Influenza NS1 directly modulates Hedgehog signaling during infection

PLoS Pathogens

Elina I. Zúñiga¹  Michael B. Oldstone²  Meghana Malur²  Robert M. Krug³  Maria Eugenia Loureiro³  Ethan Bier⁴  John R. Teijaro⁴  Prashant Jain⁵  Margery G. Smelkinson⁶  Sundar Ganesan⁶  Annabel Guichard⁶ 

[1] Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America;Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America;Immunology and Microbial Science, Scripps Research Institute, La Jolla, California, United States of America;Instituto de Ciencia y Tecnología Dr. César Milstein - CONICET, Saladillo, Argentina;Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, United States of America

关键词: Hedgehog signaling;    Influenza;    Drosophila melanogaster;    Cytokines;    Microbial mutation;    Influenza A virus;    Influenza viruses;    Point mutation;   

DOI  :  10.1371/journal.ppat.1006588

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY