A20 Deficiency in Lung Epithelial Cells Protects against Influenza A Virus Infection

MAELFAIT JONATHAN; ROOSE KENNY; VEREECKE LARS; MC GUIRE CONOR; SZE MOZES; SCHUIJS MARTIJN; WILLART MONIQUE; IBAÑEZ LORENA ITATI; HAMMAD HAMIDA; LAMBRECHT BART; BEYAERT RUDI; SAELENS XAVIER; VAN LOO GEERT

PLOS PATHOGENS

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2016

1553-7366

A20 negatively regulates multiple inflammatory signallingpathways. We here addressed the role of A20 in club cells (also known as Claracells) of the bronchial epithelium in their response to influenza A virusinfection. Club cells provide a niche for influenza virus replication, but littleis known about the functions of these cells in antiviral immunity. Using airwayepithelial cell-specific A20 knockout (A20AEC-KO) mice, we show that A20 inclub cells critically controls innate immune responses upon TNF or doublestranded RNA stimulation.Surprisingly, A20 AEC-KO mice are better protected againstinfluenza A virus challenge than their wild type littermates. This phenotype isnot due to decreased viral replication. Instead host innate and adaptive immuneresponses and lung damage are reduced in A20 AEC-KO mice. These attenuatedresponses correlate with a dampened cytotoxic T cell (CTL) response at laterstages during infection, indicating that A20 AEC-KO mice are better equipped totolerate Influenza A virus infection. Expression of the chemokine CCL2 (also namedMCP-1) is particularly suppressed in the lungs of A20 AEC-KO mice during laterstages of infection. When A20 AEC-KO mice were treated with recombinant CCL2the protective effect was abrogated demonstrating the crucial contribution ofthis chemokine to the protection of A20 AEC-KO mice to Influenza A virusinfection. Taken together, we propose a mechanism of action by which A20 expressionin club cells controls inflammation and antiviral CTL responses in response toinfluenza virus infection.