TMEM259 alleles modulate respiratory syncytial virus infection and ER-stress-triggered apoptosis

Respiratory syncytial virus (RSV) is a main cause of infant morbidity and mortality. Susceptibility factors for severe RSV bronchiolitis in previously healthy children are unclear. We analyze genetic variants in 5,141 genes involved in virus sensing, interferon (IFN) signaling and effector functions in a population of n=101 previously healthy infants with severe RSV bronchiolitis. Comparing allele frequencies of the patient cohort with the exome aggregation consortium dataset (ExAC) our analysis reveals 94 non-synonymous coding single nucleotide polymorphisms (SNPs) mapping to 79 potential risk genes. Follow up of genes expressed in human lung cells show that TMEM259 (also known as membralin), a protein involved in regulating endoplasmic reticulum (ER) stress and neuronal cell survival, restricts RSV infection. Analysis of engineered human airway cells endogenously expressing the TMEM259 major allele or the rs77868901 minor variant shows allele-dependent modulation of RSV infection and ER-stress induced apoptosis, but not IFN activity nor induction of IFN stimulated genes. TMEM259 abundance and polymorphisms modulate RSV infection likely by modulating the ER stress response and apoptosis. This data may aid future risk stratification and development of prevention and treatment strategies for RSV.