During the aging process, immune functions decline, rendering the host more vulnerable to certain viruses. The mechanisms underlying this age-dependent susceptibility to infection are an active area of research. In this issue, Vijay et al. show that secreted phospholipase A2 (PLA2) group IID (PLA2G2D) is critical in determining the impact of age on host susceptibility to severe acute respiratory syndrome coronavirus (SARS-CoV).
PLA2 hydrolyzes membrane phospholipids to release arachdonic acid, which is metabolized by multiple enzymes (e.g., cyclooxygenases and lipoxygenases) to generate functionally diverse lipid mediators including prostaglandins and leukotrienes. This group previously linked prostaglandin D2 (PGD2) expression in mouse lungs to defective immune responses and age-related susceptibility to SARS-CoV. Blocking PGD2 function restored immune responses and increased survival in older, infected mice. How and why PGD2 expression is elevated with age is the focus of the current study.
The authors first compared the transcriptomes of CD11c+ cells from the lungs of young or middle-aged mice. Of all genes in the arachidonic acid cascade, only Pla2g2d was elevated in the older mice. Lipid profiling of lung tissue revealed that older mice also had increases in multiple lipid mediators including PGD2. Using mice lacking Pla2g2d, the authors showed that PLA2G2D was uniquely responsible for age-dependent increases in lipid mediator expression. Moreover, in the absence of Plas2g2d, dendritic cell migration and T cell responses were enhanced in older mice. Notably, Pla2g2d−/− mice challenged with SARS-CoV had a striking survival advantage when compared with Plas2g2d+/+ mice. Mechanistically, the authors were able to link Pla2g2d expression with markers of oxidative stress.
This study provides strong genetic evidence that lipid mediators produced downstream of PLA2G2D contribute to age-dependent susceptibility to viral infection. These findings once again highlight lipid mediators as double-edged swords in immunology. Whereas some prostaglandins, including PGD2, have beneficial immunosuppressive effects on age-related oxidative stress, they can also adversely affect immune cell function, thereby dampening desirable antiviral responses. The observation that enhanced PLA2G2D signaling is detrimental in a virus-infected host suggests that therapies targeting this pathway may benefit older patients infected with SARS-CoV. However, the treatment may need to be tailored to specific lipid mediators to avoid dampening natural immunosuppressive responses and exacerbating comorbidities such as asthma, allergies, or autoimmune disorders.