B lymphocytes regulate airway granulocytic inflammation and cytokine production in a murine model of fungal allergic asthma (original) (raw)
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Murine models of airway fungal exposure and allergic sensitization
Medical Mycology, 2010
Inhalation of common indoor fi lamentous fungi has been associated with the induction or exacerbation of allergic respiratory disease. The understanding of fungal inhalation and allergic sensitization has signifi cantly advanced with the use of small animal models, especially mouse models. Numerous studies have employed different animal exposure and sensitization techniques, each with inherent advantages and disadvantages that are addressed in this review. In addition, most studies involve exposure of animals to fungal spores or spore extracts while neglecting the infl uence of hyphal or subcellular fragment exposures. Recent literature examining the potential for hyphae and fungal fragments to induce or exacerbate allergy is discussed. Innate immune recognition of fungal elements and their contribution to lung allergic infl ammation in animal models are also reviewed. Though physical properties of fungi play an important role following exposure, host immune development is also critical in airway infl ammation and allergy. We discuss the importance of environmental factors that infl uence early immune development and subsequent susceptibility to allergy. Murine studies that examine the role of intestinal microfl ora and prenatal or early life environmental factors that promote allergic sensitization are also evaluated. Future studies will require animal models that accurately refl ect natural fungal exposures and identify environmental factors that infl uence immune development and thus promote respiratory fungal allergy and disease.
Physiologic alterations in the murine model after nasal fungal antigenic exposure
Otolaryngology-head and Neck Surgery, 2008
To determine whether a recently developed murine model of fungus-induced sinonasal inflammation demonstrated alterations in ciliary activity and expression of inflammatory cytokines. STUDY DESIGN: A prospective randomized controlled study of rhinosinusitis after fungal antigenic sensitization was performed with intraperitoneal aspergillus antigen injection followed by intranasal antigen challenge for 4 weeks. Saline solution was used in a parallel fashion for control animals. SUBJECTS AND METHODS: Six mice were used to validate the model. Additional 15 mice were used for ciliary beat frequency (CBF) analysis and cytokine expression with multiplex technology. Mean values for degree of inflammation, secretory hyperplasia, CBF, and cytokine expression were compared. RESULTS: Histologic analyses demonstrated dense chronic inflammation in aspergillus-challenged animals versus sparse inflammatory cells in controls. Significant differences in mean of aspergillus-challenged versus control animals were observed in degree of inflammation (P Ͻ 0.01), secretory hyperplasia (P Ͻ 0.01), CBF (P Ͻ 0.00002), IL-1␣ (P Ͻ 0.0002), IL-1 (P Ͻ 0.0003), IL-4 (P Ͻ 0.02), TNF-␣ (P Ͻ 0.02), and RANTES (P Ͻ 0.01). CONCLUSION: Alteration in baseline CBF accompanied by increased expression of specific inflammatory cytokines was observed in aspergillus-challenged mice.
Anti-fungal T cell responses in the lung and modulation by the gut-lung axis
Current Opinion in Microbiology, 2020
The lung is a central organ for immune-environmental interactions ranging from tolerance against harmless substances to protection against pathogens, which are particularly sensitive to regulation by the intestinal microbiota. Airborne fungi, can cause variety of diseases, including allergies and inflammatory disorders, as well as life-threatening invasive infections. Remarkable differences exist between ubiquitous fungal species with regard to protective immune mechanisms. Recent data have surprisingly identified Aspergillus-specific regulatory T cells as an essential tolerance checkpoint and provided mechanistic insight for the loss of tolerance in the course of immune pathologies. Furthermore, pathogenic Th17 cells in Aspergillus-associated inflammatory disease seem to be induced by cross-reactivity to the intestinal commensal Candida albicans. Here we review and discuss what is known about fungus-specific T cell responses in the lung how they are modulated by the gut-lung axis and in particular discussing the modulation of adaptive immune responses by cross-reactivity to the microbiota.
Respiratory tract allergic disease and atopy: experimental evidence for a fungal infectious etiology
Medical Mycology, 2011
Allergic asthma is an obstructive lung disease linked to environmental exposures that elicit allergic airway infl ammation and characteristic antigen-specifi c immunoglobulin reactions termed atopy. Analyses of asthma pathogenesis using experimental models have shown that T helper cells, especially T helper type 2 (Th2) cells and Th2 cytokines such as interleukin 4 (IL-4) and IL-13, are critical mediators of airway obstruction following allergen challenge, but the environmental initiators of lung Th2 responses are less defi ned. Our studies demonstrate that fungal-derived proteinases that are commonly found in home environments are requisite immune adjuvants capable of eliciting robust Th2 responses and allergic lung disease in mice. We have further shown that common household fungi readily infect the mouse respiratory tract and induce both asthma-like disease and atopy to otherwise innocuous bystander antigens through the secretion of proteinases. These fi ndings support the possibility that asthma and atopy represent a reaction to respiratory tract fungal infection, suggesting novel means for diagnosis and therapy of diverse allergic disorders.
Journal of Immunotoxicology, 2014
Aspergillus fumigatus is a filamentous fungus that produces abundant pigmented conidia. Several fungal components have been identified as virulence factors, including melanin; however, the impact of these factors in a repeated exposure model resembling natural environmental exposures remains unknown. This study examined the role of fungal melanin in the stimulation of pulmonary immune responses using immunocompetent BALB/c mice in a multiple exposure model. It compared conidia from wild-type A. fumigatus to two melanin mutants of the same strain, Darp2 (tan) or Dalb1 (white). Mass spectrometry-based analysis of conidial extracts demonstrated that there was little difference in the protein fingerprint profiles between the three strains. Field emission scanning electron microscopy demonstrated that the immunologically inert Rodlet A layer remained intact in melanin-deficient conidia. Thus, the primary difference between the strains was the extent of melanization. Histopathology indicated that each A. fumigatus strain induced lung inflammation, regardless of the extent of melanization. In mice exposed to Dalb1 conidia, an increase in airway eosinophils and a decrease in neutrophils and CD8 + IL-17 + (Tc17) cells were observed. Additionally, it was shown that melanin mutant conidia were more rapidly cleared from the lungs than wild-type conidia. These data suggest that the presence of fungal melanin may modulate the pulmonary immune response in a mouse model of repeated exposures to A. fumigatus conidia.
Novel Mouse Models of Fungal Asthma
Frontiers in Cellular and Infection Microbiology, 2021
Alternaria alternata is a ubiquitous fungus and a major allergen associated with the development of asthma. Inhalation of intact spores is the primary cause of human exposure to fungal allergen. However, allergen-rich cultured fungal filtrates are oftentimes used in the current models of fungal sensitization that do not fully reflect real-life exposures. Thus, establishing novel spore exposure models is imperative. In this study, we established novel fungal exposure models of both adult and neonate to live spores. We examined pathophysiological changes in the spore models as compared to the non-exposure controls and also to the conventional filtrate models. While both Alternaria filtrate- and spore-exposed adult BALB/c mice developed elevated airway hyperresponsiveness (AHR), filtrates induced a greater IgE mediated response and higher broncholavage eosinophils than spores. In contrast, the mice exposed to Alternaria spores had higher numbers of neutrophils. Both exposures induced c...
European Journal of Immunology, 2009
Allergic airway disease is characterized by eosinophilic inflammation, mucus hypersecretion and increased airway resistance. Fungal antigens are ubiquitous within the environment and are well know triggers of allergic disease. Bacterial products are also frequently encountered within the environment and may alter the immune response to certain antigens. The consequence of simultaneous exposure to bacterial and fungal products on the lung adaptive immune response has not been explored. Here we show that oropharyngeal aspiration of fungal lysates (Candida albicans, Aspergillus fumigatus) promotes airway eosinophilia, secretion of Th2 cytokines and mucus cell metaplasia. In contrast, oropharyngeal exposure to bacterial lysates (Pseudomonas aeruginosa) promotes airway inflammation characterized by neutrophils, Th1 cytokine secretion and no mucus production. More importantly, administration of bacterial lysates together with fungal lysates deviates the adaptive immune response to a Th1 type associated with neutrophilia and diminished mucus production. The immunomodulatory effect that bacterial lysates have on the response to fungi is TLR4-independent but MyD88 dependent. Thus, different types of microbial products within the airway can alter the host's adaptive immune response, and potentially impact the development of allergic airway disease to environmental fungal antigens.
2015
Background and Aims: Aspergillus fumigatus is a sporadic fungus that causes different infections and allergies in immunocompromised patients. The allergic disease caused by this fungus is called allergic bronchopulmonary aspergillosis (ABPA). ABPA is considred important in atopic and immunocompromised individuals, which can result in inflammation and epithelial damage. Therefore, the aim of this study was to evaluate the T helper (Th)2 responses in a ABPA murine model by measuring the main cytokines involved in Th2. Materials and Methods : Twenty male BALB/c mice were divided into two groups of 10 mice each: control and ABPA group. ABPA was induced by inhalation of A. fumigatus conidia intranasally. Total and specific IgE were measured in the mice sera. Levels of cytokines in broncho alveolar lavage (BAL) of under studied groups were measured by Enzyme-linked immunosorbent assay three weeks after the treatment. Results : The obtained results indicated that total and specific IgE inc...
Infection and Immunity, 2015
Airway colonization by the moldAspergillus fumigatusis common in patients with underlying lung disease and is associated with chronic airway inflammation. Studies probing the inflammatory response to colonization withA. fumigatushyphae have been hampered by the lack of a model of chronic colonization in immunocompetent mice. By infecting mice intratracheally with conidia embedded in agar beads (Af beads), we have established anin vivomodel to study the natural history of airway colonization with liveA. fumigatushyphae. Histopathological examination and galactomannan assay of lung homogenates demonstrated that hyphae exited beads and persisted in the lungs of mice up to 28 days postinfection without invasive disease. Fungal lesions within the airways were surrounded by a robust neutrophilic inflammatory reaction and peribronchial infiltration of lymphocytes. Whole-lung cytokine analysis from Af bead-infected mice revealed an increase in proinflammatory cytokines and chemokines early ...