In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 5 ( 2022-5-5), p. e1010471-
Abstract:
The ability to treat severe viral infections is limited by our understanding of the mechanisms behind virus-induced immunopathology. While the role of type I interferons (IFNs) in early control of viral replication is clear, less is known about how IFNs can regulate the development of immunopathology and affect disease outcomes. Here, we report that absence of type I IFN receptor (IFNAR) is associated with extensive immunopathology following mucosal viral infection. This pathology occurred independent of viral load or type II immunity but required the presence of macrophages and IL-6. The depletion of macrophages and inhibition of IL-6 signaling significantly abrogated immunopathology. Tissue destruction was mediated by macrophage-derived matrix metalloproteinases (MMPs), as MMP inhibition by doxycycline and Ro 28–2653 reduced the severity of tissue pathology. Analysis of post-mortem COVID-19 patient lungs also displayed significant upregulation of the expression of MMPs and accumulation of macrophages. Overall, we demonstrate that IFNs inhibit macrophage-mediated MMP production to prevent virus-induced immunopathology and uncover MMPs as a therapeutic target towards viral infections.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010471
DOI:
10.1371/journal.ppat.1010471.g001
DOI:
10.1371/journal.ppat.1010471.g002
DOI:
10.1371/journal.ppat.1010471.g003
DOI:
10.1371/journal.ppat.1010471.g004
DOI:
10.1371/journal.ppat.1010471.g005
DOI:
10.1371/journal.ppat.1010471.g006
DOI:
10.1371/journal.ppat.1010471.g007
DOI:
10.1371/journal.ppat.1010471.g008
DOI:
10.1371/journal.ppat.1010471.s001
DOI:
10.1371/journal.ppat.1010471.s002
DOI:
10.1371/journal.ppat.1010471.s003
DOI:
10.1371/journal.ppat.1010471.s004
DOI:
10.1371/journal.ppat.1010471.s005
DOI:
10.1371/journal.ppat.1010471.s006
DOI:
10.1371/journal.ppat.1010471.s007
DOI:
10.1371/journal.ppat.1010471.s008
DOI:
10.1371/journal.ppat.1010471.s009
DOI:
10.1371/journal.ppat.1010471.s010
DOI:
10.1371/journal.ppat.1010471.s011
DOI:
10.1371/journal.ppat.1010471.r001
DOI:
10.1371/journal.ppat.1010471.r002
DOI:
10.1371/journal.ppat.1010471.r003
DOI:
10.1371/journal.ppat.1010471.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1
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