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- Title
Type I interferon regulates proteolysis by macrophages to prevent immunopathology following viral infection.
- Authors
Lee, Amanda J.; Feng, Emily; Chew, Marianne V.; Balint, Elizabeth; Poznanski, Sophie M.; Giles, Elizabeth; Zhang, Ali; Marzok, Art; Revill, Spencer D.; Vahedi, Fatemeh; Dubey, Anisha; Ayaub, Ehab; Jimenez-Saiz, Rodrigo; McGrath, Joshua J. C.; Ritchie, Tyrah M.; Jordana, Manel; Jonigk, Danny D.; Ackermann, Maximilian; Ask, Kjetil; Miller, Matthew
- 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. Author summary: Dysregulated immune responses and their associated pathologies are the culprit of severe disease symptoms in response to viral infections. The ability to properly regulate effective and controlled immune responses is a critical feature of preventing severe disease outcomes. Type I interferons are antiviral signaling molecules known to induce potent antiviral immune responses; however, their ability to suppress pathogenic immune responses is poorly understood. Employing a vaginal HSV-2 infection model in mice, we show that type I IFN signaling is critical to preventing the development of severe tissue pathology by suppressing the pathogenic functions of macrophages. In the absence of type I IFNs, these unleashed macrophages produce MMPs that can degrade tissue structure. We show that inhibiting MMPs reduces the severity of immunopathology. We further provide evidence that influenza infection in mice, as well as severe COVID-19 infection in humans, is linked to macrophage and MMP-mediated tissue destruction. Together, our study describes a distinct mechanism through which type I IFNs regulate pathogenic immune responses, and defines MMPs as a potential therapeutic target during severe viral infections.
- Subjects
DOXYCYCLINE; IMMUNOPATHOLOGY; TYPE I interferons; MACROPHAGES; VIRUS diseases; PROTEOLYSIS; IMMUNE response; MATRIX metalloproteinases
- Publication
PLoS Pathogens, 2022, Vol 18, Issue 5, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1010471