Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5219_Библиотеки_им_академика_М_И_Перельмана.pdf
466
P. Sen et al.
fungal cells by the host’s immune cells. α-(1, 3)-glucans also serve as adhesives in
interactions between hyphae and germinating conidia and contribute to the virulence of various fungal pathogens (Beauvais etal. 2007; Fontaine etal. 2010). The
predicted α-(1,3)-glucan synthase (AGS) protein, encoded by three ags genes (ags1,
ags2, and ags3) in A. fumigatus, has a molecular mass of approximately 270kDa
(Maubon etal. 2006; Beauvais etal. 2007). While the ags1 gene is responsible for
α-(1,3)-glucan biosynthesis, strains with deletions of either ags1 or ags2 do not
exhibit defects in its virulence (Beauvais etal. 2005). Studies reported a 50% reduction in the cell wall α-(1,3)-glucan content of the mycelium in the Δags1 mutant,
along with altered cell polarity and conidiation (Beauvais etal. 2005).
On the other hand, β-(1,3)-glucan is also another important polysaccharide in the
cell wall, and is produced through the action of the β-(1,3)-glucan synthase enzyme.
In A. fumigatus, this enzyme is encoded by the gene fks1 and functions as a transmembrane enzyme with 16 trans-membrane helices, boasting a high molecular
mass exceeding 200kDa. The glucan synthase complex, formed in close proximity
with the Rho-GTPase, plays a pivotal role in maintaining the cell wall integrity of
A. fumigatus. This enzyme utilizes UDP-glucose to synthesize β-(1,3)-glucan. The
outer layer of mannan acts as a shield, safeguarding the highly immunogenic
β-(1,3)-glucan from recognition by the dectin-1 receptor, thereby preventing the
activation of immune cell effector mechanisms. GAG further suppresses the host’s
inammatory response by masking the β-glucan present in the cell wall.
Both the glucan synthase complex and chitin synthase proteins are considered
essential virulence factors for A. fumigatus growth within an infected host cell (Ries
etal. 2019). Mutations in the β-(1,3)-glucan synthase gene fks1 signicantly impair
growth, leading to increased branching and cell lysis (Dichtl etal. 2015), a phenotype similar to cells treated with caspofungin, a β-(1,3)-glucan synthase inhibitor.
However, the absence of β-(1,3)-glucan prompts compensatory changes in other
components of the cell wall, such as an increase in chitin and GAG, along with a
signicant decrease in cell wall galactomannan due to extensive shedding (Dichtl
etal. 2015).
GAG, a polymer composed of galactopyranose linked to GlcNAc, serves as
another virulence factor found on the surface of the cell wall and in the extracellular
matrix (ECM) of A. fumigatus (Loussert et al. 2010). It plays a role in the host
inammatory response by masking the β-glucan present in the cell wall. Both
in vitro and in vivo studies have shown that A. fumigatus lacking GAG exposes
β-glucan, leading to increased dectin-1 binding with A. fumigatus and heightened
cytokine release by innate immune cells (Gravelat etal. 2013). It contributes to
adherence to various surfaces, a critical factor for the colonization and spread of
infection. It stimulates peripheral blood mononuclear cells, leading to the release of
the anti-inammatory interleukin IL-1 receptor antagonist and the suppression of
IL-7 and IL-22 production (Gresnigt etal. 2014).
19 Understanding Molecular Pathogenesis ofAspergillus fumigatus
467
19.3.5 Siderophores
In the host environment, iron serves as a crucial nutrient for pathogen growth, but it
is highly regulated and not readily available. The host proteins such as transferrin,
lactoferrin, and ferritin play crucial roles in sequestering iron. A. fumigatus has
developed strategies to acquire iron for its survival, primarily through the production of siderophores molecules that scavenge freely available iron from the host. In
serum, A. fumigatus utilizes siderophores, such as fusarinine C and triacetylfusarinine C (TAFC), to extract iron from host transferrin, suggesting the importance of
siderophore biosynthesis invivo (Hissen etal. 2004).
A. fumigatus employs four types of siderophores—fusarinine C, TAFC, ferricrocin, and its derivative hydroxyferricrocin—to maintain iron homeostasis. TAFC
serves as the primary siderophore for iron acquisition. The biosynthesis of these
siderophores involves a series of enzymatic steps encoded by specic genes (sidA,
sidC, sidD, sidF, and sidG) (Schrettl etal. 2007). The rst committed step in the
biosynthesis entails N5-hydroxylation of -ornithine catalyzed by the enzyme
-ornithine-N5-monooxygenase encoded by the sidA gene (Hissen et al. 2004;
Schrettl etal. 2007). Subsequently, anhydromevalonate is transferred to N5-hydroxy-ornithine, forming N5-anhydromevalonyl-N5-hydroxy--ornithine, involving the
sidF gene. This step links the biosynthesis pathways of isoprenoids and siderophores. The NRPS enzyme encoded by sidD then catalyzes the linkage of three
N5-cis-anhydromevalonyl-N5-hydroxy--ornithine residues to produce fusarinine
C, further modied by sidG to form TAFC.The biosynthetic pathways of TAFC and
ferricrocin diverge at this point.
Siderophores play a critical role in the virulence of A. fumigatus, as evidenced by
mutant studies targeting various biosynthetic steps, each revealing distinct outcomes. For instance, the inactivation of the sidA gene prevented the initiation of
mammalian infection in a mouse model for pulmonary aspergillosis (Hissen etal.
2004; Schrettl et al. 2007). Mutants lacking extracellular siderophores exhibited
reduced growth, conidiation, and oxidative stress resistance under iron limitation
conditions, consequently affecting virulence (Schrettl etal. 2007). Specically, the
ΔsidD mutant showed increased sensitivity to iron depletion and partial sensitivity
to oxidative stress, highlighting its signicant impact on virulence (Schrettl etal.
2007). Inactivation of the sidC gene in A. fumigatus resulted in a partial reduction in
virulence. Fusarinine C or its derivative constitutes a signicant portion (47–74%)
of the total iron content in A. fumigatus conidia, existing in a hydroxylated form for
iron storage (Schrettl etal. 2007). Alterations in iron availability triggered extensive
transcriptional remodeling, impacting approximately 13% of the protein-encoding
genes in A. fumigatus (Schrettl etal. 2008).
At the transcriptional level, iron regulation in A. fumigatus is orchestrated by two
key regulators: the TFs SreA and HapX (Schrettl et al. 2008; Schrettl etal. 2010).
Under conditions of iron abundance, the GATA-factor SreA inhibits high-afnity
iron uptake, including the siderophore system, to prevent iron toxicity. Conversely,
during iron starvation, the bZIP-TF HapX suppresses iron-consuming pathways,
such as respiration, heme biosynthesis, and iron–sulfur cluster-dependent processes
468
P. Sen et al.
to conserve iron. In addition, the deletion of an intracellular siderophore in A. fumigatus led to reduced expression of conidial catalase, albeit without affecting hyphal
catalase (Schrettl etal. 2007).
Siderophores represent a promising target for rational therapeutic intervention,
since they play a crucial role in the virulence of A. fumigatus and interestingly are
absent in mammalian hosts (Schrettl etal. 2007).
19.3.6 Biofilm Formation
Biolms are composed of structural microbial communities surrounded by an
ECM. Unlike their free-living counterparts, the formation of biolms exhibits
increased resistance to antimicrobial drugs and host immune responses, posing
challenges for eradication (Lee etal. 2016; Morelli etal. 2021). In both acute and
chronic infections, A. fumigatus forms biolms with structural and compositional
variations. Similar to bacterial and yeast biolms, those formed by A. fumigatus
protect antifungal treatments and host immune defenses. Despite treatment with
existing antifungal agents, recent clinical trials underscore the persistently high
mortality rate of around 30% in cases of invasive aspergillosis (Jenks and Hoenigl
2018). The presence of biolm-mediated antifungal resistance likely contributes to
treatment failures observed invivo, especially with A. fumigatus isolates that exhibit
susceptibility to antifungal agents in invitro testing (Harding etal. 2009).
A. fumigatus biolms exhibit a composition distinct from yeast biolms. In
Candida biolms, a dense network forms, incorporating various morphological
structures, such as yeast cells, hyphae, and pseudohyphae (Lohse et al. 2018).
Candida biolms exhibit a dense network comprising various morphological forms,
including yeast cells, hyphae, and pseudohyphae. In contrast, A. fumigatus biolms
are primarily characterized by interconnected, branched multinucleate vegetative
hyphae (Fig.19.5). Three-dimensional surface plot analysis has revealed specic
traits within A. fumigatus biolms, including organized hyphae arrangement, wellstructured hyphal channels, and vertical hyphal growth (Villena etal. 2010). Recent
research indicates that these distinct features in the morphologies of lamentous
fungal biolms could potentially contribute to fungal drug resistance and the virulence of A. fumigatus (Kowalski etal. 2020).
The matrix of A. fumigatus biolms consists primarily of extracellular DNA,
polyols, proteins, lipids, and exopolysaccharides, including α-glucans, galactomannan, and GAG (Tekaia and Latgé 2005; Cohen etal. 2011; Sugui etal. 2015). GAG
serves as a critical structural and functional component of the ECM produced both
in vitro and in vivo (Beauvais etal. 2007; Loussert et al. 2010). GAG-mediated
adherence plays a crucial role in A. fumigatus biolm formation; strains decient in
GAG production are unable to produce ECM and, as a result, cannot form adherent
biolms (Gravelat etal. 2013; Bamford etal. 2015; Briard etal. 2016).
In A. fumigatus, various proteins have been identied to play crucial roles in the
regulation of adhesion, ECM production, and biolm formation. Developmental
regulators StuA (ortholog of Efg1) and MedA positively inuence gene expression
19 Understanding Molecular Pathogenesis ofAspergillus fumigatus
Fig. 19.5 Schematic
representation of biolm
formation in A. fumigatus.
(Source: Chen etal.
(2020))
469
in the GAG biosynthesis cluster (Sheppard etal. 2005; Gravelat etal. 2010; Gravelat
et al. 2013). The Lim-binding protein PtaB, in collaboration with the sequencespecic TF SomA (ortholog of Flo8), forms a complex. This complex can directly
bind to conserved motifs in the promoter regions of medA, stuA, and GAG
biosynthesis- related genes agd3 and sph3 to activate transcription (Chen et al.
2020). GAG biosynthesis relies on a ve-gene cluster (uge3, gtb3, ega3, sph3, and
agd3) on chromosome 3. Loss of uge3 or gtb3 results in a complete absence of GAG
synthesis (Gravelat etal. 2013; Briard etal. 2016).
Hypoxia-responsive TFs SrbA and SrbB, essential for A. fumigatus growth in
low-oxygen conditions, also inuence biolm formation (Chung etal. 2014). The
loss of SrbA hinders the development of a mature biolm, while the loss of SrbB
results in a reduction in overall biolm biomass and abnormal biolm structure
(Kowalski etal. 2020). SrbA is additionally involved in hyphal polarity and microtubule dynamics, which may also be essential for biolm structure and maturation
(Willger etal. 2008).
19.4 Conclusion
This chapter provides valuable insights into multiple virulence factors in A. fumigatus that are crucial for it to cause diseases and survive in the host body. In addition
to targeting the fungal cell wall, siderophores, and DHN–melanin could serve as
important targets for drugs or be used to enhance the effectiveness of existing antifungal medications.
470
P. Sen et al.
References
Abad A, Fernández-Molina JV, Bikandi J, Ramírez A, Margareto J, Sendino J, Hernando FL,
Pontón J, Garaizar J, Rementeria A (2010) What makes Aspergillus fumigatus a success-
ful pathogen? Genes and molecules involved in invasive aspergillosis. Rev Iberoam Micol
27:155–182. https://doi.org/10.1016/j.riam.2010.10.003
Aimanianda V, Bayry J, Bozza S, Kniemeyer O, Perruccio K, Elluru SR, Clavaud C, Paris S,
Brakhage AA, Kaveri SV, Romani L, Latgé J-P (2009) Surface hydrophobin prevents immune
recognition of airborne fungal spores. Nature 460:1117–1121. https://doi.org/10.1038/
nature08264
Akoumianaki T, Kyrmizi I, Valsecchi I, Gresnigt MS, Samonis G, Drakos E, Boumpas D, Muszkieta
L, Prevost M-C, Kontoyiannis DP, Chavakis T, Netea MG, van de Veerdonk FL, Brakhage AA,
El-Benna J, Beauvais A, Latge J-P, Chamilos G (2016) Aspergillus cell wall melanin blocks
LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe 19:79–90. https://
doi.org/10.1016/j.chom.2015.12.002
Andrianopoulos A, Timberlake WE (1991) ATTS, a new and conserved DNA binding domain.
Plant Cell 3:747–748. https://doi.org/10.1105/tpc.3.8.747
Andrianopoulos A, Timberlake WE (1994) The Aspergillus nidulans abaA gene encodes a
transcriptional activator that acts as a genetic switch to control development. Mol Cell Biol
14:2503–2515. https://doi.org/10.1128/mcb.14.4.2503- 2515.1994
Alkhayyat F, Chang Kim S, Yu J-H (2015) Genetic control of asexual development in Aspergillus
fumigatus. Adv Appl Microbiol 90:93 107. https://doi.org/10.1016/bs.aambs.2014.09.004.
Bamford NC, Snarr BD, Gravelat FN, Little DJ, Lee MJ, Zacharias CA, Chabot JC, Geller AM,
Baptista SD, Baker P, Robinson H, Howell PL, Sheppard DC (2015) Sph3 is a glycoside hydro-
lase required for the biosynthesis of Galactosaminogalactan in Aspergillus fumigatus. J Biol
Chem 290:27438–27450. https://doi.org/10.1074/jbc.M115.679050
Bayry J, Aimanianda V, Guijarro JI, Sunde M, Latgé J-P (2012) Hydrophobins—unique fungal
proteins. PLoS Pathog 8:e1002700. https://doi.org/10.1371/journal.ppat.1002700
Bayry J, Beaussart A, Dufrêne YF, Sharma M, Bansal K, Kniemeyer O, Aimanianda V, Brakhage
AA, Kaveri SV, Kwon-Chung KJ, Latgé J-P, Beauvais A (2014) Surface structure characteriza-
tion of Aspergillus fumigatus conidia mutated in the melanin synthesis pathway and their human
cellular immune response. Infect Immun 82:3141–3153. https://doi.org/10.1128/IAI.01726- 14
Beauvais A, Maubon D, Park S, Morelle W, Tanguy M, Huerre M, Perlin DS, Latgé JP (2005)
Two α(1-3) glucan synthases with different functions in Aspergillus fumigatus. Appl Environ
Microbiol 71:1531–1538. https://doi.org/10.1128/AEM.71.3.1531- 1538.2005
Beauvais A, Schmidt C, Guadagnini S, Roux P, Perret E, Henry C, Paris S, Mallet A, Prévost MC,
Latgé JP (2007) An extracellular matrix glues together the aerial-grown hyphae of Aspergillus
fumigatus. Cell Microbiol 9:1588–1600. https://doi.org/10.1111/j.1462- 5822.2007.00895.x
Beauvais A, Bozza S, Kniemeyer O, Formosa C, Balloy V, Henry C, Roberson RW, Dague E,
Chignard M, Brakhage AA, Romani L, Latgé J-P (2013) Deletion of the α-(1,3)-glucan syn-
thase genes induces a restructuring of the conidial cell wall responsible for the avirulence of
Aspergillus fumigatus. PLoS Pathog 9:e1003716. https://doi.org/10.1371/journal.ppat.1003716
Borghetti P, De Angelis E, Saleri R, Cavalli V, Cacchioli A, Corradi A, Mocchegiani E, Martelli P
(2006) Peripheral T lymphocyte changes in neonatal piglets: relationship with growth hormone
(GH), prolactin (PRL) and cortisol changes. Vet Immunol Immunopathol 110:17–25. https://
doi.org/10.1016/j.vetimm.2005.09.001
Brakhage AA, Liebmann B (2005) Aspergillus fumigatus conidial pigment and cAMP sig-
nal transduction: signicance for virulence. Med Mycol 43(Suppl 1):S75–S82. https://doi.
org/10.1080/13693780400028967
Briard B, Muszkieta L, Latgé J-P, Fontaine T (2016) Galactosaminogalactan of Aspergillus fumig-
atus, a bioactive fungal polymer. Mycologia 108:572–580. https://doi.org/10.3852/15- 312
Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG, White TC (2012) Hidden killers: human
fungal infections. Sci Transl Med 4:165rv13. https://doi.org/10.1126/scitranslmed.3004404
19 Understanding Molecular Pathogenesis ofAspergillus fumigatus
Cerqueira GC, Arnaud MB, Inglis DO, Skrzypek MS, Binkley G, Simison M, Miyasato SR,
Binkley J, Orvis J, Shah P, Wymore F, Sherlock G, Wortman JR (2014) The Aspergillus genome
database: multispecies curation and incorporation of RNA-Seq data to improve structural gene
annotations. Nucleic Acids Res 42:D705–D710. https://doi.org/10.1093/nar/gkt1029
Chen Y, Le Mauff F, Wang Y, Lu R, Sheppard DC, Lu L, Zhang S (2020) The transcription fac-
tor SomA synchronously regulates biolm formation and cell wall homeostasis in Aspergillus
fumigatus. MBio 11:e02329–e02320. https://doi.org/10.1128/mBio.02329- 20
Chung D, Barker BM, Carey CC, Merriman B, Werner ER, Lechner BE, Dhingra S, Cheng C, Xu
W, Blosser SJ, Morohashi K, Mazurie A, Mitchell TK, Haas H, Mitchell AP, Cramer RA (2014)
ChIP-seq and invivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals
a new regulator of the fungal hypoxia response and virulence. PLoS Pathog 10:e1004487.
https://doi.org/10.1371/journal.ppat.1004487
Cohen J, Postma DS, Douma WR, Vonk JM, De Boer AH, ten Hacken NHT (2011) Particle size
matters: diagnostics and treatment of small airways involvement in asthma. Eur Respir J
37:532–540. https://doi.org/10.1183/09031936.00204109
Dagenais TRT, Keller NP (2009) Pathogenesis of Aspergillus fumigatus in invasive aspergillosis.
Clin Microbiol Rev 22:447–465. https://doi.org/10.1128/CMR.00055- 08
Dichtl K, Samantaray S, Aimanianda V, Zhu Z, Prévost M-C, Latgé J-P, Ebel F, Wagener J (2015)
Aspergillus fumigatus devoid of cell wall β-1,3-glucan is viable, massively sheds galactoman-
nan and is killed by septum formation inhibitors. Mol Microbiol 95:458–471. https://doi.
org/10.1111/mmi.12877
Dyer PS, O’Gorman CM (2012) Sexual development and cryptic sexuality in fungi:
insights from Aspergillus species. FEMS Microbiol Rev 36:165–192. https://doi.
org/10.1111/j.1574- 6976.2011.00308.x
Eisenman HC, Casadevall A (2012) Synthesis and assembly of fungal melanin. Appl Microbiol
Biotechnol 93:931–940. https://doi.org/10.1007/s00253- 011- 3777- 2
Fontaine T, Beauvais A, Loussert C, Thevenard B, ClausC F, Ohno N, Clavaud C, Prevost M-C, Latgé
J-P (2010) Cell wall α1-3glucans induce the aggregation of germinating conidia of Aspergillus
fumigatus. Fungal Genet Biol 47:707–712. https://doi.org/10.1016/j.fgb.2010.04.006
Garcia-Rubio R, de Oliveira HC, Rivera J, Trevijano-Contador N (2020) The fungal cell wall:
Candida, Cryptococcus, and Aspergillus species. Front Microbiol 10:2993
Gastebois A, Clavaud C, Aimanianda V, Latgé J-P (2009) Aspergillus fumigatus: cell wall poly-
saccharides, their biosynthesis and organization. Future Microbiol 4:583–595. https://doi.
org/10.2217/fmb.09.29
Gravelat FN, Ejzykowicz DE, Chiang LY, Chabot JC, Urb M, Macdonald KD (2010) Aspergillus
fumigatus MedA governs adherence host cell interactions and virulence. Cell Microbiol
1:473–488. https://doi.org/10.1111/j.1462- 5822.2009.01408.x
Gravelat FN, Beauvais A, Liu H, Lee MJ, Snarr BD, Chen D, Xu W, Kravtsov I, Hoareau CMQ,
Vanier G, Urb M, Campoli P, Al Abdallah Q, Lehoux M, Chabot JC, Ouimet M-C, Baptista
SD, Fritz JH, Nierman WC, Latgé JP, Mitchell AP, Filler SG, Fontaine T, Sheppard DC (2013)
Aspergillus galactosaminogalactan mediates adherence to host constituents and conceals
hyphal β-glucan from the immune system. PLoS Pathog 9:e1003575. https://doi.org/10.1371/
journal.ppat.1003575
Gresnigt MS, Bozza S, Becker KL, Joosten LAB, Abdollahi-Roodsaz S, van der Berg WB,
Dinarello CA, Netea MG, Fontaine T, De Luca A, Moretti S, Romani L, Latge J-P, van de
Veerdonk FL (2014) A polysaccharide virulence factor from Aspergillus fumigatus elicits
anti-inammatory effects through induction of Interleukin-1 receptor antagonist. PLoS Pathog
10:e1003936. https://doi.org/10.1371/journal.ppat.1003936
Gupta L, Hoda S, Vermani M, Vijayaraghavan P (2021) Understanding the fundamental role of
virulence determinants to combat Aspergillus fumigatus infections: exploring beyond cell wall.
Mycol Progr 20:365–380. https://doi.org/10.1007/s11557- 021- 01677- w
Harding MW, Marques LLR, Howard RJ, Olson ME (2009) Can lamentous fungi form biolms?
Trends Microbiol 17:475–480. https://doi.org/10.1016/j.tim.2009.08.007
471
472
Hernández-Chávez MJ, Pérez-García LA, Niño-Vega GA, Mora-Montes HM (2017) Fungal strat-
egies to evade the host immune recognition. J Fungi (Basel) 3:51. https://doi.org/10.3390/
jof3040051
Hissen AHT, Chow JMT, Pinto LJ, Moore MM (2004) Survival of Aspergillus fumigatus in serum
involves removal of iron from transferrin: the role of siderophores. Infect Immun 72:1402–1408.
https://doi.org/10.1128/IAI.72.3.1402- 1408.2004
Hoda S, Agarwal H, Ahluwalia SK, Vermani M, Vijayaraghavan P (2019) Antifungal resis-
tance analysis of environmental isolates of aspergillus in North India. J Pure Appl Microbiol
13:385–392. https://doi.org/10.22207/JPAM.13.1.42
Hoselton SA, Samarasinghe AE, Seydel JM, Schuh JM (2010) An inhalation model of airway
allergic response to inhalation of environmental Aspergillus fumigatus conidia in sensitized
BALB/c mice. Med Mycol 48:1056–1065. https://doi.org/10.3109/13693786.2010.485582
Jenks JD, Hoenigl M (2018) Treatment of Aspergillosis. J Fungi (Basel) 4:98. https://doi.
org/10.3390/jof4030098
Jiménez-Ortigosa C, Aimanianda V, Muszkieta L, Mouyna I, Alsteens D, Pire S, Beau R,
Krappmann S, Beauvais A, Dufrêne YF, Roncero C, Latgé J-P (2012) Chitin synthases with
a myosin motor-like domain control the resistance of Aspergillus fumigatus to echinocandins.
Antimicrob Agents Chemother 56:6121–6131. https://doi.org/10.1128/AAC.00752- 12
Kousha M, Tadi R, Soubani AO (2011) Pulmonary aspergillosis: a clinical review. Eur Respir Rev
20:156–174. https://doi.org/10.1183/09059180.00001011
Kowalski CH, Morelli KA, Schultz D, Nadell CD, Cramer RA (2020) Fungal biolm architecture
produces hypoxic microenvironments that drive antifungal resistance. Proc Natl Acad Sci U S
A 117:22473–22483. https://doi.org/10.1073/pnas.2003700117
Langfelder K, Streibel M, Jahn B, Haase G, Brakhage AA (2003) Biosynthesis of fungal melanins
and their importance for human pathogenic fungi. Fungal Genet Biol 38:143–158. https://doi.
org/10.1016/s1087- 1845(02)00526- 1
Latgé J-P, Chamilos G (2019) Aspergillus fumigatus and aspergillosis in 2019. Clin Microbiol Rev
33:e00140–e00118. https://doi.org/10.1128/CMR.00140- 18
Lee MJ, Geller AM, Bamford NC, Liu H, Gravelat FN, Snarr BD, Le Mauff F, Chabot J, Ralph B,
Ostapska H, Lehoux M, Cerone RP, Baptista SD, Vinogradov E, Stajich JE, Filler SG, Howell
PL, Sheppard DC (2016) Deacetylation of fungal exopolysaccharide mediates adhesion and
biolm formation. MBio 7:e00252–e00216. https://doi.org/10.1128/mBio.00252- 16
Lin C-J, Sasse C, Gerke J, Valerius O, Irmer H, Frauendorf H, Heinekamp T, Straßburger M, Tran
VT, Herzog B, Braus-Stromeyer SA, Braus GH (2015) Transcription Factor SomA Is Required
for Adhesion, Development and Virulence of the Human Pathogen Aspergillus fumigatus
PLOS Pathog 11:e1005205. https://doi.org/10.1371/journal.ppat.1005205.
Lohse MB, Gulati M, Johnson AD, Nobile CJ (2018) Development and regulation of single- and
multi-species Candida albicans biolms. Nat Rev Microbiol 16:19–31. https://doi.org/10.1038/
nrmicro.2017.107
Loussert C, Schmitt C, Prevost M-C, Balloy V, Fadel E, Philippe B, Kauffmann-Lacroix C, Latgé
JP, Beauvais A (2010) In vivo biolm composition of Aspergillus fumigatus. Cell Microbiol
12:405–410. https://doi.org/10.1111/j.1462- 5822.2009.01409.x
Manolli AO, Siqueira FS, dos Reis TF, Van Dijck P, Schrevens S, Hoefgen S, Föge M, Straßburger
M, de Assis LJ, Heinekamp T, Rocha MC, Janevska S, Brakhage AA, Malavazi I, Goldman
GH, Valiante V (2019) Mitogen-activated protein kinase cross-talk interaction modulates
the production of melanins in Aspergillus fumigatus. MBio 10:e00215–e00219. https://doi.
org/10.1128/mBio.00215- 19
Maubon D, Park S, Tanguy M, Huerre M, Schmitt C, Prévost MC, Perlin DS, Latgé JP, Beauvais
A (2006) AGS3, an α(1–3)glucan synthase gene family member of Aspergillus fumigatus,
modulates mycelium growth in the lung of experimentally infected mice. Fungal Genet Biol
43:366–375. https://doi.org/10.1016/j.fgb.2006.01.006
Morelli KA, Kerkaert JD, Cramer RA (2021) Aspergillus fumigatus biolms: toward understand-
ing how growth as a multicellular network increases antifungal resistance and disease progres-
sion. PLoS Pathog 17:e1009794. https://doi.org/10.1371/journal.ppat.1009794
P. Sen et al.
19 Understanding Molecular Pathogenesis ofAspergillus fumigatus
Morozov AA, Likhoshway YV (2016) Evolutionary history of the chitin synthases of eukaryotes.
Glycobiology 26:635–639. https://doi.org/10.1093/glycob/cww018
Muszkieta L, Aimanianda V, Mellado E, Gribaldo S, Alcàzar-Fuoli L, Szewczyk E, Prevost M-C,
Latgé J-P (2014a) Deciphering the role of the chitin synthase families 1 and 2in the invivo and
invitro growth of Aspergillus fumigatus by multiple gene targeting deletion. Cell Microbiol
16:1784–1805. https://doi.org/10.1111/cmi.12326
Muszkieta L, de Carrion SJ, Robinet P, Beau R, Elbim C, Pearlman E, Latgé J-P (2014b) The
protein phosphatase PhzA of a. fumigatus is involved in oxidative stress tolerance and fungal
virulence. Fungal Genet Biol 66:79–85. https://doi.org/10.1016/j.fgb.2014.02.009
Ojeda-López M, Chen W, Eagle CE, Gutiérrez G, Jia WL, Swilaiman SS, Huang Z, Park H-S, Yu
J-H, Cánovas D, Dyer PS (2018) Evolution of asexual and sexual reproduction in the aspergilli.
Stud Mycol 91:37–59. https://doi.org/10.1016/j.simyco.2018.10.002
Ortiz SC, Pennington K, Thomson DD, Bertuzzi M (2022) Novel insights into Aspergillus fumiga-
tus pathogenesis and host response from state-of-the-art imaging of host-pathogen interactions
during infection. J Fungi (Basel) 8:264. https://doi.org/10.3390/jof8030264
Osherov N, May GS (2001) The molecular mechanisms of conidial germination. FEMS Microbiol
Lett 199:153–160. https://doi.org/10.1111/j.1574- 6968.2001.tb10667.x
Paris S, Debeaupuis J-P, Crameri R, Carey M, Charlès F, Prévost MC, Schmitt C, Philippe B,
Latgé JP (2003) Conidial hydrophobins of Aspergillus fumigatus. Appl Environ Microbiol
69:1581–1588. https://doi.org/10.1128/AEM.69.3.1581- 1588.2003
Park H-S, Yu J-H (2012) Genetic control of asexual sporulation in lamentous fungi. Curr Opin
Microbiol 15:669–677. https://doi.org/10.1016/j.mib.2012.09.006
Park B-C, Park Y-H, Park H-M (2003) Activation of chsC transcription by AbaA during asex-
ual development of Aspergillus nidulans. FEMS Microbiol Lett 220:241–246. https://doi.
org/10.1016/S0378- 1097(03)00120- 4
Pihet M, Vandeputte P, Tronchin G, Renier G, Saulnier P, Georgeault S, Mallet R, Chabasse
D, Symoens F, Bouchara J-P (2009) Melanin is an essential component for the integrity of
the cell wall of Aspergillus fumigatus conidia. BMC Microbiol 9:177. https://doi.org/10.118
6/1471- 2180- 9- 177
Rambach G, Blum G, Latgé J-P, Fontaine T, Heinekamp T, Hagleitner M, Jeckström H, Weigel G,
Würtinger P, Pfaller K, Krappmann S, Löfer J, Lass-Flörl C, Speth C (2015) Identication of
Aspergillus fumigatus surface components that mediate interaction of conidia and hyphae with
human platelets. J Infect Dis 212:1140–1149. https://doi.org/10.1093/infdis/jiv191
Razzaghi-Abyaneh M, Chen Z-Y, Shams-Ghahfarokhi M, Rai M (2022) Editorial: research efforts,
challenges, and opportunities in mitigating aatoxins in food and agricultural crops and its
global health impacts. Front Microbiol 13:881858
Ren Z, Chhetri A, Guan Z, Suo Y, Yokoyama K, Lee S-Y (2022) Structural basis for inhibition
and regulation of a chitin synthase from Candida albicans. Nat Struct Mol Biol 29:653–664.
https://doi.org/10.1038/s41594- 022- 00791- x
Ries LNA, Steenwyk JL, de Castro PA, de Lima PBA, Almeida F, de Assis LJ, Manolli AO,
Takahashi-Nakaguchi A, Kusuya Y, Hagiwara D, Takahashi H, Wang X, Obar JJ, Rokas A,
Goldman GH (2019) Nutritional Heterogeneity Among Aspergillus fumigatus Strains Has
Consequences for Virulence in a Strain- and Host-Dependent Manner. Front Microbiol 10:854.
https://doi.org/10.3389/fmicb.2019.00854.
Rocha MC, Fabri JHTM, Franco de Godoy K, Alves de Castro P, Hori JI, Ferreira da Cunha A,
Arentshorst M, Ram AFJ, van den Hondel CAMJJ, Goldman GH, Malavazi I (2016) Aspergillus
fumigatus MADS-box transcription factor rlmA is required for regulation of the cell wall integ-
rity and virulence. G3 (Bethesda) 6:2983–3002. https://doi.org/10.1534/g3.116.031112
Rosowski EE, Raffa N, Knox BP, Golenberg N, Keller NP, Huttenlocher A (2018) Macrophages
inhibit Aspergillus fumigatus germination and neutrophil-mediated fungal killing. PLoS Pathog
14:e1007229. https://doi.org/10.1371/journal.ppat.1007229
Sabino R (2022) Aspergillus and health. Microorganisms 10:538. https://doi.org/10.3390/
microorganisms10030538
473
474
Sales-Campos H, Tonani L, Cardoso CRB, Kress MRVZ (2013) The immune interplay between the
host and the pathogen in Aspergillus fumigatus lung infection. Biomed Res Int 2013:693023.
https://doi.org/10.1155/2013/693023
Schrettl M, Bignell E, Kragl C, Sabiha Y, Loss O, Eisendle M, Wallner A Jr, Haynes K, Haas H
(2007) Distinct roles for intra- and extracellular Siderophores during Aspergillus fumigatus
infection. PLoS Pathog 3:e128. https://doi.org/10.1371/journal.ppat.0030128
Schrettl M, Kim HS, Eisendle M, Kragl C, Nierman WC, Heinekamp T, Werner ER, Jacobsen
I, Illmer P, Yi H, Brakhage AA, Haas H (2008) SreA-mediated iron regulation in Aspergillus
fumigatus. Mol Microbiol 70:27–43. https://doi.org/10.1111/j.1365- 2958.2008.06376.x
Schrettl M, Beckmann N, Varga J, Heinekamp T, Jacobsen ID, Jöchl C, Moussa TA, Wang S,
Gsaller F, Blatzer M, Werner ER, Niermann WC, Brakhage AA, Haas H (2010) HapX-
mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus. PLoS
Pathog 6:e1001124. https://doi.org/10.1371/journal.ppat.1001124
Sen P, Vijay M, Singh S, Hameed S, Vijayaraghavan P (2022) Understanding the environmen-
tal drivers of clinical azole resistance in Aspergillus species. Drug Target Insights 16:25–35.
https://doi.org/10.33393/dti.2022.2476
Sephton-Clark PCS, Voelz K (2018) Spore germination of pathogenic lamentous fungi. Adv Appl
Microbiol 102:117–157. https://doi.org/10.1016/bs.aambs.2017.10.002
Shepardson KM, Ngo LY, Aimanianda V, Latgé J-P, Barker BM, Blosser SJ, Iwakura Y, Hohl
TM, Cramer RA (2013) Hypoxia enhances innate immune activation to Aspergillus fumiga-
tus through cell wall modulation. Microbes Infect 15:259–269. https://doi.org/10.1016/j.
micinf.2012.11.010
Sheppard DC, Doedt T, Chiang LY, Kim HS, Chen D, Nierman WC, Filler SG (2005) The
Aspergillus fumigatus StuA protein governs the up-regulation of a discrete transcriptional
program during the acquisition of developmental competence. Mol Biol Cell 16:5866–5879.
https://doi.org/10.1091/mbc.e05- 07- 0617
Stewart JIP, Fava VM, Kerkaert JD, Subramanian AS, Gravelat FN, Lehoux M, Howell PL,
Cramer RA, Sheppard DC (2020) Reducing Aspergillus fumigatus virulence through targeted
dysregulation of the Conidiation pathway. MBio 11:e03202–e03219. https://doi.org/10.1128/
mBio.03202- 19
Sugui JA, Kwon-Chung KJ, Juvvadi PR, Latgé J-P, Steinbach WJ (2015) Aspergillus fumigatus
and related species. Cold Spring Harb Perspect Med 5:a019786. https://doi.org/10.1101/csh-
perspect.a019786
Tao L, Yu J-H (2011) AbaA and WetA govern distinct stages of Aspergillus fumigatus develop-
ment. Microbiology 157:313–326. https://doi.org/10.1099/mic.0.044271- 0
Tekaia F, Latgé J-P (2005) Aspergillus fumigatus: saprophyte or pathogen? Curr Opin Microbiol
8:385–392. https://doi.org/10.1016/j.mib.2005.06.017
Valiante V, Macheleidt J, Föge M, Brakhage AA (2015) The Aspergillus fumigatus cell wall integ-
rity signaling pathway: drug target, compensatory pathways, and virulence. Front Microbiol
6:325. https://doi.org/10.3389/fmicb.2015.00325
Valiante V, Baldin C, Hortschansky P, Jain R, Thywißen A, Straßburger M, Shelest E, Heinekamp
T, Brakhage AA (2016) The Aspergillus fumigatus conidial melanin production is regulated
by the bifunctional bHLH DevR and MADS-box RlmA transcription factors. Mol Microbiol
102:321–335. https://doi.org/10.1111/mmi.13462
Valsecchi I, Lai JI, Stephen-Victor E, Pillé A, Beaussart A, Lo V, Pham CLL, Aimanianda V, Kwan
AH, Duchateau M, Gianetto QG, Matondo M, Lehoux M, Sheppard DC, Dufrene YF, Bayry
J, Guijarro JI, Sunde M, Latgé J-P (2019) Assembly and disassembly of Aspergillus fumigatus
conidial rodlets. Cell Surf 5:100023. https://doi.org/10.1016/j.tcsw.2019.100023
Valsecchi I, Dupres V, Stephen-Victor E, Guijarro JI, Gibbons J, Beau R, Bayry J, Coppee JY,
Lafont F, Latgé JP, Beauvais A. (2017) Role of Hydrophobins in Aspergillus fumigatus. J Fungi
(Basel) 4:2. https://doi.org/10.3390/jof4010002.
van de Veerdonk FL, Gresnigt MS, Romani L, Netea MG, Latgé J-P (2017) Aspergillus fumiga-
tus morphology and dynamic host interactions. Nat Rev Microbiol 15:661–674. https://doi.
org/10.1038/nrmicro.2017.90
P. Sen et al.
19 Understanding Molecular Pathogenesis ofAspergillus fumigatus
Villena GK, Takashi F, Tsuyumu S, Gutiérrez-Correa M (2010) Structural analysis of biolms and
pellets of Aspergillus niger by confocal laser scanning microscopy and cryo scanning electron
microscopy. Bioresour Technol 101:1920–1926. https://doi.org/10.1016/j.biortech.2009.10.036
Warris A, Ballou ER (2019) Oxidative responses and fungal infection biology. Semin Cell Dev
Biol 89:34–46. https://doi.org/10.1016/j.semcdb.2018.03.004
Wiederhold NP, Lockhart SR, Najvar LK, Berkow EL, Jaramillo R, Olivo M, Garvey EP, Yates
CM, Schotzinger RJ, Catano G, Patterson TF (2019) The fungal Cyp51-specic inhibitor
VT-1598 demonstrates invitro and invivo activity against Candida auris. Antimicrob Agents
Chemother 63:e02233–e02218. https://doi.org/10.1128/AAC.02233- 18
Willger SD, Puttikamonkul S, Kim K-H, Burritt JB, Grahl N, Metzler LJ, Barbuch R, Bard M,
Lawrence CB, Cramer RA (2008) 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. https://doi.org/10.1371/journal.ppat.1000200
Yu J-H (2010) Regulation of development in aspergillus nidulans and Aspergillus fumigatus.
Mycobiology 38:229–237. https://doi.org/10.4489/MYCO.2010.38.4.229
475