ABSTRACT
Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy.
Subject(s)
Helminth Proteins/immunology , Interleukin-33/immunology , Nematospiroides dubius/immunology , Strongylida Infections/immunology , Allergens/immunology , Alternaria/immunology , Amino Acid Sequence , Animals , Blotting, Western , Eosinophils/immunology , Helminth Proteins/genetics , Helminth Proteins/metabolism , Host-Parasite Interactions/immunology , Humans , Immunity, Innate/immunology , Interleukin-1 Receptor-Like 1 Protein , Interleukin-33/genetics , Interleukin-33/metabolism , Lymphocytes/immunology , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Nematospiroides dubius/genetics , Nematospiroides dubius/metabolism , Protein Binding/immunology , Receptors, Interleukin/immunology , Receptors, Interleukin/metabolism , Sequence Homology, Amino Acid , Strongylida Infections/metabolism , Strongylida Infections/parasitologyABSTRACT
Respiratory syncytial virus is a common cause of bronchiolitis. Historically, point-of-care tests have involved antigen detection technology with limited sensitivity. The aim of this study was to prospectively evaluate the diagnostic accuracy and model the economic impact of the Roche cobas® Liat® point-of-care influenza A/B and respiratory syncytial virus test. The "DEC-RSV" study was a multi-centre, prospective, observational study in children under 2 years presenting with viral respiratory symptoms. A nasopharyngeal aspirate sample was tested using the point-of-care test and standard laboratory-based procedures. The primary outcome was accuracy of respiratory syncytial virus detection. The cost implications of adopting a point-of-care test were modelled using study data. A total of 186 participants were recruited, with both tests performed on 177 samples. The point-of-care test was invalid for 16 samples (diagnostic yield 91%) leaving 161 available for primary analysis. After resolving discrepancies, the cobas® Liat® respiratory syncytial virus test had 100.00% (95% CI 96.07%-100.00%) sensitivity and 98.53% (95% CI 92.08%-99.96%) specificity. Median time to result was 0.6â h (interquartile range (IQR) 0.5-1) for point-of-care testing and 28.9â h (IQR 26.3-48.1) for standard laboratory testing. Estimated non-diagnostic cost savings for 1000 patients, based on isolation decision-making on point-of-care test result, were £57â010, which would increase to £94â847 when cohort nursing is used. In young children the cobas® Liat® point-of-care respiratory syncytial virus test has high diagnostic accuracy using nasopharyngeal aspirates (currently an off-licence sample type). Time to result is clinically important and was favourable compared to laboratory-based testing. The potential exists for cost savings when adopting the point-of-care test.