| Title: |
The θ-defensin retrocyclin 101 inhibits TLR4- and TLR2-dependent signaling and protects mice against influenza infection |
| Authors: |
Prantner, Daniel; Shirey, Kari Ann; Lai, Wendy; Lu, Wuyuan; Cole, Alexander M; Vogel, Stefanie N; GARZINO DEMO, ALFREDO |
| Contributors: |
Prantner, Daniel; Shirey, Kari Ann; Lai, Wendy; Lu, Wuyuan; Cole, Alexander M; Vogel, Stefanie N; GARZINO DEMO, Alfredo |
| Publication Year: |
2017 |
| Collection: |
Padua Research Archive (IRIS - Università degli Studi di Padova) |
| Subject Terms: |
signal transduction; cytokine regulation; inflammation; innate immunity |
| Description: |
Despite widespread use of annual influenza vaccines, seasonal influenza-associated deaths number in the thousands each year, in part because of exacerbating bacterial superinfections. Therefore, discovering additional therapeutic options would be a valuable aid to public health. Recently, TLR4 inhibition has emerged as a possible mechanism for protection against influenza-associated lethality and acute lung injury. Based on recent data showing that rhesus macaque θ-defensins could inhibit TLR4-dependent gene expression, we tested the hypothesis that a novel θ-defensin, retrocyclin (RC)-101, could disrupt TLR4-dependent signaling and protect against viral infection. In this study, RC-101, a variant of the humanized θ-defensin RC-1, blocked TLR4-mediated gene expression in mouse and human macrophages in response to LPS, targeting both MyD88- and TRIF-dependent pathways. In a cell-free assay, RC-101 neutralized the biologic activity of LPS at doses ranging from 0.5 to 50 EU/ml, consistent with data showing that RC-101 binds biotinylated LPS. The action of RC-101 was not limited to the TLR4 pathway because RC-101 treatment of macrophages also inhibited gene expression in response to a TLR2 agonist, Pam3CSK4, but failed to bind that biotinylated agonist. Mouse macrophages infected in vitro with mouse-adapted A/PR/8/34 influenza A virus (PR8) also produced lower levels of proinflammatory cytokine gene products in a TLR4-independent fashion when treated with RC-101. Finally, RC-101 decreased both the lethality and clinical severity associated with PR8 infection in mice. Cumulatively, our data demonstrate that RC-101 exhibits therapeutic potential for the mitigation of influenza-related morbidity and mortality, potentially acting through TLR-dependent and TLR-independent mechanisms. |
| Document Type: |
article in journal/newspaper |
| File Description: |
STAMPA |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/28729359; info:eu-repo/semantics/altIdentifier/wos/WOS:000413396400014; firstpage:jlb.2A1215-567RR; journal:JOURNAL OF LEUKOCYTE BIOLOGY; https://hdl.handle.net/11577/3239372 |
| DOI: |
10.1189/jlb.2A1215-567RR |
| Availability: |
https://hdl.handle.net/11577/3239372; https://doi.org/10.1189/jlb.2A1215-567RR |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Accesso libero |
| Accession Number: |
edsbas.D77A645C |
| Database: |
BASE |