An ENU-induced splicing mutation reveals a role for Unc93b1 in early immune cell activation following influenza A H1N1 infection.
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.
Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
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Lafferty
Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
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Flaczyk
Department of Medicine, McGill University, Montréal, Québec, Canada.
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Angers
Yale University School of Medicine, Department of Pathology, New Haven, CT, USA.
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Homer
Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.
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d'Hennezel
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.
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Malo
1] Department of Medicine, McGill University, Montréal, Québec, Canada [2] Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.
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Piccirillo
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.
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Vidal
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.
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Qureshi
D017398:Alternative Splicing; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005038:Ethylnitrosourea; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D007370:Interferon Type I; D026901:Membrane Transport Proteins; D051193:Toll-Like Receptors; C512254:UNC93B1 protein, mouse; D019041:L-Selectin; D007371:Interferon-gamma; D005038:Ethylnitrosourea