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18 A Comprehensive and Intricate Dynamics of Aspergillus: Implications…
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Understanding Molecular Pathogenesis
ofAspergillus fumigatus
PoojaSen , LovelyGupta , AmanSingh ,
LokeshKumar , RajanKumarMishra ,
andPoojaVijayaraghavan
Abstract
Aspergillus fumigatus, a widespread fungal pathogen, poses a signicant threat
to individuals with chronic lung inammatory conditions and weakened immune
systems, often causing severe infections. The pathogenicity of A. fumigatus is
inuenced by various factors that contribute to its survival within the host.
Current treatment options for A. fumigatus infections are limited, primarily
focusing on inhibiting cell wall or cell membrane biosynthesis. However, the
emergence of resistant strains is progressively limiting the clinical effectiveness
of these drugs. There is an urgent need to explore additional virulence factors of
A. fumigatus and identify potential targets for new antifungal drugs. This chapter
emphasizes the importance of analyzing virulence factors related to cell surface
organization, including hydrophobins (associated with rodlet layer formation),
chitin, glucans, and galactosaminogalactan (involved in fungal biolm).
Furthermore, secondary metabolites such as melanin and siderophores (involved
in iron homeostasis) have been discussed. A comprehensive understanding of
these virulence factors holds the potential to uncover novel targets, facilitating
the discovery of new molecules or enhancing the effectiveness of existing anti-
fungal drugs.
19
Keywords
Aspergillus fumigatus · Pathogenicity · Cell wall · Virulence factors · Molecular
mechanism
P. Sen · L. Gupta · A. Singh · L. Kumar · R. K. Mishra · P. Vijayaraghavan (*)
Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India
e-mail: vrpooja@amity.edu
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2024
S. Hameed, P. Vijayaraghavan (eds.), Recent Advances in Human Fungal
Diseases, https://doi.org/10.1007/978-981-97-4909-6_19
457
458
P. Sen et al.
19.1 Introduction toAspergillus Species
Aspergillus species are lamentous fungi widely found in the environment. Most
Aspergillus spp. exists as saprophytes, commonly found in soil and decomposing
vegetation (Sen et al. 2022). Only a few well-known species are considered as
important opportunistic pathogens in humans (Dagenais and Keller 2009; Rosowski
et al. 2018). The Aspergillus genus encompasses a variety of species, forming a
diverse group that holds signicance in both environmental and public health contexts (Razzaghi-Abyaneh etal. 2022; Sabino 2022).
These fungi are cosmopolitan and are commonly found in various natural habitats, particularly in soil, serving as the primary reservoir. They contribute to food
spoilage, mycotoxin contamination, and various human and animal mycoses
(Razzaghi-Abyaneh etal. 2022). In addition, they serve as abundant sources of benecial metabolites, such as antibiotics, organic acids, enzymes, and additives. The
Aspergillus genus is currently recognized to include over 344 species, along with 17
sub-species. Ongoing discoveries of new species are facilitated by DNA-based phylogeny and morphological markers. Out of the numerous Aspergillus spp., only 20
have been identied as causing human infections, with Aspergillus fumigatus,
Aspergillus niger, and Aspergillus avus consistently accounting for over 95% of
fungal infection cases (Sabino 2022). Other species associated with human lesions
include Aspergillus terreus, Aspergillus glaucus, Aspergillus nidulans, Aspergillus
oryzae, and Aspergillus clavatus.
In humans, A. fumigatus stands out as the most common and life-threatening
airborne opportunistic fungal pathogen, particularly impactful among immunocompromised hosts (Wiederhold etal. 2019). A. fumigatus is identied by its small
(2–3μm), blue–green echinulate conidia, forming long chains from conidiophores
that extend from the vegetative mycelium (Dyer and O’Gorman 2012). The conidia
of A. fumigatus are enveloped by a polysaccharide-based cell wall, offering physical
protection and structural support (Sales-Campos etal. 2013). Comprising primarily
α-1,3-glucan, galactofuran, and mannan, the fungal cell wall is a dynamic structure
that adapts to the external environment (Valiante et al. 2015). When exposed to
stress, such as a hypoxic environment, A. fumigatus can adjust its transcriptome to
increase the expression of β-glucan to thicken its cell wall which provides an added
layer of protection (Shepardson etal. 2013).
Although it was long believed that A. fumigatus exclusively reproduced asexually, it is now accepted that this organism also has the capacity for sexual reproduction (Dyer and O’Gorman 2012). However, in the natural environment, the
predominant mode of reproduction remains largely asexual. A. fumigatus extensively produces small, hydrophobic conidia, enabling airborne dispersion over signicant distances (van de Veerdonk etal. 2017). Due to their widespread presence
and distinctive morphology, conidia are commonly inhaled by both humans and
animals (Latgé and Chamilos 2019). It is approximated that humans inhale between
1000 and 10 billion fungal spores daily (Hoselton etal. 2010; Ortiz etal. 2022).
These conidia exhibit remarkable resilience, enduring diverse environmental stressors, such as temperature, pH variations, and osmotic pressure (van de Veerdonk
19 Understanding Molecular Pathogenesis ofAspergillus fumigatus
459
etal. 2017). In a healthy host, when inhaled, resting conidia are effectively eliminated through innate immune defenses, including mucociliary clearance and phagocytosis, preventing them from causing disease (Dagenais and Keller 2009; Rosowski
etal. 2018). However, if this process is unsuccessful, conidia can undergo a range
of morphological changes, driven by periods of isotropic and later polarized growth,
to form hyphae that are capable of invading host tissues and causing disease
(Osherov and May 2001; Sephton-Clark and Voelz 2018). Despite germination
being heavily implicated in invasive fungal disease, the specic mechanisms behind
the transition from resting conidia to hyphae have not yet been fully elucidated.
19.2 Host–A. fumigatus Interactions
The susceptibility of the host to A. fumigatus infection depends on the effectiveness
of their innate and adaptive immune systems (Borghetti etal. 2006). In a healthy
state, individuals can inhale thousands of A. fumigatus conidia daily without experiencing infection (Abad etal. 2010; Hoda etal. 2019). The innate immune response
is promptly triggered upon inhalation of A. fumigatus conidia, with receptors on
immune cells such as neutrophils, macrophages, natural killer cells, and dendritic
cells readily recognizing A. fumigatus-associated molecular patterns (Bayry etal.
2014). Once activated, these immune responses obstruct the survival of A. fumiga-
tus, by initiating phagocytosis and preventing their invasion into the host body. Host
dectin-1 specically recognizes the β-glucan on the conidial cell wall of A. fumiga-
tus, triggering the activation of phospholipase D isoforms PLD-1 and PLD-2. This
signaling cascade facilitates the internalization of conidia and the formation of
endosomes. Within these endosomes, conidia undergo degradation, ultimately leading to their elimination from the host body (van de Veerdonk etal. 2017).
In contrast, individuals with cancer or autoimmune disorders often undergo chemotherapy and receive immunosuppressive drugs. These treatments compromise
the immune system by specically targeting rapidly dividing immune cells, including neutrophils, as well as the target cells. This can result in a weakened and
impaired immune system (van de Veerdonk etal. 2017). As a consequence of the
inactivation of the host’s airway defense system and the inability to generate effective responses, such as the release of chemokines and cytokines, A. fumigatus evades
mucociliary clearance and successfully invades host alveolar cells. Conidia adhere
to various molecules on the surface of epithelial cells, altering the signal transduction pathways within the host cells. This alteration ultimately leads to colonization
within the host’s tissue.
460
P. Sen et al.
19.3 Several Virulence Factors ofA. fumigatus
19.3.1 Hydrophobicity or Rodlet Layer
Adherence of fungal pathogens to the host cells is a pivotal step in the disease
pathogenesis (Lin etal. 2015). In the case of A. fumigatus conidia, they are characterized by an outer layer containing rod-like structures formed by amyloid bers
made of proteins from the hydrophobin family. This outer layer rmly attaches to
the conidial cell wall through a glycosylphosphatidylinositol-anchoring sequence
(Aimanianda etal. 2009). When these conidia adhere to the surface of lung epithelial cells, the rod-like layers help regulate external pressure and maintain proper
gaseous exchange (Bayry etal. 2012).
The hydrophobin protein coat serves a crucial function in masking the pathogenassociated molecular patterns (PAMPs) of A. fumigatus conidia, thereby preventing
immune recognition (Valsecchi et al. 2019). The initiation of the host immune
response occurs upon removal of this hydrophobin coat (Aimanianda etal. 2009).
The rodlet layers, composed of low molecular weight hydrophobin proteins
(approximately 20 kD) with eight conserved cysteine residues forming disulde
bridges, provide structural integrity (Paris etal. 2003).
The rodlet gene family responsible for encoding hydrophobin proteins, including
rodA, rodB, rodC, rodD, rodE, rodF, and rodG, play essential roles in surface architecture and immune evasion (Cerqueira etal. 2014). Among these, RodA is extensively characterized and is crucial for rodlet layer formation, conidial hydrophobicity,
physical resistance, and immunological inertness (Valsecchi et al. 2017). RodA
hydrophobin plays a signicant role in masking PAMPs from pattern recognition
receptors expressed by the host’s innate immune system (Fig.19.1). Point mutations
in the rodA gene conrm its signicance in rodlet formation and immune evasion
(Valsecchi etal. 2019). Under normal conditions, A. fumigatus conidia are round,
but deletion of the rodA gene or a combination of rodBCDEFGA genes results in
oval shapes. The absence of rodA alters the conidial surface, increases the drug
sensitivity of A. fumigatus, and induces the production of inammatory cytokines,
chemokines, and reactive oxygen intermediates (Aimanianda et al. 2009). The
RodB protein, such as RodA, is found on the surface of A. fumigatus conidia, while
does not contribute to the formation of rodlet layers (Paris etal. 2003). However, its
expression is upregulated and prominent in biolm conditions, suggesting potential
roles in A fumigatus virulence mechanisms (Valsecchi etal. 2019).
19.3.2 Conidiation
Aspergillus spp. are well-known for their abundant generation of asexual spores
known as conidia (Ojeda-López et al. 2018). Initially, conidia (asexual spores)
undergo germination, giving rise to lamentous hyphae that elongate as they grow.
As these hyphae mature, they develop the ability to respond to various stimuli, such
as nutrient scarcity, leading to the formation of multicellular structures called
19 Understanding Molecular Pathogenesis ofAspergillus fumigatus
461
Fig. 19.1 Schematic depiction of the sequential and distinct immune responses following the
inhalation of the ΔrodA mutant or resting conidia A. fumigatus conidia by host cells. (Source:
Gupta etal. (2021))
conidiophores (Stewart et al. 2020). These conidiophores produce single-celled
conidia, marking the beginning of the cycle once more. This stage is known as
conidiation, and hyphae capable of forming conidiophores are termed developmentally competent.
All aspergilli, including A. fumigatus, primarily spread and cause infections
through the production of conidia. A. fumigatus produces several small-sized
conidia (2–3μm) that easily disperse in the air, reaching the host’s respiratory tract
through inhalation. In healthy individuals, the innate immune defenses eliminate
inhaled A. fumigatus conidia (Tekaia and Latgé 2005; Cohen etal. 2011; Sugui etal.
2015). However, in individuals with weakened immune systems, these conidia can
germinate and develop into lamentous hyphae, invading lung tissues and leading
to necrotizing pneumonia associated with high mortality rates (Dagenais and Keller
2009; Abad etal. 2010; Kousha etal. 2011; Brown etal. 2012).
The regulatory mechanisms governing conidiation have been extensively studied
in the model of pathogenic fungi A. nidulans. The regulatory genes are classied
into central regulators, upstream activators, negative regulators, light-dependent
regulators, and velvet regulators. Within the central genetic regulatory cascade,
462
P. Sen et al.
BrlA→AbaA→WetA is integral in Aspergillus, governing both the conidiationspecic gene regulatory networks and the subsequent morphological pathway of
conidiation.
BrlA is a putative transcription factor (TF), having two C2H2–zinc nger motifs
at the C-terminus. It plays a key role by recognizing and interacting with consensus
BrlA-binding sites, i.e., BrlA response elements; 5′-(C/A)(G/A)AGGG(G/A)-3′),
thereby initiating early conidiation events such as vesicle formation and buddinglike cell growth (Stewart etal. 2020). Subsequently, the AbaA, also a TF containing
a TEA/ATTS DNA-binding motif and a potential leucine zipper (Andrianopoulos
and Timberlake 1991; Andrianopoulos and Timberlake 1994), is activated by BrlA
to regulate the formation of metulae and phialides through recognition of the AbaA
response elements (Fig.19.2). The WetA, activated by AbaA, plays a crucial role in
the late phase of conidiation, facilitating the completion of sporogenesis. The central regulatory cascade, BrlA→AbaA→WetA, acts in concert with other genes to
govern the expression of conidiation-specic genes and determine the sequence of
gene activation throughout the cellular and chemical development of spores (Yu
2010). The WetA protein is indispensable for governing the development of
Aspergillus conidia.
Loss-of-function mutations in brlA prevent the formation of conidia by inhibiting the development of conidiophores, resulting in bristle-like structures (Yu 2010).
Conversely, overexpression of brlA leads to abnormal sporulation and the production of viable spores from hyphae. BrlA activation is essential for conidiation initiation, as it cannot be bypassed by environmental signals, emphasizing its pivotal role
in fungal development (Park and Yu 2012). Park etal. (2003) reported that AbaA
regulates chitin biosynthesis in conidiophore development by modulating the
expression of specic chitin synthetase through its interaction with the promoter of
the chitin synthase gene, chsC.
In addition, WetA exhibits high and broad conservation across ascomycetes and
plays a vital role in the synthesis of essential conidial wall components. Its involvement results in conferring impermeability and maturity to the conidia. The deletion
of wetA leads to various conidial abnormalities, such as the development of colorless conidia that undergo autolysis (Yu 2010). This phenomenon has been observed
Fig. 19.2 Asexual development of conidia in A. fumigatus showing central genetic regulatory
cascade. (Source: Alkhayyat etal. (2015))
19 Understanding Molecular Pathogenesis ofAspergillus fumigatus
463
upregulation of brlA gene in ∆abaA and ∆wetA mutants, particularly during conidial stages and vegetative growth phases, indicating the crucial role of abaA and wetA
in negative feedback regulation of brlA, especially post-conidiation completion and
during specic vegetative growth phases (Tao and Yu 2011).
19.3.3 DHN Melanin
Melanins are molecules often associated with the fungal cell wall, which play an
important role in protecting organisms against external stressors (Langfelder etal.
2003). Dihydroxynaphthalene (DHN) melanin, an important pigment in A. fumiga-
tus, contributes signicantly to its pathogenesis and survival strategies (Pihet etal.
2009). This melanin type is derived from the DHN biosynthesis pathway, which
plays a crucial role in helping the pathogen adapt to challenging conditions, including ultraviolet irradiation, reactive oxygen species (ROS), and reactive nitrogen species. In addition, it contributes to thermotolerance (Pihet et al. 2009), thereby
enhancing the pathogen’s overall pathogenicity (Eisenman and Casadevall 2012).
It is an integral component of the A. fumigatus cell wall, contributing to the
brownish-grey coloration of conidia (Pihet etal. 2009). The outer layer of A. fumig-
atus conidia primarily consists of a hydrophobic rodlet protein layer (Aimanianda
etal. 2009). Underneath this layer, DHN–melanin is situated, and melanin patches
are exposed on the surface, contributing to the echinulate appearance of dormant
A. fumigatus conidia in electron microscopy studies (Bayry etal. 2014).
Melanized conidia effectively mask various A. fumigatus-associated molecular
patterns, offering protection against elimination by the host immune system (Bayry
et al. 2014). These mechanisms contribute to the enhanced dissemination of
A. fumigatus conidia within the host’s body. A. fumigatus produces melanin through
the DHN–melanin pathway, where the polyketide synthase (PKS)-mediated melanin formation is referred to as the DHN–melanin pathway. This pathway, absent in
mammals, is commonly found in ascomycetes like A. fumigatus, Magnaporthe gri-
sea, Colletotrichum lagenarium, and Wangiella dermatitidis (Pihet etal. 2009).
The DHN–melanin pathway utilizes endogenous substrates, which are malonylCoA, and acetyl-CoA for DHN–melanin production (Eisenman and Casadevall
2012; Hernández-Chávez etal. 2017). It begins with the conversion of acetyl-CoA
to 1,3,6,8-tetrahydroxynaphthalene (THN) through a series of enzymatic reactions.
Subsequently, THN undergoes polymerization and oxidation steps to form DHN
melanin. The biosynthesis of DHN–melanin involves a set of six genes: abr2, abr1,
ayg1, arp2, arp1, and pksP/alb1, arranged in a 19kb DNA cluster on chromosome
2 (Fig.19.3).
DHN melanin is intricately regulated by TFs that govern its biosynthesis pathway. Specically, the central PKS gene pksP serves as a core element in the DHN–
melanin biosynthesis cluster. The deletion of pksP leads to the production of white
conidia and diminished virulence, highlighting the signicance of this gene in fungal pathogenesis (Brakhage and Liebmann 2005; Pihet etal. 2009). However, the
regulatory mechanisms controlling the DHN–melanin gene cluster remained
464
Fig. 19.3 DHN melanin biosynthesis pathway in A. fumigatus and its gene cluster abr2, abr1,
ayg1, arp2, arp1, and pksP/alb1. (Source: Gupta etal. (2021))
P. Sen et al.
elusive due to the absence of regulatory genes within the cluster. A research report
published by Valiante etal. (2016), utilizing bioinformatics analyses, has identied
two TFs, DevR and RlmA, as key regulators of pksP expression. These TFs, a basic
helix–loop–helix and a MADS-box TF, respectively, were found to bind to specic
DNA motifs in the pksP promoter region (Manolli etal. 2019). Remarkably, DevR
and RlmA exhibit dual activities, acting as both repressors and activators depending
on the occupied binding motif. Deletion of the genes encoding these TFs resulted in
impaired sporulation and reduced expression of the DHN–melanin gene cluster
(Valiante etal. 2016). Both invitro and invivo experiments demonstrated the cooperative regulation of pksP expression by DevR and RlmA, emphasizing their essential role in modulating DHN–melanin biosynthesis through mutually exclusive
repression and activation mechanisms (Rocha etal. 2016). This elucidation of the
transcriptional regulation of DHN melanin provides valuable insights into fungal
virulence and potential targets for therapeutic interventions against A. fumigatus
infections.
Melanin and rodlet layers are immunologically inert and believed to mask fungal
PAMPs, by preventing the activation of pattern recognition receptors (Aimanianda
etal. 2009; Bayry etal. 2014). The swelling of conidia causes the removal of rodlet
proteins and DHN–melanin, exposing PAMPs, such as β-glucan and other immunestimulating polysaccharides. The presence of DHN–melanin activates dectin-1 and
other C-type lectin receptors on host lung epithelial cells. Removing cell wall melanin allows the activation of autophagy pathways, such as LC3-associated phagocytosis and fungal evasion (Akoumianaki etal. 2016). The absence of melanin in
Aspergillus species increases sensitivity to ROS, leading to enhanced phagocytic
killing (Warris and Ballou 2019).
19 Understanding Molecular Pathogenesis ofAspergillus fumigatus
465
19.3.4 Cell Wall Components ofA. fumigatus
The fungal cell wall acts as the primary point of contact with the host epithelial
cells. Studies indicated that approximately one-fourth of the fungal biomass comprises of cell wall (Gastebois etal. 2009; Morozov and Likhoshway 2016). Its components serve as protective measures against the immune system and are crucial for
pathogenesis (Briard etal. 2016). The composition and organization of the A. fumig-
atus cell wall dynamically adjust in response to various environmental stressors,
enabling the pathogen to adapt within infected human cells and survive under
adverse conditions (Hernández-Chávez etal. 2017). Polysaccharides within the cell
wall, including glucan, chitin, and galactomannan, are structured in layers, contributing to its functional versatility (Fig.19.4). Glycoproteins and galactosaminogalactan (GAG) act as a bridge to ll the gaps between polysaccharide units (Rambach
et al. 2015). The composition of the outer cell wall varies between hyphae and
conidium which has a rodlet layer composed of hydrophobins followed by
DHN–melanin.
Chitin plays a crucial role in determining the immune response during A. fumiga-
tus infection. Chitin constitutes a signicantly larger portion of the cell wall in lamentous fungi compared to yeast, accounting for approximately 10–20% of the dry
weight of cell walls. On the outer side of the membrane, nascent chitin chains fold
back on themselves, forming anti-parallel chains held together by intra-chain hydrogen bonds (Ren etal. 2022). Chitin synthases are membrane-bound proteins responsible for catalyzing the polymerization of a homopolymer of N-acetylglucosamine
(GlcNAc) from UDP-GlcNAc (Muszkieta etal. 2014b). In A. fumigatus, there are
eight CHS genes: chsA, chsB, chsC, chsG, chsD, chsF, csmA, and csmB (Jiménez-
Ortigosa etal. 2012; Muszkieta etal. 2014a).
α-(1,3)-Glucan, a signicant polysaccharide in the A. fumigatus cell wall, consti-
tutes 35–40% of the mycelial cell wall and 20% of the conidial cell wall (Beauvais
etal. 2013). It plays a crucial role in masking PAMPs, preventing the recognition of
Fig. 19.4 Structural composition of the outer conidial and hyphal cell wall of A. fumigatus.
(Source: Garcia-Rubio etal. (2020))