Age-related dysregulation in the lipidome compromises the immune response to the severe acute respiratory coronavirus (VIR5P.1140) Free

Age-associated changes have long been known to cause dysregulation in antiviral immune responses. The SARS epidemic of 2002-03 was characteristic in this respect that it exhibited an age-associated increase in mortality. We recently reported that an age-related increase in an eicosanoid, prostaglandin D2 (PGD₂) contributed to the observed higher mortality in SARS-CoV infected aged compared to young mice. To examine the factors that resulted in elevated levels of PGD₂ in aged mouse lungs, we analyzed the gene expression levels of several enzymes in the eicosanoid pathway. Remarkably, secretory phospholipase A2 group 2D (Pla2g2d), which is preferentially expressed in lung CD11c⁺ cells, was significantly higher in aged compared to young mice. Lipid profiling of aged and young SARS-CoV-infected mice revealed that unlike young mice, aged mice failed to upregulate many pro-inflammatory lipid mediators although both groups upregulated the pro-resolving ones. Further, aged mice lacking PLA2G2D expression (Pla2g2d^-/-) mice exhibited enhanced virus clearance, increased lung DC migration to the draining lymph nodes and increased virus specific T cell responses. Infection of aged Pla2g2d^-/- mice with SARS-CoV increased survival from 20% to 80-90%, compared to Pla2g2d^+/+ mice. Altogether our data identify a novel role for Pla2g2d in the lungs of aged mice in skewing the lipidome to an anti-inflammatory state and thus predisposing the animal to a worse outcome following SARS-CoV infection.