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

Genes Immun. Jul-Aug 2014;15(5):320-32. doi: 10.1038/gene.2014.22. Epub 2014 May 22.

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 Unc93b1(Letr/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, Unc93b1(Letr/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • CD8-Positive T-Lymphocytes / metabolism
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / metabolism
  • Endosomes / metabolism
  • Ethylnitrosourea
  • Immunity, Innate
  • Influenza A Virus, H1N1 Subtype / pathogenicity
  • Interferon Type I / genetics
  • Interferon Type I / metabolism
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • L-Selectin / genetics
  • L-Selectin / metabolism
  • Lung / metabolism
  • Lung / pathology
  • Lymphocyte Activation*
  • Macrophage Activation*
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism

Substances

  • Chemokine CXCL10
  • Cxcl10 protein, mouse
  • Interferon Type I
  • Membrane Transport Proteins
  • Toll-Like Receptors
  • UNC93B1 protein, mouse
  • L-Selectin
  • Interferon-gamma
  • Ethylnitrosourea