RESUMO
Humans inhale hundreds of Aspergillus conidia without adverse consequences. Powerful protective mechanisms may ensure prompt control of the pathogen and inflammation. Here we reveal a previously unknown mechanism by which the danger molecule S100B integrates pathogen- and danger-sensing pathways to restrain inflammation. Upon forming complexes with TLR2 ligands, S100B inhibited TLR2 via RAGE, through a paracrine epithelial cells/neutrophil circuit that restrained pathogen-induced inflammation. However, upon binding to nucleic acids, S100B activated intracellular TLRs eventually resolve danger-induced inflammation via transcriptional inhibition of S100B. Thus, the spatiotemporal regulation of TLRs and RAGE by S100B provides evidence for an evolving braking circuit in infection whereby an endogenous danger protects against pathogen-induced inflammation and a pathogen-sensing mechanism resolves danger-induced inflammation.
Assuntos
Aspergillus/fisiologia , Interações Hospedeiro-Patógeno/fisiologia , Fatores de Crescimento Neural/metabolismo , Receptores Imunológicos/antagonistas & inibidores , Proteínas S100/metabolismo , Receptor 2 Toll-Like/antagonistas & inibidores , Animais , Aspergillus/patogenicidade , Modelos Animais de Doenças , Pulmão/metabolismo , Pulmão/microbiologia , Camundongos , Camundongos Knockout , Aspergilose Pulmonar/metabolismo , Aspergilose Pulmonar/microbiologia , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/deficiência , Receptores Imunológicos/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100 , Receptor 2 Toll-Like/metabolismoRESUMO
Pentraxin 3 (PTX3) is a soluble pattern recognition molecule playing a nonredundant role in resistance against Aspergillus fumigatus. The present study was designed to investigate the molecular pathways involved in the opsonic activity of PTX3. The PTX3 N-terminal domain was responsible for conidia recognition, but the full-length molecule was necessary for opsonic activity. The PTX3-dependent pathway of enhanced neutrophil phagocytic activity involved complement activation via the alternative pathway; Fcγ receptor (FcγR) IIA/CD32 recognition of PTX3-sensitized conidia and complement receptor 3 (CR3) activation; and CR3 and CD32 localization to the phagocytic cup. Gene targeted mice (ptx3, FcR common γ chain, C3, C1q) validated the in vivo relevance of the pathway. In particular, the protective activity of exogenous PTX3 against A fumigatus was abolished in FcR common γ chain-deficient mice. Thus, the opsonic and antifungal activity of PTX3 is at the crossroad between complement, complement receptor 3-, and FcγR-mediated recognition. Because short pentraxins (eg, C-reactive protein) interact with complement and FcγR, the present results may have general significance for the mode of action of these components of the humoral arm of innate immunity.
Assuntos
Aspergillus fumigatus/imunologia , Proteína C-Reativa/imunologia , Proteínas do Tecido Nervoso/imunologia , Receptores de Complemento/imunologia , Receptores de IgG/imunologia , Animais , Ativação do Complemento/imunologia , Imunidade Inata , Antígeno de Macrófago 1/imunologia , Camundongos , Camundongos Mutantes , Proteínas Opsonizantes/imunologia , Receptores de Reconhecimento de Padrão , Transdução de Sinais/imunologiaRESUMO
The C-type lectin receptor Dectin-1 plays a pivotal role in antifungal immunity. In this study, the recently characterized human DECTIN1 Y238X early stop codon polymorphism leading to diminished Dectin-1 receptor activity was studied in relation to invasive aspergillosis susceptibility and severity in patients receiving hematopoietic stem cell transplantation. We found that the presence of the DECTIN1 Y238X polymorphism in either donors or recipients of hematopoietic stem cell transplantation increased susceptibility to aspergillosis, with the risk being highest when the polymorphism was present simultaneously in both donors and recipients (adjusted hazard ratio = 3.9; P = .005). Functionally, the Y238X polymorphism impaired the production of interferon-γ and interleukin-10 (IL-10), in addition to IL-1ß, IL-6, and IL-17A, by human peripheral mononuclear cells and Dectin-1 on human epithelial cells contributed to fungal recognition. Mechanistically, studies on preclinical models of infection in intact or bone marrow-transplanted Dectin-1 knockout mice revealed that protection from infection requires a distinct, yet complementary, role of both donor and recipient Dectin-1. This study discloses Dectin-1 deficiency as a novel susceptibility factor for aspergillosis in high-risk patients and identifies a previously unsuspected role for Dectin-1 in antifungal immunity that is the ability to control both resistance and tolerance to the fungus contingent on hematopoietic/nonhematopoietic compartmentalization.
Assuntos
Aspergilose/etiologia , Suscetibilidade a Doenças/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Polimorfismo Genético/imunologia , Adolescente , Adulto , Idoso , Animais , Aspergilose/genética , Aspergilose/imunologia , Criança , Citocinas/biossíntese , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Fungos/imunologia , Humanos , Lectinas Tipo C , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Proteínas de Membrana/deficiência , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/deficiência , Adulto JovemRESUMO
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening bacterial and fungal infections and hyperinflammation. The susceptibility to aspergillosis in experimental CGD (p47(phox-/-) mice) is associated with the failure to control the inherent inflammatory response to the fungus and to restrict the activation of inflammatory Th17 cells. We assessed whether pentraxin (PTX)3, a member of a family of multimeric pattern-recognition proteins with potent anti-Aspergillus activity, could limit pathogenic inflammation in p47(phox-/-) mice by curbing the IL-23/Th17 inflammatory axis in response to the fungus. We found that the production of PTX3 was delayed in CGD mice in infection but exogenous administration of PTX3 early in infection restored antifungal resistance and restrained the inflammatory response to the fungus. This occurred through down-regulation of IL-23 production by dendritic cells and epithelial cells which resulted in limited expansion of IL-23R+ gammadelta+ T cells producing IL-17A and the emergence of Th1/Treg responses with minimum pathology. Thus, PTX3 could be therapeutically used for the exploitation of NADPH-independent mechanism(s) of antifungal immune protection with limited immunopathology in CGD.
Assuntos
Antifúngicos/administração & dosagem , Proteína C-Reativa/administração & dosagem , Farmacorresistência Fúngica/imunologia , Doença Granulomatosa Crônica/patologia , Doença Granulomatosa Crônica/prevenção & controle , Mediadores da Inflamação/administração & dosagem , Aspergilose Pulmonar/patologia , Aspergilose Pulmonar/prevenção & controle , Componente Amiloide P Sérico/administração & dosagem , Animais , Antifúngicos/metabolismo , Antifúngicos/uso terapêutico , Aspergillus fumigatus/imunologia , Aspergillus fumigatus/patogenicidade , Proteína C-Reativa/biossíntese , Proteína C-Reativa/genética , Proteína C-Reativa/uso terapêutico , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Farmacorresistência Fúngica/genética , Regulação Fúngica da Expressão Gênica/imunologia , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/imunologia , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Aspergilose Pulmonar/genética , Aspergilose Pulmonar/imunologia , Componente Amiloide P Sérico/biossíntese , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/uso terapêuticoRESUMO
The ability of the fungus Aspergillus fumigatus to activate, suppress, or subvert host immune response during life cycle in vivo through dynamic changing of cell wall structure and secretion implicates discriminative immune sensing of distinct fungal components. In this study, we have comparatively assessed secreted- and membrane-anchored proteins, glycolipids, and polysaccharides for the ability to induce vaccine-dependent protection in transplanted mice and Th cytokine production by human-specific CD4(+) T cell clones. The results show that the different fungal components are endowed with the distinct capacity to activate Th cell responses in mice and humans, with secreted proteins inducing Th2 cell activation, membrane proteins Th1/Treg, glycolipids Th17, and polysaccharides mostly IL-10 production. Of interest, the side-by-side comparison revealed that at least three fungal components (a protease and two glycosylphosphatidylinositol-anchored proteins) retained their immunodominant Th1/Treg activating potential from mice to humans. This suggests that the broadness and specificity of human T cell repertoire against the fungus could be selectively exploited with defined immunoactive Aspergillus Ags.
Assuntos
Aspergillus fumigatus/imunologia , Proteínas Fúngicas/fisiologia , Vacinas Fúngicas/imunologia , Glicolipídeos/fisiologia , Polissacarídeos/fisiologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/microbiologia , Animais , Antígenos de Fungos/fisiologia , Aspergilose/imunologia , Aspergilose/microbiologia , Aspergilose/prevenção & controle , Células Clonais , Citocinas/biossíntese , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Células Dendríticas/transplante , Feminino , Vacinas Fúngicas/administração & dosagem , Humanos , Epitopos Imunodominantes/imunologia , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/prevenção & controle , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance. Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established, we determined that epithelial cells (ECs) also contributes to this balance. Mechanistically, EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor-inducing interferon (TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase (IDO) via non-canonical nuclear factor-κB activation. Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis, bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice, underexpressed the IDO-dependent T helper 1/regulatory T cell (Th1/Treg) pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs. Further studies with interferon (IFN)-γ, IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-γ/IDO/Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth. Thus, distinct immune pathways contribute to resistance and tolerance to the fungus, to which the hematopoietic/non-hematopoietic compartments contribute through distinct, yet complementary, roles.