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. 2025 Mar;155(3):988-1001.
doi: 10.1016/j.jaci.2024.10.040. Epub 2024 Nov 23.

Aspergillus-mediated allergic airway inflammation is triggered by dendritic cell recognition of a defined spore morphotype

Emma L Houlder  1 , Sara Gago  2 , George Vere  3 , Julio Furlong-Silva  3 , Daniel Conn  3 , Emer Hickey  3 , Saba Khan  4 , Darren Thomson  5 , Mark W Shepherd  4 , Ressa Lebedinec  2 , Gordon D Brown  3 , William Horsnell  3 , Mike Bromley  2 , Andrew S MacDonald  4 , Peter C Cook  6
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Free article

Aspergillus-mediated allergic airway inflammation is triggered by dendritic cell recognition of a defined spore morphotype

Emma L Houlder et al. J Allergy Clin Immunol. 2025 Mar.
Free article

Abstract

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.

Keywords: Aspergillus fumigatus; allergic airway inflammation; antifungal; asthma; dendritic cells; fungal asthma; itraconazole.

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Conflict of interest statement

Disclosure statement E.L.H. was supported by a Biotechnology and Biological Sciences Research Council CASE studentship (with GSK) (BB/P504543/1) and A.S.M. by Lydia Becker core funding and the Medical Research Council (MRC; MR/W018748/1). P.C.C. was supported with a University of Manchester Dean’s Prize Early Career Research Fellowship Springboard Award (Academy of Medical Sciences, grant SBF002/1076). G.V., J.F.S., D.C., and P.C.C. were supported by Royal Society and Wellcome Trust Sir Henry Dale Fellowship (218550/Z/19/Z, awarded to P.C.C.). G.V., J.F.S., D.C., E.H., G.D.B., W.H., and P.C.C. acknowledge funding from the MRC Centre for Medical Mycology at the University of Exeter (MR/N006364/2 and MR/V033417/1), the National Institute for Health Research (NIHR) Exeter Biomedical Research Centre (NIHR203320), and the MRC Doctoral Training Grant MR/P501995/2. G.D.B. acknowledges funding from the Wellcome Trust (217163). S.G. was cofunded by the NIHR Manchester Biomedical Research Centre (www.manchesterbrc.nihr.ac.uk/) and a National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs, www.nc3rs.org.uk/) Training Fellowship (NC/P002390/1), and by the Fungal Infection Trust and the Dowager Countess Eleanor Peel Trust. Disclosure of potential conflict of interest: Individuals based at the Lydia Becker Institute received funding from GSK. These authors (E. L. Houlder, A. S. MacDonald, and P. C. Cook) declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. In the last 5 years, S. Gago has received research funds from Pfizer and honoraria for talks from Gilead outside the current study. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The rest of the authors declare that they have no relevant conflicts of interest.

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