Cytokines in host defense against<i>Aspergillus</i>: recent advances

Phadke, Anagha P.; Mehrad, Borna

doi:10.1080/13693780500052099

Cited by 46 publications

(35 citation statements)

References 25 publications

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“…The importance of pattern recognition receptors (PRRs) to fungal recognition and modulation of host responses has been clarified with the use of knockout mice, such as those for dectin-1 and several of the Toll-like receptors (TLRs) (142). Cytokine-deficient mice have also been used to demonstrate the contribution of cytokines to host resistance (such as TNF-␣) or susceptibility (interleukin-10 [IL-10]) (33,40,158).…”

Section: Animal Models Of Invasive Aspergillosismentioning

confidence: 99%

“…Alveolar macrophages phagocytose Aspergillus conidia in an actin-dependent manner, a process mediated by the recognition of pathogen-associated molecular patterns by host cell PRRs. PRR engagement of A. fumigatus ligands generates a proinflammatory response characterized by the production of cytokines and chemokines that are important for host defense against this organism, including TNF-␣, IL-1␤, IL-6, IL-8, macrophage inflammatory protein 1␣, and monocyte chemoattractant protein 1 (39, 131,138,158). TLR2 and TLR4 and the C-type lectin receptor dectin-1 are the most well-characterized PRRs involved in the recognition of A. fumigatus and the activation of host cells.…”

Section: Aspergillus and The Alveolar Macrophagementioning

confidence: 99%

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Pathogenesis ofAspergillus fumigatusin Invasive Aspergillosis

2009

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SUMMARY Aspergillus species are globally ubiquitous saprophytes found in a variety of ecological niches. Almost 200 species of aspergilli have been identified, less than 20 of which are known to cause human disease. Among them, Aspergillus fumigatus is the most prevalent and is largely responsible for the increased incidence of invasive aspergillosis (IA) in the immunocompromised patient population. IA is a devastating illness, with mortality rates in some patient groups reaching as high as 90%. Studies identifying and assessing the roles of specific factors of A. fumigatus that contribute to the pathogenesis of IA have traditionally focused on single-gene deletion and mutant characterization. In combination with recent large-scale approaches analyzing global fungal responses to distinct environmental or host conditions, these studies have identified many factors that contribute to the overall pathogenic potential of A. fumigatus. Here, we provide an overview of the significant findings regarding A. fumigatus pathogenesis as it pertains to invasive disease.

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Section: Animal Models Of Invasive Aspergillosismentioning

confidence: 99%

Section: Aspergillus and The Alveolar Macrophagementioning

confidence: 99%

Pathogenesis ofAspergillus fumigatusin Invasive Aspergillosis

2009

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“…prolonged neutropenia and steroid therapy. IL-8 is a chemokine involved in both the recruitment of neutrophils and the neutrophil phagocytosis of A. fumigatus conidia (Richardson & Patel, 1995), TNF-a is a cytokine that plays a role in chemokine production and neutrophil activity (Mehrad et al, 1999;Phadke & Mehrad, 2005) and GM-CSF is a growth factor known to be crucial in the maturation process of granulocytes and macrophages (Walsh et al, 2005). These three mediators are released in response to activation of the NF-kB transcriptional complex.…”

Section: Mrna Quantificationmentioning

confidence: 99%

Aspergillus fumigatus germ tube growth and not conidia ingestion induces expression of inflammatory mediator genes in the human lung epithelial cell line A549

Bellanger

Millon

Khoufache

et al. 2009

Journal of Medical Microbiology

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Inhalation of conidia is the main cause of invasive pulmonary aspergillosis (IPA) and the respiratory epithelium is the first line of defence. To explore the triggering factor for the inflammatory response to Aspergillus fumigatus, the species mainly responsible for IPA, this study analysed the differential expression of three inflammatory genes in A549 cells after challenge with live and killed conidia. The influence of steroids, one of the main risk factors for developing IPA, was also investigated. Quantification of mRNAs of the inflammatory mediator genes encoding interleukin (IL)-8, tumour necrosis factor (TNF)-a and granulocyte-monocyte colony-stimulating factor (GM-CSF) was carried out using real-time PCR. Ingestion rates were studied for the conidia of A. fumigatus and Penicillium chrysogenum using a fluorescence brightener. Similar results were obtained for both species, with ingestion rates ranging from 35 to 40 %. Exposure of A549 cells to live A. fumigatus conidia only induced a four-to fivefold increase in the mRNA levels of the three genes, starting 8 h after the initial contact. Both inactivation of live A. fumigatus conidia and treatment by dexamethasone (10 "7 M) prevented the overexpression of TNF-a, IL-8 and GM-CSF. Fungal growth, rather than conidia ingestion, appears to be the main stimulus for the production of inflammatory mediators by epithelial cells, and this production is inhibited by steroid therapy. These results underline the role that the epithelium plays in the innate response against IPA. INTRODUCTIONInvasive pulmonary aspergillosis (IPA) is an opportunistic infection whose incidence is increasing at the same rate as the number of severely immunocompromised patients (Lin et al., 2001). Neutropenia and high-dose steroid treatments are the main risk factors for IPA, and these underline the importance of an appropriate inflammatory response if fungal invasion is to be avoided. Most authors stress the important roles that alveolar macrophages and neutrophils play in controlling infection (Romani, 2004;Walsh et al., 2005). The release of innate immune-related molecules from professional phagocytic cells in the course of Aspergillus fumigatus infection has been widely studied (Meier et al., 2003;Pylkkanen et al., 2004;Cortez et al., 2006). However, the respiratory epithelium is the first tissue that inhaled conidia encounter, and it probably participates in the efficient coordinated response against IPA. In animal models of IPA, most inhaled conidia are trapped in the upper respiratory tract, and the respiratory epithelium coordinates with alveolar macrophages (Stephens-Romero et al., 2005).A few studies have investigated the production of inflammatory mediators by studying the human lung epithelial cell line A549 after stimulation with moulds or mould extracts (Borger et al., 1999; Kauffman et al., 2000; Huttunen et al., 2003;Zhang et al., 2005; Tai et al., 2006). These studies have focused on fungi as the source of allergens, and on species other than A. fumigatus, which are Abbrevi...

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“…The immune response to inhaled A. fumigatus in healthy individuals is characterized by a complex interaction between innate and adaptive immune responses, both of which are activated upon exposure to the fungus (18,31,56,58). Macrophages and neutrophils efficiently phagocytize inhaled conidia in the lungs, with neutrophils being absolutely essential, and conidial clearance can occur with minimal inflammation (7,33,44,63,66,67,70).…”

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confidence: 99%

Coevolution of T_H1, T_H2, and T_H17 Responses during Repeated Pulmonary Exposure toAspergillus fumigatusConidia

et al. 2011

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Aspergillus fumigatus, a ubiquitous airborne fungus, can cause invasive infection in immunocompromised individuals but also triggers allergic bronchopulmonary aspergillosis in a subset of otherwise healthy individuals repeatedly exposed to the organism. This study addresses a critical gap in our understanding of the immunoregulation in response to repeated exposure to A. fumigatus conidia. C57BL/6 mice were challenged intranasally with A. fumigatus conidia weekly, and leukocyte composition, activation, and cytokine production were examined after two, four, and eight challenges. Approximately 99% of A. fumigatus conidia were cleared within 24 h after inoculation, and repeated exposure to A. fumigatus conidia did not result in hyphal growth or accumulation of conidia with time. After 2 challenges, there was an early influx of neutrophils and regulatory T (T reg ) cells into the lungs but minimal inflammation. Repeated exposure promoted sustained expansion of the draining lymph nodes, while the influx of eosinophils and other myeloid cells into the lungs peaked after four exposures and then decreased despite continued A. fumigatus challenges. Goblet cell metaplasia and low-level fibrosis were evident during the response. Repeated exposure to A. fumigatus conidia induced T cell activation in the lungs and the codevelopment by four exposures of T H 1, T H 2, and T H 17 responses in the lungs, which were maintained through eight exposures. Changes in CD4 T cell polarization or T reg numbers did not account for the reduction in myeloid cell numbers later in the response, suggesting a non-T-cell regulatory pathway involved in dampening inflammation during repeated exposure to A. fumigatus conidia.

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Cytokines in host defense againstAspergillus: recent advances

Cited by 46 publications

References 25 publications

Pathogenesis ofAspergillus fumigatusin Invasive Aspergillosis

Pathogenesis ofAspergillus fumigatusin Invasive Aspergillosis

Aspergillus fumigatus germ tube growth and not conidia ingestion induces expression of inflammatory mediator genes in the human lung epithelial cell line A549

Coevolution of T_H1, T_H2, and T_H17 Responses during Repeated Pulmonary Exposure toAspergillus fumigatusConidia

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Cytokines in host defense againstAspergillus: recent advances

Cited by 46 publications

References 25 publications

Pathogenesis ofAspergillus fumigatusin Invasive Aspergillosis

Pathogenesis ofAspergillus fumigatusin Invasive Aspergillosis

Aspergillus fumigatus germ tube growth and not conidia ingestion induces expression of inflammatory mediator genes in the human lung epithelial cell line A549

Coevolution of TH1, TH2, and TH17 Responses during Repeated Pulmonary Exposure toAspergillus fumigatusConidia

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Coevolution of T_H1, T_H2, and T_H17 Responses during Repeated Pulmonary Exposure toAspergillus fumigatusConidia