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PLoS Pathog. 2017 Aug 24;13(8):e1006588. doi: 10.1371/journal.ppat.1006588. [Epub ahead of print]
Influenza NS1 directly modulates Hedgehog signaling during infection.
Smelkinson MG1, Guichard A1, Teijaro JR2, Malur M3, Loureiro ME4,5, Jain P1, Ganesan S6, Z??iga EI4, Krug RM3, Oldstone MB2, Bier E1.
Author information
Abstract
The multifunctional NS1 protein of influenza A viruses suppresses host cellular defense mechanisms and subverts other cellular functions. We report here on a new role for NS1 in modifying cell-cell signaling via the Hedgehog (Hh) pathway. Genetic epistasis experiments and FRET-FLIM assays in Drosophila suggest that NS1 interacts directly with the transcriptional mediator, Ci/Gli1. We further confirmed that Hh target genes are activated cell-autonomously in transfected human lung epithelial cells expressing NS1, and in infected mouse lungs. We identified a point mutation in NS1, A122V, that modulates this activity in a context-dependent fashion. When the A122V mutation was incorporated into a mouse-adapted influenza A virus, it cell-autonomously enhanced expression of some Hh targets in the mouse lung, including IL6, and hastened lethality. These results indicate that, in addition to its multiple intracellular functions, NS1 also modifies a highly conserved signaling pathway, at least in part via cell autonomous activities. We discuss how this new Hh modulating function of NS1 may influence host lethality, possibly through controlling cytokine production, and how these new insights provide potential strategies for combating infection.
PMID: 28837667 DOI: 10.1371/journal.ppat.1006588
Influenza NS1 directly modulates Hedgehog signaling during infection.
Smelkinson MG1, Guichard A1, Teijaro JR2, Malur M3, Loureiro ME4,5, Jain P1, Ganesan S6, Z??iga EI4, Krug RM3, Oldstone MB2, Bier E1.
Author information
Abstract
The multifunctional NS1 protein of influenza A viruses suppresses host cellular defense mechanisms and subverts other cellular functions. We report here on a new role for NS1 in modifying cell-cell signaling via the Hedgehog (Hh) pathway. Genetic epistasis experiments and FRET-FLIM assays in Drosophila suggest that NS1 interacts directly with the transcriptional mediator, Ci/Gli1. We further confirmed that Hh target genes are activated cell-autonomously in transfected human lung epithelial cells expressing NS1, and in infected mouse lungs. We identified a point mutation in NS1, A122V, that modulates this activity in a context-dependent fashion. When the A122V mutation was incorporated into a mouse-adapted influenza A virus, it cell-autonomously enhanced expression of some Hh targets in the mouse lung, including IL6, and hastened lethality. These results indicate that, in addition to its multiple intracellular functions, NS1 also modifies a highly conserved signaling pathway, at least in part via cell autonomous activities. We discuss how this new Hh modulating function of NS1 may influence host lethality, possibly through controlling cytokine production, and how these new insights provide potential strategies for combating infection.
PMID: 28837667 DOI: 10.1371/journal.ppat.1006588