Critical role of phospholipase A(2) group IID in age-related susceptibility to severe acute respiratory syndrome–CoV infection

Vijay, Rahul; Hua, Xiaoyang; Meyerholz, David K.; Miki, Yoshimi; Yamamoto, Kei; Gelb, Michael; Murakami, Makoto; Perlman, Stanley

Oxidative stress and chronic low-grade inflammation in the lungs are associated with aging and may contribute to age-related immune dysfunction. To maintain lung homeostasis, chronic inflammation is countered by enhanced expression of proresolving/antiinflammatory factors. Here, we show that age-dependent increases of one such factor in the lungs, a phospholipase A(2) (PLA(2)) group IID (PLA(2)G2D) with antiinflammatory properties, contributed to worse outcomes in mice infected with severe acute respiratory syndrome-coronavirus (SARS-CoV). Strikingly, infection of mice lacking PLA(2)G2D expression (Pla2g2d(−/−) mice) converted a uniformly lethal infection to a nonlethal one (>80% survival), subsequent to development of enhanced respiratory DC migration to the draining lymph nodes, augmented antivirus T cell responses, and diminished lung damage. We also observed similar effects in influenza A virus–infected middle-aged Pla2g2d(−/−) mice. Furthermore, oxidative stress, probably via lipid peroxidation, was found to induce PLA(2)G2D expression in mice and in human monocyte–derived macrophages. Thus, our results suggest that directed inhibition of a single inducible phospholipase, PLA(2)G2D, in the lungs of older patients with severe respiratory infections is potentially an attractive therapeutic intervention to restore immune function.