Abstract
BackgroundA. fumigatus has been associated with a wide spectrum of allergic disorders such as ABPA or SAFS. It is poorly understood what allergens in particular are being expressed during fungal invasion and which are responsible for stimulation of immune responses. Study of the dynamics of allergen production by fungi may lead to insights into how allergens are presented to the immune system.MethodsExpression of 17 A. fumigatus allergen genes was examined in response to various culture conditions and stimuli as well as in the presence of macrophages in order to mimic conditions encountered in the lung.ResultsExpression of 14/17 allergen genes was strongly induced by oxidative stress caused by hydrogen peroxide (Asp f 1, -2, -4, -5, -6, -7, -8, -10, -13, -17 and -18, all >10-fold and Asp f 11, -12, and -22, 5-10-fold) and 16/17 allergen genes were repressed in the presence of cAMP. The 4 protease allergen genes (Asp f -5, -10, -13 and -18) were expressed at very low levels compared to the comparator (β-tubulin) under all other conditions examined. Mild heat shock, anoxia, lipid and presence of macrophages did not result in coordinated changes in allergen gene expression. Growth on lipid as sole carbon source contributed to the moderate induction of most of the allergen genes. Heat shock (37°C > 42°C) caused moderate repression in 11/17 genes (Asp f 1, -2, -4, -5, -6, -9, -10, -13, -17, -18 and -23) (2- to 9-fold), which was mostly evident for Asp f 1 and -9 (~9-fold). Anaerobic stress led to moderate induction of 13/17 genes (1.1 to 4-fold) with one, Asp f 8 induced over 10-fold when grown under mineral oil. Complex changes were seen in gene expression during co-culture of A. fumigatus with macrophages.ConclusionsRemarkable coordination of allergen gene expression in response to a specific condition (oxidative stress or the presence of cAMP) has been observed, implying that a single biological stimulus may play a role in allergen gene regulation. Interdiction of a putative allergen expression induction signalling pathway might provide a novel therapy for treatment of fungal allergy.
Highlights
Allergy is becoming one of the most common ailments in the developed world [1,2]
Aspergillus fumigatus is well studied as an invasive pathogen of humans [17,18,19] but is a major source of fungal allergens involved in allergy and exacerbations of asthma such as Severe Asthma with Fungal Sensitisation (SAFS) and Allergic Bronchopulmonary Aspergillosis (ABPA) [20,21,22,23]
Generation of macrophages from peripheral blood mononucleocytes and co-culture with A. fumigatus Since macrophages are one of the first immune cells that come in contact with a pathogen in the respiratory tract [28], allergen gene expression was tested after challenge of A. fumigatus with blood monocyte derived macrophages
Summary
Allergy is becoming one of the most common ailments in the developed world [1,2] This condition arises from disproportionate IgE-mediated and/or eosinophilic responses of the immune system to contact with an antigen [3]. Several possible conditions may be encountered in the lung that may trigger high levels of allergen gene expression These conditions might be expected to include presence of lung surfactant lipid as a carbon source, anaerobic growth in regions of the lung blocked off by mucus plugs, oxidative stress during phagocytosis, heat shock from inflammatory responses or the presence of immune cells such as macrophages [12,13,14,15,16]. A. fumigatus has been associated with a wide spectrum of allergic disorders such as ABPA or SAFS It is poorly understood what allergens in particular are being expressed during fungal invasion and which are responsible for stimulation of immune responses. Study of the dynamics of allergen production by fungi may lead to insights into how allergens are presented to the immune system
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