RESUMO
RIG-I-like receptors (RLR) are cytosolic RNA sensors that signal through the MAVS adaptor to activate IFN responses against viruses. Whether the RLR family has broader effects on host immunity against other pathogen families remains to be fully explored. In this study, we demonstrate that MDA5/MAVS signaling was essential for host resistance against pulmonary Aspergillus fumigatus challenge through the regulation of antifungal leukocyte responses in mice. Activation of MDA5/MAVS signaling was driven by dsRNA from live A. fumigatus serving as a key vitality-sensing pattern recognition receptor. Interestingly, induction of type I IFNs after A. fumigatus challenge was only partially dependent on MDA5/MAVS signaling, whereas type III IFN expression was entirely dependent on MDA5/MAVS signaling. Ultimately, type I and III IFN signaling drove the expression of CXCL10. Furthermore, the MDA5/MAVS-dependent IFN response was critical for the induction of optimal antifungal neutrophil killing of A. fumigatus spores. In conclusion, our data broaden the role of the RLR family to include a role in regulating antifungal immunity against A. fumigatus.
Assuntos
Aspergillus fumigatus/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Helicase IFIH1 Induzida por Interferon/metabolismo , Moléculas com Motivos Associados a Patógenos/imunologia , Moléculas com Motivos Associados a Patógenos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Feminino , Interferons/imunologia , Interferons/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/imunologiaRESUMO
Aspergillus fumigatus is responsible for a disproportionate number of invasive mycosis cases relative to other common filamentous fungi. While many fungal factors critical for infection establishment are known, genes essential for disease persistence and progression are ill defined. We propose that fungal factors that promote navigation of the rapidly changing nutrient and structural landscape characteristic of disease progression represent untapped clinically relevant therapeutic targets. To this end, we find that A. fumigatus requires a carbon catabolite repression (CCR) mediated genetic network to support in vivo fungal fitness and disease progression. While CCR as mediated by the transcriptional repressor CreA is not required for pulmonary infection establishment, loss of CCR inhibits fungal metabolic plasticity and the ability to thrive in the dynamic infection microenvironment. Our results suggest a model whereby CCR in an environmental filamentous fungus is dispensable for initiation of pulmonary infection but essential for infection maintenance and disease progression. Conceptually, we argue these data provide a foundation for additional studies on fungal factors required to support fungal fitness and disease progression and term such genes and factors, DPFs (disease progression factors).
Assuntos
Aspergilose/microbiologia , Aspergillus fumigatus/genética , Carbono/metabolismo , Repressão Catabólica , Proteínas Fúngicas/metabolismo , Redes Reguladoras de Genes , Aspergilose/patologia , Aspergillus fumigatus/fisiologia , Progressão da Doença , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Modelos Biológicos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Estresse FisiológicoRESUMO
Heterogeneity among Aspergillus fumigatus isolates results in unique virulence potential and inflammatory responses. How these isolates drive specific immune responses and how this affects fungally induced lung damage and disease outcome are unresolved. We demonstrate that the highly virulent CEA10 strain is able to rapidly germinate within the immunocompetent lung environment, inducing greater lung damage, vascular leakage, and interleukin 1α (IL-1α) release than the low-virulence Af293 strain, which germinates with a lower frequency in this environment. Importantly, the clearance of CEA10 was consequently dependent on IL-1α, in contrast to Af293. The release of IL-1α occurred by a caspase 1/11- and P2XR7-independent mechanism but was dependent on calpain activity. Our finding that early fungal conidium germination drives greater lung damage and IL-1α-dependent inflammation is supported by three independent experimental lines. First, pregermination of Af293 prior to in vivo challenge drives greater lung damage and an IL-1α-dependent neutrophil response. Second, the more virulent EVOL20 strain, derived from Af293, is able to germinate in the airways, leading to enhanced lung damage and IL-1α-dependent inflammation and fungal clearance. Third, primary environmental A. fumigatus isolates that rapidly germinate under airway conditions follow the same trend toward IL-1α dependency. Our data support the hypothesis that A. fumigatus phenotypic variation significantly contributes to disease outcomes.
Assuntos
Aspergilose/imunologia , Aspergillus fumigatus/imunologia , Aspergillus fumigatus/patogenicidade , Interleucina-1alfa/imunologia , Pulmão/imunologia , Animais , Células Cultivadas , Imunocompetência , Inflamação , Pulmão/microbiologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Esporos Fúngicos/imunologia , Esporos Fúngicos/patogenicidade , VirulênciaRESUMO
Aspergillus fumigatus airway infections are associated with increased rates of hospitalizations and declining lung function in patients with chronic lung disease. While the pathogenesis of invasive A. fumigatus infections is well studied, little is known about the development and progression of airway infections. Previous studies have demonstrated a critical role for the IL-1 cytokines, IL-1α and IL-1ß in enhancing pulmonary neutrophil recruitment during invasive aspergillosis. Here we use a mouse model of A. fumigatus airway infection to study the role of these IL-1 cytokines in immunocompetent mice. In the absence of IL-1 receptor signaling, mice exhibited reduced numbers of viable pulmonary neutrophils and increased levels of neutrophil apoptosis during fungal airway infection. Impaired neutrophil viability in these mice was associated with reduced pulmonary and systemic levels of G-CSF, and treatment with G-CSF restored both neutrophil viability and resistance to A. fumigatus airway infection. Taken together, these data demonstrate that IL-1 dependent G-CSF production plays a key role for host resistance to A. fumigatus airway infection through suppressing neutrophil apoptosis at the site of infection.
Assuntos
Aspergilose/imunologia , Aspergillus fumigatus/patogenicidade , Pulmão/imunologia , Neutrófilos/fisiologia , Aspergilose Pulmonar/imunologia , Receptores de Interleucina-1/fisiologia , Animais , Apoptose/imunologia , Quimiocinas/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Interleucina-1alfa , Interleucina-1beta , Pulmão/patologia , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Neutrófilos/imunologiaRESUMO
The relationship between B cells and CD4 T cells has been carefully studied, revealing a collaborative effort in which B cells promote the activation, differentiation, and expansion of CD4 T cells while the so-called "helper" cells provide signals to B cells, influencing their class switching and fate. Interactions between B cells and CD8 T cells are not as well studied, although CD8 T cells exhibit an accelerated contraction after certain infections in B-cell-deficient mice. Here, we find that B cells significantly enhance primary CD8 T cell responses after vaccination. Moreover, memory CD8 numbers and function are impaired in B-cell-deficient animals, leading to increased susceptibility to bacterial challenge. We also show that interleukin-27 production by B cells contributes to their impact on primary, but not memory, CD8 responses. Better understanding of the interactions between CD8 T cells and B cells may aid in the design of more effective future vaccine strategies.
Assuntos
Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Interleucina-27/imunologia , Interleucina-27/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Animais , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/imunologia , Humanos , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Receptores Virais/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , VacinaçãoRESUMO
Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how immune competent hosts maintain control of fungal infections while constantly being exposed to fungi is rapidly emerging. It is known that timely neutrophil recruitment to and activation in the lungs is critical to the host defense against development of invasive pulmonary aspergillosis, but the inflammatory sequelae necessary remains to be fully defined. Here, we show that 5-Lipoxygenase (5-LO) and Leukotriene B4 (LTB4) are critical for leukocyte recruitment and resistance to pulmonary A. fumigatus challenge in a fungal-strain-dependent manner. 5-LO activity was needed in radiosensitive cells for an optimal anti-fungal response and in vivo LTB4 production was at least partially dependent on myeloid-derived hypoxia inducible factor-1α. Overall, this study reveals a role for host-derived leukotriene synthesis in innate immunity to A. fumigatus.