The Journal of allergy and clinical immunology · 2024
Aspergillus-mediated allergic airway inflammation is triggered by dendritic cell recognition of a defined spore morphotype.
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Houlder Emma L, Gago Sara, Vere George, Furlong-Silva Julio, Conn Daniel, Hickey Emer, Khan Saba, Thomson Darren, Shepherd Mark W, Lebedinec Ressa, Brown Gordon D, Horsnell William, Bromley Mike, MacDonald Andrew S, Cook Peter C
Аннотация
BACKGROUND: Exposure to fungi, especially Aspergillus fumigatus, can elicit potent allergic inflammation that triggers and worsens asthmatic disease. Dendritic cells (DCs) initiate allergic inflammatory responses to allergic stimuli. However, it is unclear if Af spores during isotropic growth (early spore swelling) can activate DCs to initiate allergic responses or if germination is required. This lack of basic understanding of how Af causes disease is a barrier to developing new treatments.
OBJECTIVE: We sought to show that a precise Af morphotype stage during spore swelling can trigger DCs to mediate allergic inflammatory responses and ascertain if antifungal therapeutics can be effective at suppressing this process.
METHODS: We used an Af strain deficient in pyrimidine biosynthesis (ΔpyrG) to generate populations of Af spores arrested at different stages of isotropic growth (swelling) via temporal removal of uracil and uridine from growth media. These arrested spore stages were cultured with bone marrow-derived DCs (BMDCs), and their activation was measured via flow cytometry and ELISA to examine which growth stage was able to activate BMDCs. These BMDCs were then adoptively transferred into the airways to assess if they were able to mediate allergic inflammation in naïve recipient mice. Allergic airway inflammation in vivo was determined via flow cytometry, ELISA, and real-time quantitative PCR. This system was also used to determine if antifungal drug (itraconazole) treatment could alter early stages of spore swelling and therefore BMDC activation and in vivo allergic inflammation upon adoptive transfer.
RESULTS: We found that Af isotropic growth is essential to trigger BMDC activation and mediate allergic airway inflammation. Furthermore, using time-arrested Af stages, we found that at least 3 hours in growth media enabled spores to swell sufficiently to activate BMDCs to elicit allergic airway inflammation in vivo. Incubation of germinating Af with itraconazole reduced spore swelling and partially reduced their ability to activate BMDCs to elicit in vivo allergic airway inflammation.
CONCLUSION: Our results have pinpointed the precise stage of Af development when germinating spores are able to activate DCs to mediate downstream allergic airway inflammation. Furthermore, we have identified that antifungal therapeutics partially reduced the potential of Af spores to stimulate allergic responses, highlighting a potential mechanism by which antifungal treatment might help prevent the development of fungal allergy.
OBJECTIVE: We sought to show that a precise Af morphotype stage during spore swelling can trigger DCs to mediate allergic inflammatory responses and ascertain if antifungal therapeutics can be effective at suppressing this process.
METHODS: We used an Af strain deficient in pyrimidine biosynthesis (ΔpyrG) to generate populations of Af spores arrested at different stages of isotropic growth (swelling) via temporal removal of uracil and uridine from growth media. These arrested spore stages were cultured with bone marrow-derived DCs (BMDCs), and their activation was measured via flow cytometry and ELISA to examine which growth stage was able to activate BMDCs. These BMDCs were then adoptively transferred into the airways to assess if they were able to mediate allergic inflammation in naïve recipient mice. Allergic airway inflammation in vivo was determined via flow cytometry, ELISA, and real-time quantitative PCR. This system was also used to determine if antifungal drug (itraconazole) treatment could alter early stages of spore swelling and therefore BMDC activation and in vivo allergic inflammation upon adoptive transfer.
RESULTS: We found that Af isotropic growth is essential to trigger BMDC activation and mediate allergic airway inflammation. Furthermore, using time-arrested Af stages, we found that at least 3 hours in growth media enabled spores to swell sufficiently to activate BMDCs to elicit allergic airway inflammation in vivo. Incubation of germinating Af with itraconazole reduced spore swelling and partially reduced their ability to activate BMDCs to elicit in vivo allergic airway inflammation.
CONCLUSION: Our results have pinpointed the precise stage of Af development when germinating spores are able to activate DCs to mediate downstream allergic airway inflammation. Furthermore, we have identified that antifungal therapeutics partially reduced the potential of Af spores to stimulate allergic responses, highlighting a potential mechanism by which antifungal treatment might help prevent the development of fungal allergy.