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An ENU-induced splicing mutation reveals a role for Unc93b1 in early immune cell activation following influenza A H1N1 infection

Genes & Immunity volume 15, pages 320–332 (2014)Cite this article

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Abstract

Genetic and immunological analysis of host–pathogen interactions can reveal fundamental mechanisms of susceptibility and resistance to infection. Modeling human infectious diseases among inbred mouse strains is a proven approach but is limited by naturally occurring genetic diversity. Using N-ethyl-N-nitrosourea mutagenesis, we created a recessive loss-of-function point mutation in Unc93b1 (unc-93 homolog B1 (C. elegans)), a chaperone for endosomal Toll-like receptors (TLR)3, TLR7 and TLR9, which we termed Letr for ‘loss of endosomal TLR response’. We used Unc93b1Letr/Letr mice to study the role of Unc93b1 in the immune response to influenza A/PR/8/34 (H1N1), an important global respiratory pathogen. During the early phase of infection, Unc93b1Letr/Letr mice had fewer activated exudate macrophages and decreased expression of CXCL10, interferon (IFN)-γ and type I IFN. Mutation of Unc93b1 also led to reduced expression of the CD69 activation marker and a concomitant increase in the CD62L naive marker on CD4+ and CD8+ T cells in infected lungs. Finally, loss of endosomal TLR signaling resulted in delayed viral clearance that coincided with increased tissue pathology during infection. Taken together, these findings establish a role for Unc93b1 and endosomal TLRs in the activation of both myeloid and lymphoid cells during the innate immune response to influenza.

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Acknowledgements

We thank Gregory Boivin and François Coulombe for advice with experimental procedures, Marie-Line Goulet for advice on experimental design as well as helpful comments on the manuscript, and Dr David Logan Burk for help with three-dimensional protein modeling. We also acknowledge Dr Veronika von Messling and Dr Maziar Divangahi for providing materials and advice on working with the influenza virus. This work was supported by a CIHR Team Grant in Mouse Mutagenesis and Infectious Diseases (CTP-87520), a Canada Research Chair in Host Resistance to Respiratory Infections (STQ) and the Fonds de Recherche du Québec—Santé. EIL is a recipient of awards from the CIHR Québec Respiratory Health Training Program, the McGill University Health Centre and the McGill University Faculty of Medicine.

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Authors and Affiliations

  1. Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada

    E I Lafferty, A Flaczyk & S T Qureshi

  2. Department of Medicine, McGill University, Montréal, Québec, Canada

    I Angers, D Malo, C A Piccirillo, S M Vidal & S T Qureshi

  3. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    R Homer

  4. Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada

    E d'Hennezel & C A Piccirillo

  5. Department of Human Genetics, McGill University, Montréal, Québec, Canada

    D Malo & S M Vidal

  6. Complex Traits Group, McGill University, Montréal, Québec, Canada

    D Malo & S M Vidal

  7. Department of Critical Care, McGill University Health Centre, Montréal, Québec, Canada

    S T Qureshi

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  1. E I Lafferty
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Lafferty, E., Flaczyk, A., Angers, I. et al. An ENU-induced splicing mutation reveals a role for Unc93b1 in early immune cell activation following influenza A H1N1 infection. Genes Immun 15, 320–332 (2014). https://doi.org/10.1038/gene.2014.22

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