title: Innate imprinting by the modified heat-labile toxin of Escherichia coli (LTK63) provides generic protection against lung infectious disease.
abstract: In a healthy individual, the lung contains few lymphoid cells. However, amplified immune responses, as exemplified during lung infection, can cause extensive tissue damage. We have previously demonstrated that one lung infection modulates the immunopathological outcome to a subsequent unrelated pathogen. Mimicking heterologous immunity may provide a means of enhancing both innate and acquired immunity. We now show that prior lung administration of a modified heat-labile toxin from Escherichia coli (LTK63) enhances immunity to respiratory syncytial virus, influenza virus, and the fungus Cryptococcus neoformans. Treatment with LTK63 decreased lung inflammation and tissue damage and improved the ability to resolve the infection. APCs expressing the activation markers MHC class II, CD80, and CD40 increased in number in the lung. LTK63 treatment increased the pathogen-specific IgA response in the nasal mucosa and simultaneously decreased inflammatory cytokine production (IFN-gamma and TNF-alpha) after infection. The number of activated CD8(+)CD44(+) T cells and the respiratory syncytial virus- or influenza-specific CD8-proliferative responses increased, although the total inflammatory infiltrate was reduced. LTK63 treatment matured lung APCs (LTK63 prevented efficient presentation of whole OVA to DO11.10 cells, whereas OVA peptide presentation was unaffected), enhanced immunity in both a Th1 and Th2 environment, was long lasting, and was not pathogen or host strain specific; the protective effects were partially independent of T and B cells. Innate imprinting by toxin-based immunotherapeutics may provide generic protection against infectious disease in the lung, without the need for coadministered pathogen-specific Ag.
authors.affiliation: Centre For Molecular Microbiology and Infection, Department of Biological Sciences, Imperial College London, London, United Kingdom. a.williams@imperial.ac.uk
authors.forename: Andrew Evan
authors.initials: AE
authors.lastname: Williams
authors.forename: Lorna
authors.initials: L
authors.lastname: Edwards
authors.forename: Ian Robert
authors.initials: IR
authors.lastname: Humphreys
authors.forename: Robert
authors.initials: R
authors.lastname: Snelgrove
authors.forename: Aaron
authors.initials: A
authors.lastname: Rae
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Tracy
authors.initials: T
authors.lastname: Hussell
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D001427:Bacterial Toxins / Q000008:administration & dosage* / Q000276:immunology; D049109:Cell Proliferation; D003453:Cryptococcosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004768:Enterotoxins / Q000008:administration & dosage* / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D029968:Escherichia coli Proteins / Q000008:administration & dosage* / Q000276:immunology; D022361:Escherichia coli Vaccines / Q000008:administration & dosage* / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D007070:Immunoglobulin A / Q000096:biosynthesis; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D015431:Weight Loss / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D016207:Cytokines; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines; D007070:Immunoglobulin A; C027538:heat-labile enterotoxin, E coli