Ci a ion: Sánchez, P.;
Vélez-del-Bu go, A.; Suñén, E.;
Ma ínez, J.; Pos igo, I. Fungal
Alle gen and Mold Alle gy
Diagnosis: Role and Rele ance o
Al e na ia al e na a Al a 1 P o ein
Family. J. Fungi 2022,8, 277.
h ps://doi.o g/10.3390/jo 8030277
Academic Edi o : Kuang R. Chung
Recei ed: 31 Janua y 2022
Accep ed: 7 Ma ch 2022
Published: 9 Ma ch 2022
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Fungi
Jou nal o
Re iew
Fungal Alle gen and Mold Alle gy Diagnosis: Role and
Rele ance o Al e na ia al e na a Al a 1 P o ein Family
Pa icia Sánchez , Aina a Vélez-del-Bu go , Es e Suñén, Jo ge Ma ínez and Idoia Pos igo *
Depa men o Immunology, Mic obiology and Pa asi ology, Facul y o Pha macy and Labo a o y o Pa asi ology
and Immunoalle gy, Lasca ay Resea ch Cen e, Uni e si y o he Basque Coun y, 01006 Vi o ia-Gas eiz, Spain;
[email p o ec ed] (P.S.); aina a. elezdelbu [email p o ec ed] (A.V.-d.-B.); es e [email p o ec ed] (E.S.);
[email p o ec ed] (J.M.)
*Co espondence: [email p o ec ed]; Tel.: +34-954-013-910
Abs ac :
Al e na ia is a genus o wo ldwide ungi ound in di e en habi a s such as soil, he
a mosphe e, plan s o indoo en i onmen s. Al e na ia species a e sap obic—la gely in ol ed in he
decomposi ion o o ganic ma e ial—bu hey can also ac as animal pa hogens, causing disease in
humans and animals, de eloping in ec ions, oxicosis and alle gic diseases. A. al e na a is conside ed
one o he mos impo an sou ces o ungal alle gens wo ldwide and i is associa ed wi h se e e
as hma and espi a o y s a us. Among he A. al e na a alle gens, Al a 1 is he main sensi izing
alle gen and i s use ulness in diagnosis and immuno he apy has been demons a ed. Al a 1 seems o
de ine a p o ein amily ha can be used o iden i y ela ed pa hogenic ungi in plan s and ui s, and
o es ablish axonomic ela ionships be ween he di e en ungal di isions.
Keywo ds: Al a 1; ungal alle gy; as hma; Al e na ia; alle gic disease
1. In oduc ion
Alle gic diseases a e a g oup o immune-media ed diso de s wi h a high wo ldwide
p e alence a ec ing 30% o he gene al popula ion and inc easing d ama ically. As hma,
hini is; anaphylaxis; d ug, ood, and insec alle gy; eczema; u ica ia (hi es) and an-
gioedema a e included in his g oup o diseases.
The main alle gens causing ype I alle gies a e con ained in di e en sou ces, o which
mi es, pollens, epi helia, ungi and some oods a e he mos impo an [
1
,
2
]. Fungi a e
he ou h sou ce o sensi iza ion in ol ed in alle gic espi a o y diseases p eceded by
pollens and dus mi es. The exposu e o alle genic molds can cause IgE-media ed alle gic
hini is, as hma and a opic de ma i is [
3
], and i has been desc ibed ha he sensi iza ion o
some ungi such as Aspe gillus and/o Al e na ia is ela ed o he se e i y o an as hma ic
a es [4].
The e a e se e al epidemiologic s udies abou ungal alle gy p e alence, bu he
da a a y acco ding o he me hod o diagnosis [
4
]. I is es ima ed ha he p e alence o
alle gies o molds is abou 3–10%, al hough he p e alence o ungal sensi iza ion shows a
wide geog aphical a iabili y [
3
]. Among he alle genic mold species, Al e na ia al e na a,
Aspe gillus umiga us,Cladospo ium he ba um and Penicillium no a um a e he ones wi h
he highes p e alence in alle gic disease o sensi iza ions [
5
]. Da a om he Eu opean
Communi y show a p e alence o posi i e skin p ick es s (SPT) using Al e na ia and
Cladospo ium alle genic sou ces anged om 0.2% o 14.4% in he adul gene al popula ion
(aged 20–44) [
6
]. In he USA, ungal sensi iza ion o as hma ic pa ien s e ealed a p e alence
o 80% [
7
]. A. al e na a is conside ed one o he mos impo an ungal alle gens wo ldwide
and is associa ed wi h se e e as hma and espi a o y s a us [
4
,
8
]. I accoun s o 60% o
SPT among pa ien s sensi ized o ungi [9].
Al e na ia is a wo ldwide genus o Deu e omyce es ungi ound in di e en habi a s,
such as soil, he a mosphe e, plan s o indoo en i onmen s, ha include many sap o-
J. Fungi 2022,8, 277. h ps://doi.o g/10.3390/jo 8030277 h ps://www.mdpi.com/jou nal/jo
J. Fungi 2022,8, 277 2 o 11
phy ic and pa hogenic species. The axonomy o hese ungi has mainly been based on
mo phological conidial cha ac e s and o a lesse ex en on hos associa ion, biochemis y
and me aboli es [
10
]. Recen phylogene ic s udies ha e made signi ican changes o he
sys ema ic axonomy wi hin Al e na ia by ele a ing 26 clades o he subgene ic axonomic
s a us o sec ion [
10
]. Acco ding o phylogene ic and mo phological s udies, Al e na ia
con ains mos Al e na ia species wi h conidia succession, including impo an plan , human
and pos ha es pa hogens. In spi e o he ac ha he majo i y o Al e na ia species a e
sap obic—la gely in ol ed in he decomposi ion o o ganic ma e ial—many o hei species
a e endophy ic, li ing in a ious pa s o c ops including lea es, seeds and ui s [
11
]. To a
lesse deg ee, hey can ac as animal pa hogens, causing disease in human and animals,
de eloping in ec ions, oxicosis and alle gic diseases [
10
,
12
]. In he ield o human ail-
men s, alle gic disease is undoub edly he mos common human pa hology caused by
Al e na ia [
11
,
13
–
15
]. The Global As hma and Alle gy Eu opean Ne wo k (GA2LEN) is a
conso ium o leading Eu opean esea ch cen e s specialized in alle gic diseases, which in-
clude as hma. I was unded by he Eu opean Union unde he 6 h F amewo k P og amme
wi h he pu pose o add essing he g owing public heal h conce n o alle gic diseases.
The GA2LEN ini ia i e pe o med a s udy in 14 coun ies o he Eu opean Communi y
(n= 3034) and showed a p e alence o sensi iza ion o A. al e na a o 9%, anging om
2% in Finland o 23.8% in G eece [
16
]. In he Uni ed S a es, he p e alence o A. al e na a
sensi iza ion in he gene al popula ion (aged 6 o 74 yea s) was abou 13% [
7
]. In Spain,
his p e alence was es ima ed o be a ound 20% [17].
2. Fungal Alle gen and Mold Alle gy Diagnosis
The diagnosis and ea men o human alle gic diseases classically in ol es he use o
ex ac s ob ained om biological ma e ial. Howe e , in ecen decades he applica ion o
molecula diagnos ic p ocedu es using indi idualized alle gens has been decisi e in he
managemen o a opic indi iduals and alle gic pa ien s [
18
]. Desc ibed mo e han 20 yea s
ago, i is known ha he Al a 1 alle gen is he main alle gen o A. al e na a [
19
–
21
], wi h
mo e han 80% o Al e na ia alle gic pa ien s being sensi i e o his alle gen [
3
,
22
,
23
]. Since
hen, se e al o he alle gens belonging o his ungal species ha e been desc ibed (Table 1).
The o icial WHO/IUIS da abase cu en ly lis s 113 ungal alle gens belonging o
a ious p o ein amilies, o which 88 belong o Ascomyco a species, 23 o Basidiomyco a
and 2 o Muco ales. The o de Eu o iales includes 48 alle gens belonging o Aspe gillus and
Penicillium species. The o de Capnodiales includes 10 alle gens belonging o Cladospo ium
species, and he Pleospo ales o de includes 18 alle gens belonging o Al e na ia,Epicoccum,
Ulocladium and Cu ula ia species [24].
To da e, only 10 indi idualized alle gens om 5 mold species a e a ailable o alle gy
diagnosis and mold sensi iza ion es ing. These include nAl a 1/ Al a 1, he majo alle gen
in A. al e na a-sensi ized indi iduals, and A. al e na a enolase, Al a 6, wi h i s po en ial
c oss- eac i i y o molds and o na u al la ex alle gens. The ecombinan alle gens Asp
1, 2, 3, 4 and 6 om Aspe gillus umiga us o alle gy diagnos ic pu poses, including he
speci ic e alua ion o alle gic b onchopulmona y aspe gillosis (ABPA) and, inally he
Cla h 8 alle gen, conside ed he majo alle gen o Cladospo ium he ba um wi h possible
c oss- eac i i y o o he dehyd ogenase alle gens [25].
The clinical and diagnos ic ele ance o indi idualized alle gens and alle gen ex ac s
om se en common gene a o ungi has been ex ensi ely e iewed [
4
,
5
]. Mos au ho s
ag ee on he impo ance o gene a Al e na ia,Cladospo ium,Penicillium,Aspe gillus, and
Malassezia in clinical diagnosis [
13
,
15
,
26
–
29
]. The Al e na ia and Cladospo ium species a e
conside ed he mos impo an ou doo alle gens and he sensi iza ion o species o hese
gene a is associa ed wi h he de elopmen o as hma and hini is and exace ba ion o
as hma [
13
,
15
,
26
]. The Penicillium and Aspe gillus species a e bo h in ol ed in alle gic
diseases as indoo alle gens [
27
]. A. umiga us is able o colonize he b onchial ac o
as hma ic pa ien s, causing acu e pe sis en as hma and ABPA [
28
]. The Malassezia species
a e common commensals o heal hy skin and may be associa ed wi h a opic de ma i is [
29
].
J. Fungi 2022,8, 277 3 o 11
Table 1.
Al e na ia al e na a alle gens and hei c oss- eac i i y wi h homologous p o eins om o he
ungal species.
Alle gen 1P o ein Type MW (kDa) Rele ance
Homologs C oss-Reac i e Alle gens (S uc u al Da abase
o Alle genic P o eins E Sco e)
IUIS/Alle gen.o g/Alle gome.o g Da a Bases
Al a 1
I has a unique, dime ic
β-ba el s uc u e ha
de ine a new p o ein
amily wi h unknown
unc ion ound exclusi ely
in ungi.
16.4 and
15.3 bands Majo alle gen
Al b 1 Al e na ia b asicola and o he 138 Al e na ia species
Ulo c 1 Ulocladium cha a um
Emb a 1 Embellisia allii and o he 6 Embellisia species
Nim c 1 Nimbya celosiae and o he 4 Nimbya species
Sin u 1 Sinomyces usoideus
S e b 1 S emphylium bo yosum and o he 2 S emphylium species
Ulo c 1 Ulocladium cha a um and o he 11 Ulocladium species
Al a 3 Hea shock p o ein 70 85 Mino alle gen Pen c 19 Penicillium ci inum (1.9 ×10−27)
Mala s 10 Malassezia sympodialis (1.2 ×10−3)
Al a 4 Disul ide isome ase 57 Mino alle gen
Al a 5 Ribosomal p o ein P2 11 Mino alle gen
Fus c 1 Fusa ium culmo um (3.4 ×10−27)
Cla h 5 Cladospo ium he ba um (8.4 ×10−25)
Asp 8 Aspe gillus umiga us (2.0 ×10−22)
Al a 6 Enolase 45 Mino alle gen
Cla h 6 Cladospo ium he ba um (1.2 ×10−157)
Asp 22 Aspe gillus umiga us (1.9 ×10−154)
Pen c 22 Penicillium ci inum (4.7 ×10−153)
Cu l 2 Cu ula ia luna a (8.4 ×10−153)
Rho m 1 Rhodo o ula mucilaginosa (2.5 ×10−129)
Al a 7 Fla odoxin, YCP4 p o ein 22 Mino alle gen Cla h 7 Cladospo ium he ba um (9.4 ×10−61)
Al a 8 Manni ol dehyd ogenase 29 Mino alle gen Cla h 8 Cladospo ium he ba um (6.6 ×10−91)
Al a10 Aldehyde dehyd ogenase 53 Mino alle gen Cla h 10 Cladospo ium he ba um (5.9 ×10−168)
Al a 12 Aid ibosomal p o ein P1 11 Mino alle gen
Cla h 12 Cladospo ium he ba um (1.8 ×10−30)
Pen c 26 Penicillium c us osum (4.2 ×10−28)
Pen b 26 Penicillium b e icompac um (6.8 ×10−28)
Al a 13 Glu a hione- ans e ase 26 Mino alle gen
Al a 14 Manganese SO dismu ase 24 Mino alle gen Asp 6 Aspe gillus umiga us (5.5 ×10−48)
Mala s 11 Malassezia sympodialis (4.9 ×10−36)
Al a 15 Vacuola se ine p o ease 58 Mino alle gen
Cu l 4 Cu ula ia luna a (4.3 ×10−152)
Cla h 9 Cladospo ium he ba um (5.3 ×10−119)
Pen o 18 Penicillium oxalicum (2.4 ×10−114)
Asp 18 Aspe gillus umiga us (4.8 ×10−111)
Pen ch 18 Penicillium ch ysogenum (7.9 ×10−111)
Cla c 9 Cladospo ium cladospo ioides (1.2 ×10−99)
Rho m 2 Rhodo o ula mucilaginosa (1.6 ×10−73)
T i 2 T ichophy on ub um (1.6 ×10−37)
Pen ch 13 Penicillium ch ysogenum (1.1 ×10−23)
Asp 13 Aspe gillus e sicolo (1.5 ×10−20)
Asp 13 Aspe gillus umiga us (2.8 ×10−20)
Asp o 13 Aspe gillus o yzae (9.8 ×10−19)
Asp l 13 Aspe gillus la us (9.8 ×10−19)
Pen c 13 Penicillium ci inum (5.3 ×10−15)
1
Wo ld Heal h O ganiza ion and In e na ional Union o Immunological Socie ies (WHO/IUIS) Alle gen Nomen-
cla u e Sub-Commi ee S uc u al Da abase o Alle genic P o eins (SDAP), In e na ional Union o Immunological
Socie ies. Fi e o he A. al e na a alle gen p o eins (Al a TCTP, Al a NTF2, Al a 2, Al a 9 and Al a 70 kDa) a e
no included in he e e ed o icial alle gen lis , bu hey we e al eady included in he Alle gome da abase.
Howe e , in he associa ion be ween alle gic diseases and ungal species, which ha e
been iden i ied in bo h indoo and ou doo en i onmen s, he ungal concen a ion and
dis ibu ion o he species in bo h en i onmen s should be aken in o accoun in any case [
5
].
Sha pe e al. ci e ha Cladospo ium,Al e na ia,Aspe gillus and Penicillium species we e ound
o be p esen in highe concen a ions in homes o as hma ic pa icipan s [
30
]. The p esence
o high concen a ions o spo es belonging o hese ungal gene a inc eased he exace ba ion
o as hma symp oms compa ed o indi iduals exposed o lowe concen a ions o hese
ungi [30].
J. Fungi 2022,8, 277 4 o 11
Rapid p og ess in gene and p o ein echnology o e he pas decades has con ibu ed
signi ican ly o he iden i ica ion o species-speci ic and c oss- eac i e alle gen molecules
om di e en alle genic ungal sou ces [
5
]. Ne e heless, da a e i ying he clinical and
diagnos ic ele ance o hese alle gens a e insu icien and, mo e ex ensi e s udies a e
needed. S udies conduc ed in Japan in 2015, sugges ed he possible con ibu ion o
o he ungal alle gen sou ces, including Basidiomyce e species (
Schizophyllum commune
and
Bje kande a adus a
) o pa hogenesis o espi a o y diseases, including alle gic as hma/ hini is
o alle gic b onchopulmona y mycosis [5].
3. Rele ance o Mold Dis ibu ion and Fungal Ex ac s in Alle gy Diagnosis
The dis ibu ion and quan i ica ion o indoo and ou doo ungal species is s ongly
associa ed wi h he de elopmen o ungal alle gy [
27
,
31
]. The mycological ca alogs o
ungal species ha include ae obiological da a a e di e en acco ding o egion, clima e and
me eo ological condi ions o he geog aphical a ea s udied [
32
,
33
]. The esul s epo ed
in each coun y a e clea ly di e en and include a high numbe o gene a belonging o
Ascomyco a, Basidiomyco a, Muco omyco a and Deu e omyco a [
34
–
38
]. Rega ding he
quan i ica ion o spo es, only a ew gene a ha e maximums o mo e han 100 spo es/m
3
,
such as
Aga icus
(350 spo es/m
3
); Al e na ia (180 spo es/m
3
); Aspe gillus/Penicillium
(450 spo es/m
3
);
Cop inus
(500 spo es/m
3
) and Us ilago (750 spo es/m
3
); Cladospo ium
(4500 spo es/m
3
) [
28
]. Mos s udies ag ee ha Cladospo ium is he genus ha gi es ise
o he highes concen a ion o ai bo ne spo es [
34
–
40
]. Spo es o o he axa conside ed
he mos impo an in alle gy de elopmen co esponding o Aspe gillaceae (Aspe gillus,
Penicillium) and Pleospo aceae (Al e na ia sec ion Al e na ia,S emphyllium,Al e na ia sec ion
Ulocladium), also ha e signi ican ly highe le els o spo es in he ai [31,34–40].
The p e alence o ungal sensi iza ion shows a signi ican geog aphic a ia ion wi h se -
e al ungal species in ol ed in alle gic diseases including he gene a
Al e na ia
,
Aspe gillus
,
Au eobasidium,Bipola is,Bo y is,Candida,Cu ula ia,Cladospo ium,D echsle a,Epicoccum,
Fusa ium,Muco ,Penicillium,Phoma,Saccha omyces,Malassezia,T ichphy on,S emphylium,
Ganode ma
,Us ilago and Pleu o us [
5
,
23
,
28
,
41
], bu Al e na ia,Aspe gillus and Cladospo ium
a e he mos epo ed sensi izing gene a o ungal na u e [
3
,
41
–
43
]. This would be in line
wi h he mos ele an ungal alle gens ound in indoo en i onmen s, e. g., Asp 1 (Mi-
ogillin), Al a 1 (Unknown p o ein), Cla h 6 (Enolase), Cla h 8 (Manni ol dehyd ogenase),
Pen ch 13 (Se ine p o ease) and Pen ch 18 (Se ine p o ease) [44].
Howe e , i mus be conside ed ha he quali y o ungal alle genic ex ac s used as
a diagnos ic ool is no simila o all species due o se e al di icul ies in he p ocess o
ob aining he ex ac such as ungal iden i ica ion, cul u e condi ions and s anda diza ion,
s ain a ia ion, biological s anda diza ion, use o he e ogeneous in-house e e ence se a
and o he biological, biochemical and immunochemical pa ame e s [
28
,
45
,
46
]. These ac o s
ep esen se ious limi a ions o asse ha he ou gene a indica ed as he mos ele an in
alle gy diagnosis a e he only ones o be aken in o accoun . A e he e o he species ha ,
due o di icul ies in ob aining diagnos ic eagen s, go unno iced?
On he o he hand, a ious ungi a e known o cause sensi iza ion in as hma ics, bu
he mos impo an ungal agen s causing se e e as hma wi h ungal sensi iza ion a e no
well de ined [
12
]. Acco ding o da a epo ed in he li e a u e only Al e na ia,Aspe gillus,
Penicillium and Cladospo ium seem o be he s onges candida es o he de elopmen
o se e e as hma and hini is [
4
,
13
,
36
,
47
–
50
]. The e a e only a ew case epo s abou
he associa ion be ween occupa ional ungal exposu e and as hma in ol ing he species:
Pleu o us co nucopiae,Lycopodium cla a um,Dic yos elium discoideum,Rhizopus nig icans and
Neu ospo a [
13
], whe eas sensi iza ion o Al e na ia, Cladospo ium and Aspe gillus has a
s ong link wi h as hma se e i y [
51
–
54
]. Pa ien s monosensi ized o ungal alle gens a e
associa ed wi h a high isk o de eloping clinical symp oms [
55
], while hose who p esen
mul iple sensi iza ions o ungi a e associa ed wi h poo as hma con ol [56].
J. Fungi 2022,8, 277 5 o 11
4. Molecula Diagnosis and Fungal Molecules
The applica ion o genomics and p o eomics o he s udy o alle genic p o eins has been
he basis o building mo e accu a e diagnos ic ools. The iden i ica ion and p oduc ion o
he indi idual alle gen molecules has been key o add essing hi he o un esol ed concep s,
such as he causes o c oss- eac i i y phenomena, h ough molecula diagnosis.
A he beginning o he 21s cen u y, Valen a e al. desc ibed he basis o he molec-
ula diagnosis o alle gy, a classical echnique o measu e speci ic IgE concen a ions in
se um by coupling indi idualized na i e o ecombinan alle gens o he solid phase
(ImmunoCAP
®
) [
18
]. A ew yea s la e , he mic oa ay/mac oa ay echniques we e ap-
plied o he componen esol ed diagnosis and immuno he apy concep (CRD/CRIT).
These echniques made a ailable he wide IgE eac i i y p o iles o indi iduals o achie e a
comple e indi idualized managemen o he alle gic pa ien [57].
Cu en ly, he diagnos ic accu acy and e ec i eness o eplacing alle genic sou ces
by indi idual alle gens is a ac . By applying he CRD, i is possible o minimize se e al
p oblems wi h he s anda diza ion o alle genic ex ac s, such as ungal s ains and ba ch-
o-ba ch a iabili y, he choice o ungal s uc u e o be used as aw ma e ial, he ype o
cul u e and echnology used o p epa e alle genic ex ac s and he sel -deg ada ion o he
ex ac once ob ained [18].
Alle gy molecula diagnos ic is imp o ing he ou ine ca e. Cu en ly, mo e han
130 alle gens om mo e han 50 sou ces a e comme cially a ailable and hei use ep esen s
an undeniable ad ance. This is especially no iceable in he case o ood and insec alle gy
and o he selec ion o alle gen immuno he apy [28,58].
O he 113 de ined indi idualized ungal alle gens, only 8 a e a ailable o pe o m he
molecula diagnosis o ungal alle gy and de ine clinical pa e ns associa ed wi h ungal
alle gens. Fo example, da a epo ed om he li e a u e show ha Aspe gillus alle gens
could di e en ia e Aspe gillus sensi iza ion om ABPA [59–61].
Al e na ia Al e na a Alle gens in Molecula Diagnosis
Few wo ks ha e been published add essing he diagnosis o ungal alle gy using he
CRD wi h he mos common ungal alle gens a ailable [
3
,
8
,
23
,
42
,
62
–
64
]. All o he exis ing
s udies ag ee ha A. al e na a sensi iza ion is he mos p e alen in alle gic pa ien s o ungi
and ha Al a 1 is an accu a e ma ke o es species-speci ic sensi iza ion o IgE-media ed
alle gy o A. al e na a. Nine y pe cen o pa ien s o mo e labeled as alle gic o Al e na ia
eac speci ically o Al a 1.
Pos igo e al. epo ed ha 28 ou o 30 pa ien s diagnosed wi h an alle gy o Al e na ia
e ealed speci ic IgE alues o Al a 1, and he o he wo we e posi i e o Al a 6, showing
highly ele an speci ic IgE alues [
23
]. The demons a ion ha Asp 6 has a homologous
alle gen in A. al e na a (Al a 16) suppo s he mislabeling o Al e na ia alle gy and he
possible diagnosis o Aspe gillus alle gy wi h conno a ions o ABPA [
65
]. Pos igo e al.
also demons a ed ha 2 ou o 30 pa ien s e ealed low le els o speci ic IgE o Al a 1
and speci ic IgE o Cu ula ia was 4–6 imes highe [
23
]. Conside ing ha he Cu ula ia
majo alle gen is a homolog o he Al a 15, i could be conside ed he mislabeling o
he Al e na ia alle gy and he possible diagnosis o an alle gy o Cu ula ia [
66
]. These
esul s sugges ha o de ine he main sensi ize no only sensi izing he alle gen p o ile is
use ul, bu also he quan i ica ion o speci ic IgE o each posi i e alle gen eac ion. This is
especially impo an in he managemen o he alle gic pa ien , including he decision on
immuno he apy. Acco ding o Rod iguez e al., speci ic IgE o Al a 1 should be assessed
be o e conside ing he p esc ip ion o AIT in a pa ien wi h a clinically ele an sensi iza ion
o Al e na ia [
53
]. In hese cases, he majo alle gen Al a 1, should be ecognized as a ma ke
o p ima y sensi iza ion o his ungus. Luengo e al. ci e ha Al a 1 should be assessed
when conside ing mold immuno he apy [
67
]. A ecen clinical ial has demons a ed he
e icacy and sa e y o alle gen immuno he apy wi h a comme cial ex ac o Al a 1 [
68
,
69
].
J. Fungi 2022,8, 277 6 o 11
5. Al a 1 P o ein Family Is a Phylogene ic-Rela ed Al e na ia Ma ke o Taxonomy,
Alle gy and Phy opa hology
Al hough Al a 1 has been a de ined alle genic p o ein since 1991 [
19
,
21
], in 2012 i
was de ined and desc ibed as a unique
β
-ba el p o ein dime ound exclusi ely in ungi.
The only alle gens wi h a simila s uc u e o Al a 1 a e lipocalins, which ha e an
α
-helix
in addi ion o a
β
-ba el. Despi e he simila i ies be ween lipocalins and Al a 1, hey a e
he homologs o Al a 1 which de ine a dis inc s uc u al amily o p o eins [70].
Cu en phylogene ic s udies ha e made signi ican changes o he sys ema ic axon-
omy o Al e na ia by ele a ing 26 clades o he subgene ic axonomic s a us o sec ion [
10
].
Al e na ia sec ion consis s o only 11 phylogene ic species and 1 species complex [71–73].
Al a 1 gene sequences con ain mo e pa simony-in o ma i e si es han o he phyloge-
ne ic ma ke s. Analyses o Al a 1 gene s ongly suppo he clus e ing o Al e na ia spp.
and ela ed axa in o se e al species-g oups: in ec o ia, al e na a, po i, b assicicola, sonchi,
adicina and embellisia g oup. The monophyly o he Nimbya g oup was mode a ely
suppo ed and he monophyly o he Ulocladium g oup was weakly suppo ed [
74
]. Despi e
he high le els o a ia ion in amino acid sequences, he esul s o in silico p edic ion o
p o ein seconda y s uc u e o Al a 1, demons a ed a high deg ee o s uc u al simila i y
be ween mos o he species, sugges ing conse a ion o unc ion [10,12,74].
Acco ding o his concep , se e al au ho s ha e used Al a 1 DNA sequence o Al
a 1 p o ein o iden i y and quan i y A. al e na a om he en i onmen , his being o pa ic-
ula in e es o associa ing Al e na ia wi h sensi iza ion o espi a o y alle gy [
55
,
75
,
76
].
Gab iel e al. we e able o iden i y Al a 1 homologs om A. al e na a,
A. enuissima
,
A. in ec o ia,U. bo y is and S. bo yosum using di e en Al a 1 exp ession gene sequences.
The speci ic sequence o Al a 1 was able o de ec an amplicon o app oxima ely 390 bp
om Al a 1, encoding genes om species closely ela ed axonomically o
A. al e na a
,
such as
A. enuissima
. By con as , he PCR sys em using a conse ed sequence o Al
a 1 homologs was able o de ec an amplicon o app oxima ely 180 bp om Al a 1 and
Al a 1-like encoding genes om A. al e na a,A. enuissima,A. in ec o ia,U. bo y is and
S. bo yosum [
77
]. Simila esul s we e epo ed by Tei oo i e al., who we e able o am-
pli y Al a 1 gene sequences om in A. al e na a [
78
] and o he ela ed axa [
79
,
80
]. All
hese au ho s ag ee ha he Al a 1 sequence is an excellen ool o de ine a monophyle ic
Al e na ia-Nimbya-Embellisia-Ulocladium and o he clade wi h S emphylium belonging o
clade a e y close o he men ioned abo e. A. al e na a and A. enuissima a e axonomically
closely ela ed species and a e placed in a di e en g oup om hose including A. in ec o ia,
U. bo y is, and S. bo yosum. O he analyzed Pleospo aceae, as Cu ula ia luna a o D echsle a
i ici- epen is did no e ealed homologous genes o Al a 1 [
77
]. Despi e he di e ences in
Al a 1 gene sequences among he di e en Pleospo aceae species s udied, he ecogni ion o
Al a 1 homologs by an ibodies is always ele an and Al a 1 can be conside ed an excellen
ool o be used in he se ological diagnosis o alle gic diseases caused by Al e na ia.
I we accep ha he gene encoding Al a 1-homologous-p o eins is a axonomic
ma ke [
4
] and ha Al a 1, exp essed in some Pleospo aceae species, de ines a p o ein
amily [
74
], i would be possible ha Al a 1 would ha e an impo an biological ole in
he e olu iona y adap a ion o he Pleospo aceae amily because Al a 1 de ines a g oup o
phylogene ically ela ed species.
Un o una ely, so a , no da a on he biological ole o Al a 1 has been conclusi ely
elucida ed.
F om an alle gological poin o iew, i could be sugges ed ha he Al a 1 p o ein,
bo h in i s na i e and ecombinan o m, is an excellen diagnos ic ma ke o eplace he
A. al e na a
ex ac , whe he used in skin es s o o he de ec ion and quan i ica ion o
speci ic IgE/IgG [
22
]. The Al a 1 alle gen, undamen ally in i s na i e o m, is cu en ly
he mos accu a e and e ec i e ool o he immuno he apeu ic ea men o Al e na ia
espi a o y alle gy [68].
Al e na ia species is a common sap ophy e ound on many plan s and o he subs a es
wo ldwide. I is an oppo unis ic pa hogen ha in ec s many ag icul u al c ops in he
J. Fungi 2022,8, 277 7 o 11
ield and du ing pos ha es s o age o ege ables and ui s. Al e na ia species ha e been
isola ed om a wide ange o ui s and ege ables. Ce ainly, his g oup includes he
main pa hogenic ungi in ag icul u e and ood indus y, esul ing in se e e ag icul u al
and economic losses [
81
]. Accu a e iden i ica ion o plan pa hogens is essen ial o unde -
s anding epidemiology and he iden i ica ion o new ools o be e managemen o he
plan pa hologies and pos ha es con amina ion [82,83].
The de elopmen o DNA echnology has p o ided e ec i e me hods o he s udy
o di e en ungi, and se e al gene ic ma ke s ha e been p o ided o hei iden i ica ion.
These ma ke s a e widely used in PCR o chip de ec ion [
84
]. In ecen yea s, mul igene phy-
logeny has been widely employed o he iden i ica ion and cha ac e iza ion o Al e na ia
species. Molecula app oaches based on ba coding he gene egion o gene agmen s,
such as he in e nal ansc ibed space (ITS) [
85
–
88
], mi ochond ial small subuni (m SSU),
la ge subuni ibosomal DNA (LSU) [
87
], A. al e na a majo alle gen (Al a 1) [
87
,
89
,
90
],
glyce aldehyde-3-phospha e dehyd ogenase (GAPDH) [
86
–
89
], anonymous genomics e-
gions (OPA 1–3 and OPA 2–1) [
85
,
88
,
89
], ansla ion elonga ion ac o 1 (TEF1) [
87
–
89
],
RNA polyme ase, he second la ges subuni (RPB2) [
87
,
88
], plasma memb ane, ATPase,
calmodulin [
87
,
89
] and ac in [
89
], ha e been used o de ine he monophyly o Al e na ia-
Nimbya-Embellisia-Ulocladium in he Ascomyce e amily Pleospo aceae ela ionships [
74
].
Cu en ad ances, especially in mul i-gene phylogeny and compa a i e genomics, ha e
made i possible o ede ine and delinea e he di e en Al e na ia sec ions, wi h accu a e
molecula di e en ia ion and iden i ica ion o isola es showing ha he Al e na ia sec ion
consis s o 11 phylogene ic species and 1 species complex [71–73].
Recen ly, some ungal alle gens (Al a 1 and Asp n 3) ha e been p esen ed as aluable
molecula ma ke s o axonomy and pa hology/con amina ion in ege ables and ui s and
also as molecula ma ke s o alle genic con amina ion in indoo en i onmen s [4,84,91].
Gab iel e al., using p ime s de ining he Al a 1 encoding gen (390 bp) and he
conse ed egion o Al a 1 encoding gen (180 bp) om A. al e na a, we e able o de ec he
in ec ion o ci us ui s by A. al e na a a he onse o in ec ion [
84
]. The conse ed egion
was able o de ec Al a 1 homologs in se e al species o Al e na ia sec ion, bu he agmen
encoding o he Al a 1 gen (390 bp) only de ec ed A. al e na a and A. enuissima. They also
sugges ha his p o ein could play a ole in he pa hogenici y and i ulence o Al e na ia
species [
77
,
91
]. Ga ido-A andia e al. p opose ha Al a 1 would block some plan de ense
mechanisms, ac ing as a pa hogenici y ac o acili a ing in ec ion by he Al e na ia species
o he plan [92].
6. Conclusions
Al a 1 de ines he espi a o y alle gy caused by Al e na ia, a phylogene ic ela ed
species belonging o Pleospo aceae amily. Al hough he Al e na ia axonomy has bene i ed
om ecen phylogene ic e isions, he basis o di e en ia ion among he majo phyloge-
ne ic clades o he g oup is no ye unde s ood [10,12,71,74].
I could be accep ed ha Al a 1 is a p o ein associa ed wi h pa hological phenomena in
bo h animals and plan s. Al a 1 is use ul o de ec ing and iden i ying indoo and ou doo
amoun s o he mos impo an ungal alle gen causing espi a o y alle gy and sensi iza ion.
I is aci ly accep ed ha Al a 1 is an impo an ma ke o assessing he isk ac o and
se e i y o alle gic espi a o y disease [
55
]. While many e o s ha e been made o disco e
he biological ole o Al a 1, no conclusi e esul s ha e been eached [70,74,92,93].
Au ho Con ibu ions:
Concep ualiza ion, P.S., J.M. and I.P.; da a e iew: P.S., A.V.-d.-B. and E.S.;
w i ing—o iginal d a p epa a ion, P.S.; w i ing— e iew and edi ing, P.S., A.V.-d.-B., E.S., J.M. and
I.P.; supe ision, I.P. All au ho s ha e ead and ag eed o he published e sion o he manusc ip .
Funding:
This wo k was suppo ed by he Basque Coun y Go e nmen : Consolida ed Resea ch
G oups o he Basque Uni e si y Resea ch Sys em: P ojec IT-1043-16 and he Heal h Resea ch
Depa men o he Basque Go e nmen : P ojec s: SAN18/16 and SAN20/04.
Ins i u ional Re iew Boa d S a emen : No applicable.
J. Fungi 2022,8, 277 8 o 11
In o med Consen S a emen : No applicable.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
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