In this work, we explored how a class of oxidized lipids, spontaneously created during tissue damage and unprogrammed cell lysis, block the earliest events in RNA virus infection in the human epithelium. This gives us novel insight into the ways that we view infection models, unveiling a built-in mechanism to slow viral growth that neither engages the interferon response nor is subject to known viral antagonism. ABSTRACT Mammalian cells detect microbial molecules known as pathogen-associated molecular patterns (PAMPs) as indicators of potential infection. Upon PAMP detection, diverse defensive responses are induced by the host, including those that promote inflammation and cell-intrinsic antimicrobial activities. Host-encoded molecules released from dying or damaged cells, known as damage-associated molecular patterns (DAMPs), also induce defensive responses. Both DAMPs and PAMPs are recognized for their inflammatory potential, but only the latter are well established to stimulate cell-intrinsic host defense. Here, we report a class of DAMPs that engender an antiviral state in human epithelial cells. These DAMPs include oxPAPC (oxidized 1-palmitoyl-2-arachidonoyl- sn -glycero-3-phosphocholine), PGPC (1-palmitoyl-2-glutaryl phosphatidylcholine), and POVPC [1-palmitoyl-2-(5-oxovaleroyl)- sn -glycero-3-phosphatidylcholine], oxidized lipids that are naturally released from dead or dying cells. Exposing cells to these DAMPs prior to vesicular stomatitis virus (VSV) infection limits viral replication. Mechanistically, these DAMPs prevent viral entry, thereby limiting the percentage of cells that are productively infected and consequently restricting viral load. We found that the antiviral actions of oxidized lipids are distinct from those mediated by the PAMP Poly I:C, in that the former induces a more rapid antiviral response without the induction of the interferon response. These data support a model whereby interferon-independent defensive activities can be induced by DAMPs, which may limit viral replication before PAMP-mediated interferon responses are induced. This antiviral activity may impact viruses that disrupt interferon responses in the oxygenated environment of the lung, such as influenza virus and SARS-CoV-2.
【저자키워드】 DAMP, Innate immunity, SARS, virus, oxPAPC, 【초록키워드】 SARS-CoV-2, Antiviral, Infection, lung, Influenza virus, antiviral activity, virus, viral entry, activity, VSV, Viral load, cells, viral replication, response, RNA virus, lipids, interferon response, mechanism, DAMPs, vesicular stomatitis virus, antiviral response, Lipid, Inflammatory, PAMPs, PAMP, Phosphatidylcholine, microbial, Support, damage-associated molecular pattern, pathogen-associated molecular pattern, tissue damage, subject, activities, human epithelial cells, antiviral action, viral growth, Defense, damaged cells, dead, cell lysis, Host, responses, Prevent, limit, Cell, event, detect, include, induce, the interferon, released, stimulate, disrupt, engage, oxidized, oxygenated, promote inflammation, 【제목키워드】 RNA, pattern, restriction, class,