage dependent anion channel (VDAC1) and this interaction induces apoptosis via the mitochondrial pathway as shown by Zamarin et al. It has also been shown in the mouse model that viruses knocked out for PB1-F2 expression have reduced pathogenicity. Previous studies show that PB1-F2 contributes to pathogenesis and that amino acid change N66S in the C-terminus can increase pathogenicity in the mouse model. In this study we will examine the effects of PB1-F2 on transmission in the guinea pig model. We hypothesize that increased virus replication and pathogenesis caused by PB1-F2 in animal models may lead to more efficient transmission. Our study will focus on the use of the recombinant A/Texas/91 virus. This virus model has been used in previous transmission experiments in ferrets to examine the contribution of H5N1 and 1918 pandemic virus genes to pathogenesis. A/Texas/91 is a good model to study transmission because preliminary experiments have shown that this virus has a 17% transmission rate without expressing a full-length PB1-F2. PB1-F2 can be expressed without changing any other proteins or genes of the virus, by fixing a stop codon to a tryptophan in the coding sequence of PB1-F2. This is ideal because we know that there is not an inherent block in transmission coming from other genes of the virus, but we will also be able to observe changes, either increases or decreases in transmission. The experiments outlined in this proposal are designed to examine the effects of PB1-F2 on transmission in the guinea pig model using the recombinant A/Texas/91 virus. Contribution of PB1-F2 to transmission in the guinea pig model. [unreadable] [unreadable] [unreadable]