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Viruses2024; 16(8); doi: 10.3390/v16081208

Aspergillus Fumigatus Spore Proteases Alter the Respiratory Mucosa Architecture and Facilitate Equine Herpesvirus 1 Infection.

Abstract: Numerous Aspergillus fumigatus (Af) airborne spores are inhaled daily by humans and animals due to their ubiquitous presence. The interaction between the spores and the respiratory epithelium, as well as its impact on the epithelial barrier function, remains largely unknown. The epithelial barrier protects the respiratory epithelium against viral infections. However, it can be compromised by environmental contaminants such as pollen, thereby increasing susceptibility to respiratory viral infections, including alphaherpesvirus equine herpesvirus type 1 (EHV-1). To determine whether Af spores disrupt the epithelial integrity and enhance susceptibility to viral infections, equine respiratory mucosal ex vivo explants were pretreated with Af spore diffusate, followed by EHV-1 inoculation. Spore proteases were characterized by zymography and identified using mass spectrometry-based proteomics. Proteases of the serine protease, metalloprotease, and aspartic protease groups were identified. Morphological analysis of hematoxylin-eosin (HE)-stained sections of the explants revealed that Af spores induced the desquamation of epithelial cells and a significant increase in intercellular space at high and low concentrations, respectively. The increase in intercellular space in the epithelium caused by Af spore proteases correlated with an increase in EHV-1 infection. Together, our findings demonstrate that Af spore proteases disrupt epithelial integrity, potentially leading to increased viral infection of the respiratory epithelium.
Publication Date: 2024-07-27 PubMed ID: 39205182PubMed Central: PMC11358968DOI: 10.3390/v16081208Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article investigates how Aspergillus Fumigatus (Af) spores, a common airborne fungus, can compromise the epithelial barrier of the respiratory system, thereby increasing susceptibility to viral infections such as Equine Herpesvirus type 1 (EHV-1).

Introducing the Research Context

  • The study begins by highlighting the fact that humans and animals inhale a substantial quantity of Aspergillus Fumigatus (Af) airborne spores daily due to their widespread distribution.
  • The impact of such spores on the respiratory system and its protective epithelial barrier remains largely understudied.
  • The researchers note that while the epithelial barrier serves to protect the respiratory system from viral infections, it can become disrupted by environmental contaminants, including pollen and Af spores, leading to an increased vulnerability to viruses such as EHV-1.

Methodologies of The Study

  • To investigate this issue, the researchers pretreated equine (horse) respiratory mucosal explants (tissue samples) with a substance derived from Af spores, then exposed the tissue to EHV-1.
  • The proteases (proteins that digest other proteins) present in Af spores were analyzed and identified using techniques called zymography and mass spectrometry-based proteomics. The researchers found proteases from the serine, metallo-, and aspartic protease groups.

Results and Discussion

  • Analyses of these tissue samples showed that Af spores caused the shedding or desquamation of epithelial cells and an increase in the space between cells.
  • This disruption to the epithelial integrity caused by the Af spore proteases correlated with an increase in susceptibility to EHV-1 infection.
  • Broadly, the results suggest that Af spores and their associated proteases damage the protective epithelial barrier of the respiratory system, thereby potentially enhancing the risk of viral infections.

Cite This Article

APA
Portaels J, Van Crombrugge E, Van Den Broeck W, Lagrou K, Laval K, Nauwynck H. (2024). Aspergillus Fumigatus Spore Proteases Alter the Respiratory Mucosa Architecture and Facilitate Equine Herpesvirus 1 Infection. Viruses, 16(8). https://doi.org/10.3390/v16081208

Publication

ISSN: 1999-4915
NlmUniqueID: 101509722
Country: Switzerland
Language: English
Volume: 16
Issue: 8

Researcher Affiliations

Portaels, Joren
  • Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
Van Crombrugge, Eline
  • Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
Van Den Broeck, Wim
  • Department of Morphology, Medical Imaging, Orthopedics and Nutrition, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
Lagrou, Katrien
  • Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, 3000 Leuven, Belgium.
Laval, Kathlyn
  • Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
Nauwynck, Hans
  • Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.

MeSH Terms

  • Animals
  • Herpesvirus 1, Equid / physiology
  • Herpesvirus 1, Equid / pathogenicity
  • Aspergillus fumigatus / enzymology
  • Horses
  • Spores, Fungal
  • Respiratory Mucosa / virology
  • Herpesviridae Infections / virology
  • Herpesviridae Infections / veterinary
  • Peptide Hydrolases / metabolism
  • Horse Diseases / virology
  • Horse Diseases / microbiology
  • Epithelial Cells / virology
  • Epithelial Cells / microbiology

Grant Funding

  • 01D15319 / Ghent University
  • G035920N / Research Foundation - Flanders

Conflict of Interest Statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

This article includes 76 references
  1. Mullins J, Harvey R, Seaton A. Sources and incidence of airborne Aspergillus fumigatus (Fres). Clin. Allergy 1976;6:209–217.
  2. VandenBergh M.F., Verweij P.E., Voss A. Epidemiology of nosocomial fungal infections: Invasive aspergillosis and the environment. Diagn. Microbiol. Infect. Dis. 1999;34:221–227.
    doi: 10.1016/S0732-8893(99)00026-7pubmed: 10403102google scholar: lookup
  3. O’Gorman C.M.. Airborne Aspergillus fumigatus conidia: A risk factor for aspergillosis. Fungal Biol. Rev. 2011;25:151–157.
    doi: 10.1016/j.fbr.2011.07.002google scholar: lookup
  4. McCormick A., Loeffler J., Ebel F. Aspergillus fumigatus: Contours of an opportunistic human pathogen. Cell. Microbiol. 2010;12:1535–1543.
  5. Brakhage A.A., Langfelder K. Menacing mold: The molecular biology of Aspergillus fumigatus. Annu. Rev. Microbiol. 2002;56:433–455.
  6. World Health Organization. WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action. World Health Organization Geneva, Switzerland: 2022.
  7. Tomee J.F.C., van der Werf T.S.. Pulmonary aspergillosis. Neth. J. Med. 2001;59:244–258.
    doi: 10.1016/S0300-2977(01)00163-2pubmed: 11705644google scholar: lookup
  8. Agarwal R., Chakrabarti A., Shah A., Gupta D., Meis J.F., Guleria R., Moss R., Denning D.W.. Allergic bronchopulmonary aspergillosis: Review of literature and proposal of new diagnostic and classification criteria. Clin. Exp. Allergy 2013;43:850–873.
    doi: 10.1111/cea.12141pubmed: 23889240google scholar: lookup
  9. Kurup V.P.. Aspergillus antigens: Which are important?. Med. Mycol. 2005;43((Suppl. S1)):S189–S196.
    doi: 10.1080/13693780500064763pubmed: 16110811google scholar: lookup
  10. Vrinceanu D., Dumitru M., Patrascu O.M., Costache A., Papacocea T., Cergan R.. Current diagnosis and treatment of rhinosinusal aspergilloma. Exp. Ther. Med. 2021;22:1264.
    doi: 10.3892/etm.2021.10699pmc: PMC8453335pubmed: 34603532google scholar: lookup
  11. Kendall A., Bröjer J., Karlstam E., Pringle J.. Enilconazole Treatment of Horses with Superficial Aspergillus spp. Rhinitis. J. Vet. Intern. Med. 2008;22:1239–1242.
  12. Ludwig A., Gatineau S., Reynaud M.C., Cadoré J.L., Bourdoiseau G.. Fungal isolation and identification in 21 cases of guttural pouch mycosis in horses (1998–2002). Vet. J. 2005;169:457–461.
    doi: 10.1016/j.tvjl.2004.06.005pubmed: 15848789google scholar: lookup
  13. Lepage O.M., Perron M.F., Cadoré J.L.. The mystery of fungal infection in the guttural pouches. Vet. J. 2004;168:60–64.
    doi: 10.1016/S1090-0233(03)00108-4pubmed: 15158209google scholar: lookup
  14. Latgé J.P.. Aspergillus fumigatus and aspergillosis. Clin Microbiol. Rev. 1999;12:310–350.
    doi: 10.1128/CMR.12.2.310pmc: PMC88920pubmed: 10194462google scholar: lookup
  15. Denning D.W.. Invasive Aspergillosis. Clin. Infect. Dis. 1998;26:781–803.
    doi: 10.1086/513943pubmed: 9564455google scholar: lookup
  16. Balloy V., Chignard M.. The innate immune response to Aspergillus fumigatus. Microbes Infect. 2009;11:919–927.
    doi: 10.1016/j.micinf.2009.07.002pubmed: 19615460google scholar: lookup
  17. Dagenais T.R., Keller N.P.. Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis. Clin. Microbiol. Rev. 2009;22:447–465.
    doi: 10.1128/CMR.00055-08pmc: PMC2708386pubmed: 19597008google scholar: lookup
  18. Paris S., Boisvieux-Ulrich E., Crestani B., Houcine O., Taramelli D., Lombardi L., Latgé J.P.. Internalization of Aspergillus fumigatus conidia by epithelial and endothelial cells. Infect. Immun. 1997;65:1510–1514.
  19. Wasylnka J.A., Moore M.M.. Uptake of Aspergillus fumigatus Conidia by phagocytic and nonphagocytic cells in vitro: Quantitation using strains expressing green fluorescent protein. Infect. Immun. 2002;70:3156–3163.
  20. Tomee J.F.C., Wierenga A.T.J., Hiemstra P.S., Kauffman H.F.. Proteases from Aspergillus fumigatus Induce Release of Proinflammatory Cytokines and Cell Detachment in Airway Epithelial Cell Lines. J. Infect. Dis. 1997;176:300–303.
    doi: 10.1086/517272pubmed: 9207388google scholar: lookup
  21. Kogan T.V., Jadoun J., Mittelman L., Hirschberg K., Osherov N.. Involvement of Secreted Aspergillus fumigatus Proteases in Disruption of the Actin Fiber Cytoskeleton and Loss of Focal Adhesion Sites in Infected A549 Lung Pneumocytes. J. Infect. Dis. 2004;189:1965–1973.
    doi: 10.1086/420850pubmed: 15143461google scholar: lookup
  22. Kauffman H.F., Tomee J.F., van de Riet M.A., Timmerman A.J., Borger P.. Protease-dependent activation of epithelial cells by fungal allergens leads to morphologic changes and cytokine production. Pt 1. J. Allergy Clin. Immunol. 2000;105:1185–1193.
    doi: 10.1067/mai.2000.106210pubmed: 10856154google scholar: lookup
  23. Asif A.R., Oellerich M., Amstrong V.W., Riemenschneider B., Monod M., Reichard U.. Proteome of conidial surface associated proteins of Aspergillus fumigatus reflecting potential vaccine candidates and allergens. J. Proteome Res. 2006;5:954–962.
    doi: 10.1021/pr0504586pubmed: 16602703google scholar: lookup
  24. Shende R., Wong S.S.W., Rapole S., Beau R., Ibrahim-Granet O., Monod M., Gührs K.-H., Pal J.K., Latgé J.-P., Madan T.. Aspergillus fumigatus conidial metalloprotease Mep1p cleaves host complement proteins. J. Biol. Chem. 2018;293:15538–15555.
    doi: 10.1074/jbc.RA117.001476pmc: PMC6177592pubmed: 30139746google scholar: lookup
  25. Allen G.. Respiratory Infections by Equine Herpesvirus Types 1 and 4. Equine Respiratory Diseases International Veterinary Information Service; Ithaca, NY, USA: 2002.
  26. Edington N., Welch H.M., Griffiths L.. The prevalence of latent Equid herpesviruses in the tissues of 40 abattoir horses. Equine Vet. J. 1994;26:140–142.
  27. Patel J.R., Heldens J.. Equine herpesviruses 1 (EHV-1) and 4 (EHV-4)—Epidemiology, disease and immunoprophylaxis: A brief review. Vet. J. 2005;170:14–23.
    doi: 10.1016/j.tvjl.2004.04.018pubmed: 15993786google scholar: lookup
  28. Allen G., Yeargan M., Costa L.R., Cross R.. Major histocompatibility complex class I-restricted cytotoxic T-lymphocyte responses in horses infected with equine herpesvirus 1. J. Virol. 1995;69:606–612.
    doi: 10.1128/jvi.69.1.606-612.1995pmc: PMC188619pubmed: 7983765google scholar: lookup
  29. Gryspeerdt A.C., Vandekerckhove A.P., Garré B., Barbé F., Van de Walle G.R., Nauwynck H.J.. Differences in replication kinetics and cell tropism between neurovirulent and non-neurovirulent EHV1 strains during the acute phase of infection in horses. Vet. Microbiol. 2010;142:242–253.
    doi: 10.1016/j.vetmic.2009.10.015pubmed: 19926232google scholar: lookup
  30. Vandekerckhove A.P., Glorieux S., Gryspeerdt A.C., Steukers L., Van Doorsselaere J., Osterrieder N., Van de Walle G.R., Nauwynck H.J.. Equine alphaherpesviruses (EHV-1 and EHV-4) differ in their efficiency to infect mononuclear cells during early steps of infection in nasal mucosal explants. Vet. Microbiol. 2011;152:21–28.
    doi: 10.1016/j.vetmic.2011.03.038pubmed: 21536394google scholar: lookup
  31. Bannazadeh Baghi H., Nauwynck H.J.. Effect of equine herpesvirus type 1 (EHV-1) infection of nasal mucosa epithelial cells on integrin alpha 6 and on different components of the basement membrane. Arch. Virol. 2016;161:103–110.
    doi: 10.1007/s00705-015-2643-4pubmed: 26497179google scholar: lookup
  32. Smith K.C., Mumford J.A., Lakhani K.. A comparison of equid herpesvirus-1 (EHV-1) vascular lesions in the early versus late pregnant equine uterus. J. Comp. Pathol. 1996;114:231–247.
    doi: 10.1016/S0021-9975(96)80045-4pubmed: 8762581google scholar: lookup
  33. Wilson W.D.. Equine herpesvirus 1 myeloencephalopathy. Vet. Clin. N. Am. Equine Pract. 1997;13:53–72.
    doi: 10.1016/S0749-0739(17)30255-9pubmed: 9106343google scholar: lookup
  34. Edington N., Smyth B., Griffiths L.. The role of endothelial cell infection in the endometrium, placenta and foetus of equid herpesvirus 1 (EHV-1) abortions. J. Comp. Pathol. 1991;104:379–387.
    doi: 10.1016/S0021-9975(08)80148-Xpubmed: 1651960google scholar: lookup
  35. Grinde B.. Herpesviruses: Latency and reactivation—Viral strategies and host response. J. Oral Microbiol. 2013;5.
    doi: 10.3402/jom.v5i0.22766pmc: PMC3809354pubmed: 24167660google scholar: lookup
  36. Jacquot J., Spilmont C., de Bentzmann S., Dupuit F., Puchelle E.. Structure and secretory functions of the respiratory epithelium. Arch. Int. Physiol. Biochim. Biophys. 1992;100:A41–A46.
    doi: 10.3109/13813459209000712pubmed: 1382688google scholar: lookup
  37. Van Cleemput J., Poelaert K.C.K., Laval K., Maes R., Hussey G.S., Van den Broeck W., Nauwynck H.J.. Access to a main alphaherpesvirus receptor, located basolaterally in the respiratory epithelium, is masked by intercellular junctions. Sci. Rep. 2017;7:16656.
    doi: 10.1038/s41598-017-16804-5pmc: PMC5709510pubmed: 29192251google scholar: lookup
  38. Van Crombrugge E., Vanbeylen E., Van Cleemput J., Van den Broeck W., Laval K., Nauwynck H.. Bacterial Toxins from Staphylococcus aureus and Bordetella bronchiseptica Predispose the Horse’s Respiratory Tract to Equine Herpesvirus Type 1 Infection. Viruses 2022;14:149.
    doi: 10.3390/v14010149pmc: PMC8778808pubmed: 35062352google scholar: lookup
  39. Van Cleemput J., Poelaert K.C.K., Laval K., Van den Broeck W., Nauwynck H.J.. Deoxynivalenol, but not fumonisin B1, aflatoxin B1 or diesel exhaust particles disrupt integrity of the horse’s respiratory epithelium and predispose it for equine herpesvirus type 1 infection. Vet. Microbiol. 2019;234:17–24.
    doi: 10.1016/j.vetmic.2019.05.009pubmed: 31213268google scholar: lookup
  40. Van Cleemput J., Poelaert K.C.K., Laval K., Impens F., Van den Broeck W., Gevaert K., Nauwynck H.J.. Pollens destroy respiratory epithelial cell anchors and drive alphaherpesvirus infection. Sci. Rep. 2019;9:4787.
    doi: 10.1038/s41598-019-41305-ypmc: PMC6423322pubmed: 30886217google scholar: lookup
  41. Van Waeyenberghe L., Baré J., Pasmans F., Claeys M., Bert W., Haesebrouck F., Houf K., Martel A.. Interaction of Aspergillus fumigatus conidia with Acanthamoeba castellanii parallels macrophage–fungus interactions. Environ. Microbiol. Rep. 2013;5:819–824.
    doi: 10.1111/1758-2229.12082pubmed: 24249290google scholar: lookup
  42. Perez-Riverol Y., Bai J., Bandla C., García-Seisdedos D., Hewapathirana S., Kamatchinathan S., Kundu D.J., Prakash A., Frericks-Zipper A., Eisenacher M.. The PRIDE database resources in 2022: A hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 2021;50:D543–D552.
    doi: 10.1093/nar/gkab1038pmc: PMC8728295pubmed: 34723319google scholar: lookup
  43. Vandekerckhove A., Glorieux S., Van den Broeck W., Gryspeerdt A., van der Meulen K.M., Nauwynck H.J.. In vitro culture of equine respiratory mucosa explants. Vet. J. 2009;181:280–287.
    doi: 10.1016/j.tvjl.2008.03.027pubmed: 18539059google scholar: lookup
  44. Glorieux S., Van den Broeck W., van der Meulen K.M., Van Reeth K., Favoreel H.W., Nauwynck H.J.. In vitro culture of porcine respiratory nasal mucosa explants for studying the interaction of porcine viruses with the respiratory tract. J. Virol. Methods. 2007;142:105–112.
  45. Vairo S., Van den Broeck W., Favoreel H., Scagliarini A., Nauwynck H.. Development and use of a polarized equine upper respiratory tract mucosal explant system to study the early phase of pathogenesis of a European strain of equine arteritis virus. Vet. Res. 2013;44:22.
    doi: 10.1186/1297-9716-44-22pmc: PMC3668984pubmed: 23537375google scholar: lookup
  46. van Der Meulen K.M., Nauwynck H.J., Bí¶®rt W., Pensaert M.B.. Replication of equine herpesvirus type 1 in freshly isolated equine peripheral blood mononuclear cells and changes in susceptibility following mitogen stimulation. Pt 1. J. Gen. Virol. 2000;81:21–25.
    doi: 10.1099/0022-1317-81-1-21pubmed: 10640538google scholar: lookup
  47. van der Meulen K.M., Nauwynck H.J., Pensaert M.B.. Absence of viral antigens on the surface of equine herpesvirus-1-infected peripheral blood mononuclear cells: A strategy to avoid complement-mediated lysis. Pt 1. J. Gen. Virol. 2003;84 Pt 1:93–97.
    doi: 10.1099/vir.0.18864-0pubmed: 12533704google scholar: lookup
  48. Cerqueira G.C., Arnaud M.B., Inglis D.O., Skrzypek M.S., Binkley G., Simison M., Miyasato S.R., Binkley J., Orvis J., Shah P.. TheAspergillusGenome Database: Multispecies curation and incorporation of RNA-Seq data to improve structural gene annotations. Nucleic Acids Res. 2014;42:D705–D710.
    doi: 10.1093/nar/gkt1029pmc: PMC3965050pubmed: 24194595google scholar: lookup
  49. Mostafa E., Szabo E., Gates R.S., Buescher W.. Identification of airborne particles and fungus spores concentrations within horses stables. Atmos. Pollut. Res. 2021;12:93–103.
    doi: 10.1016/j.apr.2020.10.012google scholar: lookup
  50. Webster A.J.F., Clarke A.F., Madelin T.M., Wathes C.M.. Air hygiene in stables 1: Effects of stable design, ventilation and management on the concentration of respirable dust. Equine Vet. J. 1987;19:448–453.
  51. Cowley A.C., Thornton D.J., Denning D.W., Horsley A.. Aspergillosis and the role of mucins in cystic fibrosis. Pediatr. Pulmonol. 2017;52:548–555.
    doi: 10.1002/ppul.23618pmc: PMC5396363pubmed: 27870227google scholar: lookup
  52. Amitani R., Kawanami R.. Interaction of Aspergillus with human respiratory mucosa: A study with organ culture model. Med. Mycol. 2009;47:S127–S131.
    doi: 10.1080/13693780802558959pubmed: 19253140google scholar: lookup
  53. Amitani R., Murayama T., Nawada R., Lee W., Niimi A., Suzuki K., Tanaka E., Kuze F.. Aspergillus culture filtrates and sputum sols from patients with pulmonary aspergillosis cause damage to human respiratory ciliated epithelium in vitro. Eur. Respir. J. 1995;8:1681–1687.
    doi: 10.1183/09031936.95.08101681pubmed: 8586122google scholar: lookup
  54. Dunne K., Reece E., McClean S., Doyle S., Rogers T.R., Murphy P., Renwick J.. Aspergillus fumigatus Supernatants Disrupt Bronchial Epithelial Monolayers: Potential Role for Enhanced Invasion in Cystic Fibrosis. J. Fungi. 2023;9:490.
    doi: 10.3390/jof9040490pmc: PMC10141846pubmed: 37108944google scholar: lookup
  55. Botterel F., Cordonnier C., Barbier V., Wingerstmann L., Liance M., Coste A., Escudier E., Bretagne S.. Aspergillus fumigatus causes in vitro electrophysiological and morphological modifications in human nasal epithelial cells. Histol. Histopathol. 2002;17:1095–1101.
    doi: 10.14670/hh-17.1095pubmed: 12371137google scholar: lookup
  56. Reed C.E., Kita H.. The role of protease activation of inflammation in allergic respiratory diseases. J. Allergy Clin. Immunol. 2004;114:997–1008.
    doi: 10.1016/j.jaci.2004.07.060pubmed: 15536399google scholar: lookup
  57. Homma T., Kato A., Bhushan B., Norton J.E., Suh L.A., Carter R.G., Gupta D.S., Schleimer R.P.. Role of Aspergillus fumigatus in Triggering Protease-Activated Receptor-2 in Airway Epithelial Cells and Skewing the Cells toward a T-helper 2 Bias. Am. J. Respir. Cell Mol. Biol. 2016;54:60–70.
    doi: 10.1165/rcmb.2015-0062OCpmc: PMC4742929pubmed: 26072921google scholar: lookup
  58. Cocks T.M., Moffatt J.D.. Protease-activated receptor-2 (PAR2) in the airways. Pulm. Pharmacol. Ther. 2001;14:183–191.
    doi: 10.1006/pupt.2001.0285pubmed: 11448145google scholar: lookup
  59. Abad A., Victoria Fernández-Molina J., Bikandi J., Ramírez A., Margareto J., Sendino J., Luis Hernando F., Pontón J., Garaizar J., Rementeria A.. What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. Rev. Iberoam. Micol. 2010;27:155–182.
    doi: 10.1016/j.riam.2010.10.003pubmed: 20974273google scholar: lookup
  60. Monod M., Togni G., Rahalison L., Frenk E.. Isoation and characterisation of an extracellular alkaline protease of Aspergillus fumigatus. J. Med. Microbiol. 1991;35:23–28.
    doi: 10.1099/00222615-35-1-23pubmed: 2072376google scholar: lookup
  61. Druey K.M., McCullough M., Krishnan R.. Aspergillus fumigatus Protease Alkaline Protease 1 (Alp1): A New Therapeutic Target for Fungal Asthma. J. Fungi. 2020;6:88.
    doi: 10.3390/jof6020088pmc: PMC7345148pubmed: 32560087google scholar: lookup
  62. Behnsen J., Lessing F., Schindler S., Wartenberg D., Jacobsen I.D., Thoen M., Zipfel P.F., Brakhage A.A.. Secreted Aspergillus fumigatus Protease Alp1 Degrades Human Complement Proteins C3, C4, and C5. Infect. Immun. 2010;78:3585–3594.
    doi: 10.1128/IAI.01353-09pmc: PMC2916278pubmed: 20498262google scholar: lookup
  63. Beauvais A., Monod M., Debeaupuis J.-P., Diaquin M., Kobayashi H., Latgé J.-P.. Biochemical and Antigenic Characterization of a New Dipeptidyl-Peptidase Isolated from Aspergillus fumigatus. J. Biol. Chem. 1997;272:6238–6244.
    doi: 10.1074/jbc.272.10.6238pubmed: 9045640google scholar: lookup
  64. Monod M., Paris S., Sanglard D., Jaton-Ogay K., Bille J., Latgé J.P.. Isolation and characterization of a secreted metalloprotease of Aspergillus fumigatus. Infect. Immun. 1993;61:4099–4104.
  65. St Leger R.J., Screen S.E.. In vitro utilization of mucin, lung polymers, plant cell walls and insect cuticle by Aspergillus fumigatus, Metarhizium anisopliae and Haematonectria haematococca. Mycol. Res. 2000;104:463–471.
    doi: 10.1017/S0953756299001525google scholar: lookup
  66. Stillwell W.. Chapter 5—Membrane Polar Lipids. An Introduction to Biological Membranes 2nd ed. Elsevier; Amsterdam, The Netherlands: 2016. pp. 63–87.
  67. Wiesner D.L., Merkhofer R.M., Ober C., Kujoth G.C., Niu M., Keller N.P., Gern J.E., Brockman-Schneider R.A., Evans M.D., Jackson D.J.. Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation. Cell Host Microbe 2020;27:614–628.e6.
    doi: 10.1016/j.chom.2020.02.006pmc: PMC7305569pubmed: 32130954google scholar: lookup
  68. Frampton A.R. Jr., Goins W.F., Cohen J.B., von Einem J., Osterrieder N., O’Callaghan D.J., Glorioso J.C.. Equine herpesvirus 1 utilizes a novel herpesvirus entry receptor. J. Virol. 2005;79:3169–3173.
  69. Hadigal S.R., Agelidis A.M., Karasneh G.A., Antoine T.E., Yakoub A.M., Ramani V.C., Djalilian A.R., Sanderson R.D., Shukla D.. Heparanase is a host enzyme required for herpes simplex virus-1 release from cells. Nat. Commun. 2015;6:6985.
    doi: 10.1038/ncomms7985pmc: PMC4413471pubmed: 25912399google scholar: lookup
  70. Namvar S., Labram B., Rowley J., Herrick S.. Aspergillus fumigatus—Host Interactions Mediating Airway Wall Remodelling in Asthma. J. Fungi. 2022;8:159.
    doi: 10.3390/jof8020159pmc: PMC8879933pubmed: 35205913google scholar: lookup
  71. Houtmeyers E., Gosselink R., Gayan-Ramirez G., Decramer M.. Regulation of mucociliary clearance in health and disease. Eur. Respir. J. 1999;13:1177–1188.
  72. Stevens D.A., Moss R.B., Kurup V.P., Knutsen A.P., Greenberger P., Judson M.A., Denning D.W., Crameri R., Brody A.S., Light M.. Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis—State of the Art: Cystic Fibrosis Foundation Consensus Conference. Clin. Infect. Dis. 2003;37:S225–S264.
    doi: 10.1086/376525pubmed: 12975753google scholar: lookup
  73. Denning D.W., Pashley C., Hartl D., Wardlaw A., Godet C., Del Giacco S., Delhaes L., Sergejeva S.. Fungal allergy in asthma–state of the art and research needs. Clin. Transl. Allergy 2014;4:14.
    doi: 10.1186/2045-7022-4-14pmc: PMC4005466pubmed: 24735832google scholar: lookup
  74. Jones Jane T., Liu K.-W., Wang X., Kowalski Caitlin H., Ross Brandon S., Mills Kathleen A.M., Kerkaert Joshua D., Hohl Tobias M., Lofgren Lotus A., Stajich Jason E.. Aspergillus fumigatus Strain-Specific Conidia Lung Persistence Causes an Allergic Broncho-Pulmonary Aspergillosis-Like Disease Phenotype. mSphere 2021;6:e01250-20.
    doi: 10.1128/mSphere.01250-20pmc: PMC8544898pubmed: 33597172google scholar: lookup
  75. Hotchkiss J.W., Reid S.W., Christley R.M.. A survey of horse owners in Great Britain regarding horses in their care. Part 2: Risk factors for recurrent airway obstruction. Equine Vet. J. 2007;39:301–308.
    doi: 10.2746/042516407X180129pubmed: 17722720google scholar: lookup
  76. Choi S., Sohn K.-H., Jung J.-W., Kang M.-G., Yang M.-S., Kim S., Choi J.-H., Cho S.-H., Kang H.-R., Yi H.. Lung virome: New potential biomarkers for asthma severity and exacerbation. J. Allergy Clin. Immunol. 2021;148:1007–1015.e9.
    doi: 10.1016/j.jaci.2021.03.017pubmed: 33757721google scholar: lookup