A20 Deficiency in Lung Epithelial Cells Protects against Influenza A Virus Infection
In: PLOS Pathogens, Jg. 12 (2016-01-27), Heft 1, p e1005410, S. e1005410
Online
unknown
Zugriff:
A20 negatively regulates multiple inflammatory signalling pathways. We here addressed the role of A20 in club cells (also known as Clara cells) of the bronchial epithelium in their response to influenza A virus infection. Club cells provide a niche for influenza virus replication, but little is known about the functions of these cells in antiviral immunity. Using airway epithelial cell-specific A20 knockout (A20AEC-KO) mice, we show that A20 in club cells critically controls innate immune responses upon TNF or double stranded RNA stimulation. Surprisingly, A20AEC-KO mice are better protected against influenza A virus challenge than their wild type littermates. This phenotype is not due to decreased viral replication. Instead host innate and adaptive immune responses and lung damage are reduced in A20AEC-KO mice. These attenuated responses correlate with a dampened cytotoxic T cell (CTL) response at later stages during infection, indicating that A20AEC-KO mice are better equipped to tolerate Influenza A virus infection. Expression of the chemokine CCL2 (also named MCP-1) is particularly suppressed in the lungs of A20AEC-KO mice during later stages of infection. When A20AEC-KO mice were treated with recombinant CCL2 the protective effect was abrogated demonstrating the crucial contribution of this chemokine to the protection of A20AEC-KO mice to Influenza A virus infection. Taken together, we propose a mechanism of action by which A20 expression in club cells controls inflammation and antiviral CTL responses in response to influenza virus infection.
Author Summary Influenza viruses are a major public health threat. Each year, the typical seasonal flu epidemic affects millions of people with sometimes fatal outcomes, especially in high risk groups such as young children and elderly. The sporadic pandemic outbreaks can have even more disastrous consequences. The protein A20 is an important negative regulator of antiviral immune responses. We show that the specific deletion of A20 in bronchial epithelial cells improves the protection against influenza virus infections. This increased protection correlates with a dampened pulmonary cytotoxic T cell response and a strongly suppressed expression of the chemokine CCL2 during later stages of infection.
Titel: |
A20 Deficiency in Lung Epithelial Cells Protects against Influenza A Virus Infection
|
---|---|
Autor/in / Beteiligte Person: | Lorena Itatí Ibañez ; Willart, Monique ; Sze, Mozes ; Hammad, Hamida ; Lambrecht, Bart N. ; Vereecke, Lars ; Conor Mc Guire ; Saelens, Xavier ; Geert van Loo ; Beyaert, Rudi ; Schuijs, Martijn J. ; Maelfait, Jonathan ; Roose, Kenny |
Link: | |
Zeitschrift: | PLOS Pathogens, Jg. 12 (2016-01-27), Heft 1, p e1005410, S. e1005410 |
Veröffentlichung: | Public Library of Science (PLoS), 2016 |
Medientyp: | unknown |
ISSN: | 1553-7374 (print) ; 1553-7366 (print) |
DOI: | 10.1371/journal.ppat.1005410 |
Schlagwort: |
|
Sonstiges: |
|