OXIDIZED PHOSPHOLIPIDS AS ANTIVIRALS AND IMMUNE MODLATORS

Abstract

The innate immune system is critical in blocking the first steps of infection, thus preventing robust pathogen growth. Innate immune responses are primarily mediated by pathogen recognition receptors (PRRs), which sense molecular patterns that warn of microbial infection or nearby tissue damage. One indicator of tissue damage is the release and oxidation of the common membrane lipid 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine (PAPC) to form oxPAPC, a heterogenous mix of oxidized lipids. While oxPAPC is well known to induce hyperactive states in primed professional immune cells, very little is known about how it interacts with non-immune cells and with the adaptive immune system as a whole. To explore the impact of oxidized phospholipids on these compartments, we assessed alterations in cytokine production and antibody expression in in vitro and in vivo settings induced by oxidized phospholipids, along with viral replication in cells that were pretreated with these oxidized phospholipids. Our studies indicated that oxidized phospholipids can, in vitro, lead to increased production of adaptive immune stimulating cytokines such as interleukin 1. Further, when included in an experimental admixture in OVA sensitization experiments in mice, oxidized phospholipids increase antibody titers. This augmentation of the antibody response was observed in the blood, in the gut mucosa, and in the pulmonary mucosa. When epithelial cells from oxygenated tissues such as the lung epithelium and the mouth were treated with oxidized phospholipids, they became refractory to infection by the RNA viruses Influenza and Vesicular Stomatitis Virus. This viral restriction occurred in a manner independent of interferon signaling. These data revealed a limitation of viral entry, restricting viral infection by preventing viruses from infecting the cells in the first place rather than inhibiting viral processes within the cell. This resulted in a smaller initial pool of infected cells and resulted in a kinetic defect in viral replication. Together, these data suggest a multifaced role for oxidized phospholipids in modulating both the innate and adaptive immune responses.