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1.
Immunity ; 47(4): 739-751.e5, 2017 10 17.
Article En | MEDLINE | ID: mdl-29045903

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.


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/parasitology
2.
J Allergy Clin Immunol ; 140(4): 1068-1078.e6, 2017 Oct.
Article En | MEDLINE | ID: mdl-28196762

BACKGROUND: Helminth parasites have been reported to have beneficial immunomodulatory effects in patients with allergic and autoimmune conditions and detrimental consequences in patients with tuberculosis and some viral infections. Their role in coinfection with respiratory viruses is not clear. OBJECTIVE: Here we investigated the effects of strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus (RSV) infection in a mouse model. METHODS: A murine helminth/RSV coinfection model was developed. Mice were infected by means of oral gavage with 200 stage 3 H polygyrus larvae. Ten days later, mice were infected intranasally with either RSV or UV-inactivated RSV. RESULTS: H polygyrus-infected mice showed significantly less disease and pulmonary inflammation after RSV infection associated with reduced viral load. Adaptive immune responses, including TH2 responses, were not essential because protection against RSV was maintained in Rag1-/- and Il4rα-/- mice. Importantly, H polygyrus infection upregulated expression of type I interferons and interferon-stimulated genes in both the duodenum and lung, and its protective effects were lost in both Ifnar1-/- and germ-free mice, revealing essential roles for type I interferon signaling and microbiota in H polygyrus-induced protection against RSV. CONCLUSION: These data demonstrate that a strictly enteric helminth infection can have remote protective antiviral effects in the lung through induction of a microbiota-dependent type I interferon response.


Intestines/immunology , Lung/immunology , Microbiota/immunology , Nematospiroides dubius/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/immunology , Strongylida Infections/immunology , Th2 Cells/immunology , Animals , Antigens, Helminth/immunology , Cells, Cultured , Coinfection , Female , Humans , Immunity, Mucosal , Interferon Type I/metabolism , Intestines/parasitology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptor, Interferon alpha-beta/genetics , Signal Transduction , Th2 Cells/parasitology
3.
Thorax ; 72(7): 620-627, 2017 07.
Article En | MEDLINE | ID: mdl-27531529

RATIONALE: The pathogenesis of respiratory syncytial virus (RSV) bronchiolitis in infants remains poorly understood. Mouse models implicate pulmonary T cells in the development of RSV disease. T cell responses are initiated by dendritic cells (DCs), which accumulate in lungs of RSV-infected mice. In infants with RSV bronchiolitis, previous reports have shown that DCs are mobilised to the nasal mucosa, but data on lower airway DC responses are lacking. OBJECTIVE: To determine the presence and phenotype of DCs and associated immune cells in bronchoalveolar lavage (BAL) and peripheral blood samples from infants with RSV bronchiolitis. METHODS: Infants intubated and ventilated due to severe RSV bronchiolitis or for planned surgery (controls with healthy lungs) underwent non-bronchoscopic BAL. Immune cells in BAL and blood samples were characterised by flow cytometry and cytokines measured by Human V-Plex Pro-inflammatory Panel 1 MSD kit. MEASUREMENTS AND MAIN RESULTS: In RSV cases, BAL conventional DCs (cDCs), NK T cells, NK cells and pro-inflammatory cytokines accumulated, plasmacytoid DCs (pDCs) and T cells were present, and blood cDCs increased activation marker expression. When stratifying RSV cases by risk group, preterm and older (≥4 months) infants had fewer BAL pDCs than term born and younger (<4 months) infants, respectively. CONCLUSIONS: cDCs accumulate in the lower airways during RSV bronchiolitis, are activated systemically and may, through activation of T cells, NK T cells and NK cells, contribute to RSV-induced inflammation and disease. In addition, the small population of airway pDCs in preterm and older infants may reveal a distinct endotype of RSV bronchiolitis with weak antiviral pDC responses.


Bronchiolitis, Viral/immunology , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cytokines/analysis , Dendritic Cells/immunology , Respiratory Syncytial Virus Infections/complications , Age Factors , Antigens, CD/blood , Bronchiolitis, Viral/blood , Bronchiolitis, Viral/virology , Bronchoalveolar Lavage Fluid/chemistry , CD4-Positive T-Lymphocytes , CD40 Antigens/blood , CD8-Positive T-Lymphocytes , Case-Control Studies , Cell Count , Cytokines/blood , Female , Humans , Immunoglobulins/blood , Infant , Infant, Newborn , Killer Cells, Natural , Macrophages , Male , Membrane Glycoproteins/blood , Monocytes , Natural Killer T-Cells , Phenotype , Premature Birth/immunology , Term Birth/immunology , CD83 Antigen
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