Wang, F. et al. Transcription in fungal conidia before dormancy produces phenotypically variable conidia that maximize survival in different environments. Nat. Microbiol. 6, 1066–1081 (2021).
Blatzer, M. & Latge, J. P. Fungal spores are future-proofed. Nat. Microbiol. 6, 979–980 (2021). This study shows that dormant fungal spores exhibit diversity and anticipate future conditions by activating transcriptional processes influenced by their developmental environment.
Taha, M. P., Pollard, S. J., Sarkar, U. & Longhurst, P. Estimating fugitive bioaerosol releases from static compost windrows: feasibility of a portable wind tunnel approach. Waste Manag. 25, 445–450 (2005).
O’Gorman, C. M., Fuller, H. & Dyer, P. S. Discovery of a sexual cycle in the opportunistic fungal pathogen Aspergillus fumigatus. Nature 457, 471–474 (2009).
Auxier, B. et al. The human fungal pathogen Aspergillus fumigatus can produce the highest known number of meiotic crossovers. PLoS Biol. 21, e3002278 (2023).
Fang, W. & Latge, J. P. Microbe profile: Aspergillus fumigatus: a saprotrophic and opportunistic fungal pathogen. Microbiology 164, 1009–1011 (2018).
Ries, L. N. A., Beattie, S., Cramer, R. A. & Goldman, G. H. Overview of carbon and nitrogen catabolite metabolism in the virulence of human pathogenic fungi. Mol. Microbiol. 107, 277–297 (2018).
Wiesner, D. L. et al. Club cell TRPV4 serves as a damage sensor driving lung allergic inflammation. Cell Host Microbe 27, 614–628.e616 (2020).
Griffiths, J. S. et al. Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases. FASEB J. 32, 3385–3397 (2018).
Beattie, S. R. et al. Filamentous fungal carbon catabolite repression supports metabolic plasticity and stress responses essential for disease progression. PLoS Pathog. 13, e1006340 (2017).
Ries, L. N. A. et al. Aspergillus fumigatus acetate utilization impacts virulence traits and pathogenicity. mBio 12, e0168221 (2021).
Krappmann, S. et al. The Aspergillus fumigatus transcriptional activator CpcA contributes significantly to the virulence of this fungal pathogen. Mol. Microbiol. 52, 785–799 (2004).
Amich, J. & Bignell, E. Amino acid biosynthetic routes as drug targets for pulmonary fungal pathogens: what is known and why do we need to know more? Curr. Opin. Microbiol. 32, 151–158 (2016).
Zelante, T. et al. Aspergillus fumigatus tryptophan metabolic route differently affects host immunity. Cell Rep. 34, 108673 (2021).
Barber, A. E. et al. Aspergillus fumigatus pan-genome analysis identifies genetic variants associated with human infection. Nat. Microbiol. 6, 1526–1536 (2021).
Mirhakkak, M. H. et al. Genome-scale metabolic modeling of Aspergillus fumigatus strains reveals growth dependencies on the lung microbiome. Nat. Commun. 14, 4369 (2023).
Misslinger, M., Hortschansky, P., Brakhage, A. A. & Haas, H. Fungal iron homeostasis with a focus on Aspergillus fumigatus. Biochim. Biophys. Acta Mol. Cell Res. 1868, 118885 (2021).
Schrettl, M. et al. SreA-mediated iron regulation in Aspergillus fumigatus. Mol. Microbiol. 70, 27–43 (2008).
Schrettl, M. et al. HapX-mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus. PLoS Pathog. 6, e1001124 (2010).
Gsaller, F. et al. The Janus transcription factor HapX controls fungal adaptation to both iron starvation and iron excess. EMBO J. 33, 2261–2276 (2014).
Yap, A., Volz, R., Paul, S., Moye-Rowley, W. S. & Haas, H. Regulation of high-affinity iron acquisition, including acquisition mediated by the iron permease FtrA, is coordinated by AtrR, SrbA, and SreA in Aspergillus fumigatus. mBio 14, e0075723 (2023).
Amich, J. et al. The ZrfC alkaline zinc transporter is required for Aspergillus fumigatus virulence and its growth in the presence of the Zn/Mn-chelating protein calprotectin. Cell. Microbiol. 16, 548–564 (2014).
Moreno, M. A. et al. The regulation of zinc homeostasis by the ZafA transcriptional activator is essential for Aspergillus fumigatus virulence. Mol. Microbiol. 64, 1182–1197 (2007).
Vicentefranqueira, R. et al. The transcription factor ZafA regulates the homeostatic and adaptive response to zinc starvation in Aspergillus fumigatus. Genes https://doi.org/10.3390/genes9070318 (2018).
Wiemann, P. et al. Aspergillus fumigatus copper export machinery and reactive oxygen intermediate defense counter host copper-mediated oxidative antimicrobial offense. Cell Rep. 19, 1008–1021 (2017).
Lim, F. Y. et al. Fungal isocyanide synthases and xanthocillin biosynthesis in Aspergillus fumigatus. mBio https://doi.org/10.1128/mBio.00785-18 (2018).
Steinbach, W. J. et al. Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus. Eukaryot. Cell 5, 1091–1103 (2006).
Cramer, R. A. Jr. et al. Calcineurin target CrzA regulates conidial germination, hyphal growth, and pathogenesis of Aspergillus fumigatus. Eukaryot. Cell 7, 1085–1097 (2008).
de Castro, P. A. et al. Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. PLoS Genet. 15, e1008551 (2019).
Grahl, N. et al. In vivo hypoxia and a fungal alcohol dehydrogenase influence the pathogenesis of invasive pulmonary aspergillosis. PLoS Pathog. 7, e1002145 (2011).
Grahl, N., Dinamarco, T. M., Willger, S. D., Goldman, G. H. & Cramer, R. A. Aspergillus fumigatus mitochondrial electron transport chain mediates oxidative stress homeostasis, hypoxia responses and fungal pathogenesis. Mol. Microbiol. 84, 383–399 (2012).
Ben-Ami, R., Lewis, R. E., Leventakos, K. & Kontoyiannis, D. P. Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites. Blood 114, 5393–5399 (2009).
Gresnigt, M. S. et al. Reducing hypoxia and inflammation during invasive pulmonary aspergillosis by targeting the interleukin-1 receptor. Sci. Rep. 6, 26490 (2016).
Kowalski, C. H. et al. Heterogeneity among isolates reveals that fitness in low oxygen correlates with Aspergillus fumigatus virulence. mBio https://doi.org/10.1128/mBio.01515-16 (2016).
Willger, S. D. et al. A sterol-regulatory element binding protein is required for cell polarity, hypoxia adaptation, azole drug resistance, and virulence in Aspergillus fumigatus. PLoS Pathog. 4, e1000200 (2008).
Chung, D. et al. ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence. PLoS Pathog. 10, e1004487 (2014).
Le Mauff, F. & Sheppard, D. C. Understanding Aspergillus fumigatus galactosaminogalactan biosynthesis: a few questions remain. Cell Surf. 9, 100095 (2023).
Speth, C., Rambach, G., Lass-Florl, C., Howell, P. L. & Sheppard, D. C. Galactosaminogalactan (GAG) and its multiple roles in Aspergillus pathogenesis. Virulence 10, 976–983 (2019).
Gravelat, F. N. et al. Aspergillus galactosaminogalactan mediates adherence to host constituents and conceals hyphal β-glucan from the immune system. PLoS Pathog. 9, e1003575 (2013).
Lee, M. J. et al. Deacetylation of fungal exopolysaccharide mediates adhesion and biofilm formation. mBio 7, e00252–00216 (2016).
Bamford, N. C. et al. Ega3 from the fungal pathogen Aspergillus fumigatus is an endo-α-1,4-galactosaminidase that disrupts microbial biofilms. J. Biol. Chem. 294, 13833–13849 (2019).
Kerkaert, J. D. et al. An alanine aminotransferase is required for biofilm-specific resistance of Aspergillus fumigatus to echinocandin treatment. mBio 13, e0293321 (2022).
Morelli, K. A., Kerkaert, J. D. & Cramer, R. A. Aspergillus fumigatus biofilms: toward understanding how growth as a multicellular network increases antifungal resistance and disease progression. PLoS Pathog. 17, e1009794 (2021).
Kowalski, C. H., Morelli, K. A., Schultz, D., Nadell, C. D. & Cramer, R. A. Fungal biofilm architecture produces hypoxic microenvironments that drive antifungal resistance. Proc. Natl Acad. Sci. USA 117, 22473–22483 (2020).
Kowalski, C. H. et al. Fungal biofilm morphology impacts hypoxia fitness and disease progression. Nat. Microbiol. 4, 2430–2441 (2019).
Kowalski, C. H., Morelli, K. A., Stajich, J. E., Nadell, C. D. & Cramer, R. A. A heterogeneously expressed gene family modulates the biofilm architecture and hypoxic growth of Aspergillus fumigatus. mBio https://doi.org/10.1128/mBio.03579-20 (2021).
Westphalen, K. et al. Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity. Nature 506, 503–506 (2014).
Neupane, A. S. et al. Patrolling alveolar macrophages conceal bacteria from the immune system to maintain homeostasis. Cell 183, 110–125.e111 (2020).
Hatinguais, R., Willment, J. A. & Brown, G. D. PAMPs of the fungal cell wall and mammalian PRRs. Curr. Top. Microbiol. Immunol. 425, 187–223 (2020).
Plato, A., Hardison, S. E. & Brown, G. D. Pattern recognition receptors in antifungal immunity. Semin. Immunopathol. 37, 97–106 (2015).
Heung, L. J., Wiesner, D. L., Wang, K., Rivera, A. & Hohl, T. M. Immunity to fungi in the lung. Semin. Immunol. 66, 101728 (2023).
Becker, K. L., Ifrim, D. C., Quintin, J., Netea, M. G. & van de Veerdonk, F. L. Antifungal innate immunity: recognition and inflammatory networks. Semin. Immunopathol. 37, 107–116 (2015).
Jhingran, A. et al. Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection. PLoS Pathog. 11, e1004589 (2015).
Caffrey, A. K. et al. IL-1α signaling is critical for leukocyte recruitment after pulmonary Aspergillus fumigatus challenge. PLoS Pathog. 11, e1004625 (2015).
Rieber, N. et al. Extrapulmonary Aspergillus infection in patients with CARD9 deficiency. JCI Insight 1, e89890 (2016).
Mills, K. A. M. et al. GM-CSF-mediated epithelial-immune cell crosstalk orchestrates pulmonary immunity to Aspergillus fumigatus. Sci. Immunol. 10, eadr0547 (2025).
Caffrey-Carr, A. K. et al. Host-derived leukotriene B4 is critical for resistance against invasive pulmonary aspergillosis. Front. Immunol. 8, 1984 (2017).
Shende, R. et al. Protective role of host complement system in Aspergillus fumigatus infection. Front. Immunol. 13, 978152 (2022).
Garlanda, C. et al. Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature 420, 182–186 (2002).
Cunha, C. et al. Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N. Engl. J. Med. 370, 421–432 (2014).
Sarden, N. et al. A B1a-natural IgG-neutrophil axis is impaired in viral- and steroid-associated aspergillosis. Sci. Transl. Med. 14, eabq6682 (2022). This study shows that viral pneumonia depletes circulating innate B1a cells and lowers anti-A. fumigatus IgG levels, resulting in reduced opsonization and neutrophil uptake and killing of conidia.
Espinosa, V. et al. Inflammatory monocytes orchestrate innate antifungal immunity in the lung. PLoS Pathog. 10, e1003940 (2014).
Hohl, T. M. et al. Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe 6, 470–481 (2009).
Guo, Y. et al. During Aspergillus infection, monocyte-derived DCs, neutrophils, and plasmacytoid DCs enhance innate immune defense through CXCR3-dependent crosstalk. Cell Host Microbe 28, 104–116.e104 (2020).
Espinosa, V. et al. Type III interferon is a critical regulator of innate antifungal immunity. Sci. Immunol. https://doi.org/10.1126/sciimmunol.aan5357 (2017). This study shows that type III interferons regulate NADPH oxidase activity in neutrophils and are critical regulators of anti-A. fumigatus immunity.
Guo, Y. et al. An IFN–STAT1–CYBB axis defines protective plasmacytoid DC to neutrophil crosstalk during Aspergillus fumigatus infection. Preprint at bioRxiv https://doi.org/10.1101/2024.10.24.620079 (2024).
Dutta, O., Espinosa, V., Wang, K., Avina, S. & Rivera, A. Dectin-1 promotes type I and III interferon expression to support optimal antifungal immunity in the lung. Front. Cell Infect. Microbiol. 10, 321 (2020).
Reedy, J. L. et al. The C-type lectin receptor dectin-2 is a receptor for Aspergillus fumigatus galactomannan. mBio 14, e0318422 (2023).
Dichtl, K. et al. Aspergillus fumigatus devoid of cell wall β-1,3-glucan is viable, massively sheds galactomannan and is killed by septum formation inhibitors. Mol. Microbiol. 95, 458–471 (2015).
Ballou, E. R. et al. Lactate signalling regulates fungal β-glucan masking and immune evasion. Nat. Microbiol. 2, 16238 (2016).
Gresnigt, M. S. et al. A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of interleukin-1 receptor antagonist. PLoS Pathog. 10, e1003936 (2014).
Heilig, L. et al. CD56-mediated activation of human natural killer cells is triggered by Aspergillus fumigatus galactosaminogalactan. PLoS Pathog. 20, e1012315 (2024).
Briard, B. et al. Galactosaminogalactan activates the inflammasome to provide host protection. Nature 588, 688–692 (2020). First demonstration that galactosaminogalactan of A. fumigatus is a pathogen-associated molecular pattern molecule that activates the NLRP3 inflammasome by binding to ribosomal proteins and inhibiting cellular translation machinery.
Delliere, S. et al. Interplay between host humoral pattern recognition molecules controls undue immune responses against Aspergillus fumigatus. Nat. Commun. 15, 6966 (2024).
Becker, K. L. et al. Aspergillus cell wall chitin induces anti- and proinflammatory cytokines in human PBMCs via the Fc-gamma receptor/Syk/PI3K pathway. mBio https://doi.org/10.1128/mBio.01823-15 (2016).
Aimanianda, V. et al. Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature 460, 1117–1121 (2009).
Pinzan, C. F. et al. Aspergillus fumigatus conidial surface-associated proteome reveals factors for fungal evasion and host immunity modulation. Nat. Microbiol. 9, 2710–2726 (2024).
Desai, J. V. & Lionakis, M. S. The role of neutrophils in host defense against invasive fungal infections. Curr. Clin. Microbiol. Rep. 5, 181–189 (2018).
Shlezinger, N. et al. Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death. Science 357, 1037–1041 (2017).
Desai, J. V. et al. BTK drives neutrophil activation for sterilizing antifungal immunity. J. Clin. Invest. https://doi.org/10.1172/JCI176142 (2024).
Lionakis, M. S. et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell 31, 833–843.e835 (2017).
Kyrmizi, I. et al. Calcium sequestration by fungal melanin inhibits calcium-calmodulin signalling to prevent LC3-associated phagocytosis. Nat. Microbiol. 3, 791–803 (2018).
Kyrmizi, I. et al. Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling. J. Immunol. 191, 1287–1299 (2013).
Akoumianaki, T. et al. Aspergillus cell wall melanin blocks LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe 19, 79–90 (2016).
Akoumianaki, T. et al. Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis. Cell Host Microbe 29, 1277–1293.e1276 (2021).
Ibrahim-Granet, O. et al. Phagocytosis and intracellular fate of Aspergillus fumigatus conidia in alveolar macrophages. Infect. Immun. 71, 891–903 (2003).
Hohl, T. M. et al. Aspergillus fumigatus triggers inflammatory responses by stage-specific β-glucan display. PLoS Pathog. 1, e30 (2005).
Mansour, M. K. et al. Dectin-1 activation controls maturation of β-1,3-glucan-containing phagosomes. J. Biol. Chem. 288, 16043–16054 (2013).
Carrion Sde, J. et al. The RodA hydrophobin on Aspergillus fumigatus spores masks dectin-1- and dectin-2-dependent responses and enhances fungal survival in vivo. J. Immunol. 191, 2581–2588 (2013).
Hooper, K. M. et al. V-ATPase is a universal regulator of LC3-associated phagocytosis and non-canonical autophagy. J. Cell Biol. https://doi.org/10.1083/jcb.202105112 (2022).
Fletcher, K. et al. The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes. EMBO J. https://doi.org/10.15252/embj.201797840 (2018).
Xu, Y. et al. A bacterial effector reveals the V-ATPase–ATG16L1 axis that initiates xenophagy. Cell 178, 552–566.e520 (2019).
Shah, A. et al. Calcineurin orchestrates lateral transfer of Aspergillus fumigatus during macrophage cell death. Am. J. Respir. Crit. Care Med. 194, 1127–1139 (2016).
Bruns, S. et al. Production of extracellular traps against Aspergillus fumigatus in vitro and in infected lung tissue is dependent on invading neutrophils and influenced by hydrophobin RodA. PLoS Pathog. 6, e1000873 (2010).
Hopke, A. et al. Neutrophil swarming delays the growth of clusters of pathogenic fungi. Nat. Commun. 11, 2031 (2020).
Song, Z. et al. NADPH oxidase controls pulmonary neutrophil infiltration in the response to fungal cell walls by limiting LTB4. Blood 135, 891–903 (2020).
Gazendam, R. P. et al. Human neutrophils use different mechanisms to kill Aspergillus fumigatus conidia and hyphae: evidence from phagocyte defects. J. Immunol. 196, 1272–1283 (2016).
Malamud, M. et al. Recognition and control of neutrophil extracellular trap formation by MICL. Nature 633, 442–450 (2024).
Clark, H. L. et al. Zinc and manganese chelation by neutrophil S100A8/A9 (calprotectin) limits extracellular Aspergillus fumigatus hyphal growth and corneal infection. J. Immunol. 196, 336–344 (2016).
Happacher, I. et al. The siderophore ferricrocin mediates iron acquisition in Aspergillus fumigatus. Microbiol. Spectr. 11, e0049623 (2023).
Leal, S. M. Jr. et al. Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum. PLoS Pathog. 9, e1003436 (2013).
Hsu, J. L. et al. Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aag2616 (2018).
Fallon, J. P., Reeves, E. P. & Kavanagh, K. Inhibition of neutrophil function following exposure to the Aspergillus fumigatus toxin fumagillin. J. Med. Microbiol. 59, 625–633 (2010).
Lionakis, M. S., Drummond, R. A. & Hohl, T. M. Immune responses to human fungal pathogens and therapeutic prospects. Nat. Rev. Immunol. 23, 433–452 (2023).
Desai, J. V. et al. C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection. Cell 186, 2802–2822.e2822 (2023).
McDermott, A. J. & Klein, B. S. Helper T-cell responses and pulmonary fungal infections. Immunology 155, 155–163 (2018).
Feys, S. et al. Lower respiratory tract single-cell RNA sequencing and neutrophil extracellular trap profiling of COVID-19-associated pulmonary aspergillosis: a single centre, retrospective, observational study. Lancet Microbe https://doi.org/10.1016/S2666-5247(23)00368-3 (2024).
Song, L., Zhao, Y., Wang, G., Zou, W. & Sai, L. Investigation of predictors for invasive pulmonary aspergillosis in patients with severe fever with thrombocytopenia syndrome. Sci. Rep. 13, 1538 (2023).
Dewi, I. M. W., van de Veerdonk, F. L. & Gresnigt, M. S. The multifaceted role of T-helper responses in host defense against Aspergillus fumigatus. J. Fungi https://doi.org/10.3390/jof3040055 (2017).
Cenci, E. et al. Cytokine- and T helper-dependent lung mucosal immunity in mice with invasive pulmonary aspergillosis. J. Infect. Dis. 178, 1750–1760 (1998).
Moss, R. B. Pathophysiology and immunology of allergic bronchopulmonary aspergillosis. Med. Mycol. 43, S203–S206 (2005).
Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Break, T. J. et al. Aberrant type 1 immunity drives susceptibility to mucosal fungal infections. Science https://doi.org/10.1126/science.aay5731 (2021).
Romani, L. et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451, 211–215 (2008).
Chamilos, G. & Carvalho, A. Aspergillus fumigatus DHN-Melanin. Curr. Top. Microbiol. Immunol. 425, 17–28 (2020).
Graf, K. T., Liu, H., Filler, S. G. & Bruno, V. M. Depletion of extracellular chemokines by Aspergillus melanin. mBio 14, e0019423 (2023).
Jahn, B., Langfelder, K., Schneider, U., Schindel, C. & Brakhage, A. A. PKSP-dependent reduction of phagolysosome fusion and intracellular kill of Aspergillus fumigatus conidia by human monocyte-derived macrophages. Cell Microbiol. 4, 793–803 (2002).
Jia, L. J. et al. Aspergillus fumigatus hijacks human p11 to redirect fungal-containing phagosomes to non-degradative pathway. Cell Host Microbe 31, 373–388 e310 (2023). The study identifies the conidial HscA protein of A. fumigatus as an anchoring factor for host p11, which enables the fungus to divert phagosomal trafficking through the non-degradative pathway and favour immune evasion.
Robinet, P. et al. A polysaccharide virulence factor of a human fungal pathogen induces neutrophil apoptosis via NK cells. J. Immunol. 192, 5332–5342 (2014).
Lee, M. J. et al. The fungal exopolysaccharide galactosaminogalactan mediates virulence by enhancing resistance to neutrophil extracellular traps. PLoS Pathog. 11, e1005187 (2015).
Dagenais, T. R. & Keller, N. P. Pathogenesis of Aspergillus fumigatus in invasive aspergillosis. Clin. Microbiol. Rev. 22, 447–465 (2009).
Raffa, N. & Keller, N. P. A call to arms: mustering secondary metabolites for success and survival of an opportunistic pathogen. PLoS Pathog. 15, e1007606 (2019).
Arias, M. et al. Preparations for invasion: modulation of host lung immunity during pulmonary aspergillosis by gliotoxin and other fungal secondary metabolites. Front. Immunol. 9, 2549 (2018).
Sugui, J. A. et al. Host immune status-specific production of gliotoxin and bis-methyl-gliotoxin during invasive aspergillosis in mice. Sci. Rep. 7, 10977 (2017).
Gunther, K. et al. Aspergillus fumigatus-derived gliotoxin impacts innate immune cell activation through modulating lipid mediator production in macrophages. Immunology https://doi.org/10.1111/imm.13857 (2024).
de Castro, P. A. et al. Regulation of gliotoxin biosynthesis and protection in Aspergillus species. PLoS Genet. 18, e1009965 (2022).
Alves de Castro, P. et al. Aspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection. Nat. Commun. 15, 33 (2024).
Guruceaga, X. et al. Aspergillus fumigatus fumagillin contributes to host cell damage. J. Fungi https://doi.org/10.3390/jof7110936 (2021).
Niu, M. & Keller, N. P. Co-opting oxylipin signals in microbial disease. Cell. Microbiol. 21, e13025 (2019).
Niu, M. et al. Fungal oxylipins direct programmed developmental switches in filamentous fungi. Nat. Commun. 11, 5158 (2020).
Calise, D. G., Park, S. C., Bok, J. W., Goldman, G. H. & Keller, N. P. An oxylipin signal confers protection against antifungal echinocandins in pathogenic aspergilli. Nat. Commun. 15, 3770 (2024).
Steffan, B. N. et al. Loss of the mammalian G-protein coupled receptor, G2A, modulates severity of invasive pulmonary aspergillosis. Front. Immunol. 14, 1173544 (2023).
Arastehfar, A. et al. Aspergillus fumigatus and aspergillosis: from basics to clinics. Stud. Mycol. 100, 100115 (2021).
Donnelly, J. P. et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin. Infect. Dis. 71, 1367–1376 (2020).
van de Veerdonk, F. L. et al. Influenza-associated aspergillosis in critically ill patients. Am. J. Respir. Crit. Care Med. 196, 524–527 (2017).
Schauwvlieghe, A. et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir. Med. https://doi.org/10.1016/S2213-2600(18)30274-1 (2018).
Koehler, P. et al. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis. https://doi.org/10.1016/S1473-3099(20)30847-1 (2020).
Dewi, I. M. et al. Invasive pulmonary aspergillosis associated with viral pneumonitis. Curr. Opin. Microbiol. 62, 21–27 (2021).
Feys, S. et al. Influenza-associated and COVID-19-associated pulmonary aspergillosis in critically ill patients. Lancet Respir. Med. 12, 728–742 (2024).
van de Veerdonk, F. L. et al. COVID-19-associated Aspergillus tracheobronchitis: the interplay between viral tropism, host defence, and fungal invasion. Lancet Respir. Med. 9, 795–802 (2021).
van de Veerdonk, F. L., Gresnigt, M. S., Verweij, P. E. & Netea, M. G. Personalized medicine in influenza: a bridge too far or the near future? Curr. Opin. Pulm. Med. 23, 237–240 (2017).
Konig, S. et al. The influenza A virus promotes fungal growth of Aspergillus fumigatus via direct interaction in vitro. Microbes Infect. 26, 105264 (2024).
Dewi, I. M. W. et al. Neuraminidase and SIGLEC15 modulate the host defense against pulmonary aspergillosis. Cell Rep. Med. 2, 100289 (2021).
Feys, S. et al. Lung epithelial and myeloid innate immunity in influenza-associated or COVID-19-associated pulmonary aspergillosis: an observational study. Lancet Respir. Med. 10, 1147–1159 (2022). This study reveals a three-level breach in antifungal immunity in influenza-associated and COVID-19-associated pulmonary aspergillosis, affecting epithelial barrier integrity, spores phagocytosis and killing, and destruction of A. fumigatus hyphae by neutrophils.
Wauters, E. et al. Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages. Cell Res. 31, 272–290 (2021).
Cambier, S. et al. Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza. JCI Insight https://doi.org/10.1172/jci.insight.155055 (2022).
Ghoneim, H. E., Thomas, P. G. & McCullers, J. A. Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections. J. Immunol. 191, 1250–1259 (2013).
Liu, K. W. et al. Postinfluenza environment reduces Aspergillus fumigatus conidium clearance and facilitates invasive aspergillosis in vivo. mBio 13, e0285422 (2022).
Seldeslachts, L. et al. Damping excessive viral-induced IFN-γ rescues the impaired anti-Aspergillus host immune response in influenza-associated pulmonary aspergillosis. eBioMedicine 108, 105347 (2024).
Vanderbeke, L. et al. A pathology-based case series of influenza- and COVID-19-associated pulmonary aspergillosis: the proof is in the tissue. Am. J. Respir. Crit. Care Med. 208, 301–311 (2023).
Wurster, S. et al. Development of a corticosteroid-immunosuppressed mouse model to study the pathogenesis and therapy of influenza-associated pulmonary aspergillosis. J. Infect. Dis. 227, 901–906 (2023).
Feys, S., Hoenigl, M., Gangneux, J. P., Verweij, P. E. & Wauters, J. Fungal fog in viral storms: necessity for rigor in aspergillosis diagnosis and research. Am. J. Respir. Crit. Care Med. 209, 631–633 (2024).
Zuniga-Moya, J. C. et al. Incidence and mortality of COVID-19-associated invasive fungal infections among critically ill intubated patients: a multicenter retrospective cohort analysis. Open. Forum Infect. Dis. 11, ofae108 (2024).
Vanderbeke, L. et al. Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial. Intensive Care Med. 47, 674–686 (2021).
Hatzl, S. et al. Antifungal prophylaxis for prevention of COVID-19-associated pulmonary aspergillosis in critically ill patients: an observational study. Crit. Care 25, 335 (2021).
Rombauts, A. et al. Antifungal prophylaxis with nebulized amphotericin-B in solid-organ transplant recipients with severe COVID-19: a retrospective observational study. Front. Cell Infect. Microbiol. 13, 1165236 (2023).
Herivaux, A. et al. Lung microbiota predict invasive pulmonary aspergillosis and its outcome in immunocompromised patients. Thorax 77, 283–291 (2022).
Gow, N. A. R. et al. The importance of antimicrobial resistance in medical mycology. Nat. Commun. 13, 5352 (2022).
Hokken, M. W. J. et al. The transcriptome response to azole compounds in Aspergillus fumigatus shows differential gene expression across pathways essential for azole resistance and cell survival. J. Fungi https://doi.org/10.3390/jof9080807 (2023).
Verweij, P. E. et al. In-host adaptation and acquired triazole resistance in Aspergillus fumigatus: a dilemma for clinical management. Lancet Infect. Dis. 16, e251–e260 (2016). This overview challenges current A. fumigatus management strategies and highlights the need to study genomic dynamics during infection to understand the key factors facilitating fungal adaptation.
Zhang, J., Verweij, P. E., Rijs, A., Debets, A. J. M. & Snelders, E. Flower bulb waste material is a natural niche for the sexual cycle in Aspergillus fumigatus. Front. Cell Infect. Microbiol. 11, 785157 (2021).
Zhang, J., Debets, A. J. M., Verweij, P. E. & Snelders, E. Azole-resistance development; how the Aspergillus fumigatus lifecycle defines the potential for adaptation. J. Fungi https://doi.org/10.3390/jof7080599 (2021).
Engel, T. et al. Parasexual recombination enables Aspergillus fumigatus to persist in cystic fibrosis. ERJ Open Res. https://doi.org/10.1183/23120541.00020-2020 (2020).
Howard, S. J. et al. Major variations in Aspergillus fumigatus arising within aspergillomas in chronic pulmonary aspergillosis. Mycoses 56, 434–441 (2013).
Fisher, M. C. et al. Tackling the emerging threat of antifungal resistance to human health. Nat. Rev. Microbiol. 20, 557–571 (2022).
Schoustra, S. E. et al. Environmental hotspots for azole resistance selection of Aspergillus fumigatus, the Netherlands. Emerg. Infect. Dis. 25, 1347–1353 (2019).
Rivelli Zea, S. M. & Toyotome, T. Azole-resistant Aspergillus fumigatus as an emerging worldwide pathogen. Microbiol. Immunol. 66, 135–144 (2022).
Snelders, E. et al. Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus. PLoS ONE 7, e31801 (2012).
Shelton, J. M. G. et al. Citizen science reveals landscape-scale exposures to multiazole-resistant Aspergillus fumigatus bioaerosols. Sci. Adv. 9, eadh8839 (2023).
Kolwijck, E. et al. Voriconazole-susceptible and voriconazole-resistant Aspergillus fumigatus coinfection. Am. J. Respir. Crit. Care Med. 193, 927–929 (2016).
Herbrecht, R. et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N. Engl. J. Med. 347, 408–415 (2002).
Maertens, J. A. et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 387, 760–769 (2016).
Maertens, J. A. et al. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial. Lancet 397, 499–509 (2021).
Resendiz-Sharpe, A. et al. Prevalence of voriconazole-resistant invasive aspergillosis and its impact on mortality in haematology patients. J. Antimicrob. Chemother. 74, 2759–2766 (2019).
Lestrade, P. P. et al. Voriconazole resistance and mortality in invasive aspergillosis: a multicenter retrospective cohort study. Clin. Infect. Dis. 68, 1463–1471 (2019).
Hamaoui, D. & Subtil, A. ATG16L1 functions in cell homeostasis beyond autophagy. FEBS J. 289, 1779–1800 (2022).
Cunha, C. et al. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood 116, 5394–5402 (2010).
Chai, L. Y. et al. The Y238X stop codon polymorphism in the human β-glucan receptor dectin-1 and susceptibility to invasive aspergillosis. J. Infect. Dis. 203, 736–743 (2011).
Fisher, C. E. et al. Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation. Blood 129, 2693–2701 (2017).
Feys, S. et al. A signature of differential gene expression in bronchoalveolar lavage fluid predicts mortality in influenza-associated pulmonary aspergillosis. Intensive Care Med. 49, 254–257 (2023).
Mezger, M. et al. Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. Blood 111, 534–536 (2008).
Lupianez, C. B. et al. Polymorphisms in host immunity-modulating genes and risk of invasive aspergillosis: results from the AspBIOmics Consortium. Infect. Immun. 84, 643–657 (2015).
Wojtowicz, A. et al. IL1B and DEFB1 polymorphisms increase susceptibility to invasive mold infection after solid-organ transplantation. J. Infect. Dis. 211, 1646–1657 (2015).
Chorny, A. et al. The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells. J. Exp. Med. 213, 2167–2185 (2016).
Fischer, M. et al. Polymorphisms of dectin-1 and TLR2 predispose to invasive fungal disease in patients with acute myeloid leukemia. PLoS ONE 11, e0150632 (2016).
Lionakis, M. S. Primary immunodeficiencies and invasive fungal infection: when to suspect and how to diagnose and manage. Curr. Opin. Infect. Dis. 32, 531–537 (2019).
Goncalves, S. M., Cunha, C. & Carvalho, A. Understanding the genetic basis of immune responses to fungal infection. Expert. Rev. Anti Infect. Ther. 20, 987–996 (2022).
Wojtowicz, A. et al. PTX3 polymorphisms and invasive mold infections after solid organ transplant. Clin. Infect. Dis. 61, 619–622 (2015).
Cunha, C. & Carvalho, A. Toward the identification of a genetic risk signature for pulmonary aspergillosis in chronic obstructive pulmonary disease. Clin. Infect. Dis. 66, 1153–1154 (2018).
He, Q. et al. Pentraxin 3 gene polymorphisms and pulmonary aspergillosis in chronic obstructive pulmonary disease patients. Clin. Infect. Dis. 66, 261–267 (2018).
Brunel, A. S. et al. Pentraxin-3 polymorphisms and invasive mold infections in acute leukemia patients receiving intensive chemotherapy. Haematologica 103, e527–e530 (2018).
Doni, A. et al. Serum amyloid P component is an essential element of resistance against Aspergillus fumigatus. Nat. Commun. 12, 3739 (2021).
Stappers, M. H. T. et al. Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus. Nature https://doi.org/10.1038/nature25974 (2018).
Gresnigt, M. S. et al. Genetic deficiency of NOD2 confers resistance to invasive aspergillosis. Nat. Commun. 9, 2636 (2018).
Schmidt, F. et al. Flotillin-dependent membrane microdomains are required for functional phagolysosomes against fungal infections. Cell Rep. 32, 108017 (2020).
Sueiro-Olivares, M. et al. Fungal and host protein persulfidation are functionally correlated and modulate both virulence and antifungal response. PLoS Biol. 19, e3001247 (2021).
Cunha, C. et al. IL-10 overexpression predisposes to invasive aspergillosis by suppressing antifungal immunity. J. Allergy Clin. Immunol. 140, 867–870 e869 (2017).
Goncalves, S. M. et al. Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to invasive pulmonary aspergillosis. mBio 12, e0036921 (2021).
Matzaraki, V. et al. Genetic determinants of fungi-induced ROS production are associated with the risk of invasive pulmonary aspergillosis. Redox Biol. 55, 102391 (2022).
