Format

Send to

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

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

Author information

1
Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
2
Department of Medicine, McGill University, Montréal, Québec, Canada.
3
Yale University School of Medicine, Department of Pathology, New Haven, CT, USA.
4
Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.
5
1] Department of Medicine, McGill University, Montréal, Québec, Canada [2] Department of Human Genetics, McGill University, Montréal, Québec, Canada [3] Complex Traits Group, McGill University, Montréal, Québec, Canada.
6
1] Department of Medicine, McGill University, Montréal, Québec, Canada [2] Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.
7
1] Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada [2] Department of Medicine, McGill University, Montréal, Québec, Canada [3] Department of Critical Care, McGill University Health Centre, Montréal, Québec, Canada.

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.

PMID:
24848930
PMCID:
PMC4978536
DOI:
10.1038/gene.2014.22
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center