Retinol binding protein 4 enhances cellular cholesterol uptake to facilitate influenza A virus infection

Viruses hijack host cell machinery to facilitate their own replication. Therefore, identifying key cellular factors and processes involved in viral infection is crucial for developing host-directed therapies. Herein, we demonstrate that retinol-binding protein 4 (RBP4), a lipocalin family member and major retinol carrier, is significantly induced by influenza A virus (IAV) infection in both cellular models and clinical patients. Moreover, RBP4 deficiency impairs IAV replication both in vitro and in vivo. Mechanistically, RBP4 promotes the expression of CD36, a cholesterol uptake receptor protein, thereby increasing cellular cholesterol levels. This elevation in cholesterol subsequently boosts cell-surface sialic acid levels, facilitating IAV attachment. Consequently, enforced expression of CD36 restores IAV replication in RBP4-deficient cells and mice. In summary, our study identifies RBP4 as a pivotal host factor that facilitates IAV infection by modulating cellular cholesterol homeostasis.