Vi uses 2014, 6, 2214-2241; doi:10.3390/ 6052214
i uses
ISSN 1999-4915
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Re iew
Immunogene ic Fac o s A ec ing Suscep ibili y o Humans and
Roden s o Han a i uses and he Clinical Cou se o Han a i al
Disease in Humans
Na halie Cha bonnel 1,*, Ma ie Pagès 1,2, Ta ja Si onen 3, Heikki Hen onen 4, Olli Vapalah i 3,5,6,
Jukka Mus onen 7,8 and An i Vahe i 3,5
1 INRA, UMR CBGP (INRA/IRD/Ci ad/Mon pellie SupAg o), Campus in e na ional de Bailla gue ,
CS 30016, Mon e ie -su -Lez F-34988, F ance; E-Mail: [email p o ec ed]
2 Labo a oi e de géné ique des mic oo ganismes, Uni e si é de Liège, Liège 4000, Belgium
3 Depa men o Vi ology, Haa man Ins i u e, Uni e si y o Helsinki, POB 21, FI-00014 Helsinki,
Finland; E-Mails: [email p o ec ed] (T.S.); [email p o ec ed] (O.V.);
[email p o ec ed] (A.V.)
4 Finnish Fo es Resea ch Ins i u e, POB 18, FI-01301 Van aa, Finland;
E-Mail: heikki.hen onen@me la. i
5 Depa men o Vi ology and Immunology, HUSLAB, Helsinki Uni e si y Cen al Hospi al,
FI-00014 Helsinki, Finland
6 Depa men o Ve e ina y Biosciences, Facul y o Ve e ina y Medicine, Uni e si y o Helsinki,
FI-00014 Helsinki, Finland
7 School o Medicine, Uni e si y o Tampe e, FI-33521 Tampe e, Finland;
E-Mail: [email p o ec ed]
8 Depa men o In e nal Medicine, Tampe e Uni e si y Hospi al, FI-33521 Tampe e, Finland
* Au ho o whom co espondence should be add essed; E-Mail: na halie.cha bonnel@supag o.in a. ;
Tel.: +33-499-623-302; Fax: +33-499-623-345.
Recei ed: 29 No embe 2013; in e ised o m: 17 Ma ch 2014 / Accep ed: 16 May 2014 /
Published: 26 May 2014
Abs ac : We e iewed he associa ions o immuni y- ela ed genes wi h suscep ibili y o
humans and oden s o han a i uses, and wi h se e i y o han a i al diseases in humans.
Se e al class I and class II HLA haplo ypes we e linked wi h se e e o benign han a i us
in ec ions, and hese haplo ypes a ied among locali ies and han a i uses. The polymo phism
o o he immuni y- ela ed genes including he C4A gene and a high-p oducing geno ype o
TNF gene associa ed wi h se e e PUUV in ec ion. Addi ional genes ha may con ibu e o
disease o o PUUV in ec ion se e i y include non-ca iage o he in e leukin-1 ecep o
OPEN ACCESS
Vi uses 2014, 6 2215
an agonis (IL-1RA) allele 2 and IL-1β (-511) allele 2, polymo phisms o plasminogen
ac i a o inhibi o (PAI-1) and pla ele GP1a. In addi ion, immunogene ic s udies ha e
been conduc ed o iden i y mechanisms ha could be linked wi h he pe sis ence/clea ance
o han a i uses in ese oi s. Pe sis ence was associa ed du ing expe imen al in ec ions
wi h an up egula ion o an i-in lamma o y esponses. Using na u al oden popula ion
samples, polymo phisms and/o exp ession le els o se e al genes ha e been analyzed.
These genes we e selec ed based on he li e a u e o oden o human/han a i us in e ac ions
(some Mhc class II genes, Tn p omo e , and genes encoding he p o eins TLR4, TLR7,
Mx2 and β3 in eg in). The compa ison o gene ic di e en ia ion es ima ed be ween bank
ole popula ions sampled o e Eu ope, a neu al and candida e genes, has allowed o
e idence signa u es o selec ion o Tn , Mx2 and he D b Mhc class II genes.
Al oge he , hese esul s co obo a ed he hypo hesis o an e olu ion o ole ance s a egies
in oden s. We inally discuss he impo ance o hese esul s om he medical and
epidemiological pe spec i es.
Keywo ds: han a i us; Puumala i us; in e ac ion; hos s; ese oi s; oden s;
immuni y- ela ed genes
1. In oduc ion
1.1. Immunogene ics and Diseases
I is now well es ablished ha hos gene ic a ia ion in luences indi idual suscep ibili y o
in ec ious as well as au oimmune diseases [1]. The ield o immunogene ics is a he co e o esea ch
aiming a iden i ying and unde s anding associa ions be ween gene ic ac o s and immunological
pheno ypes o immuni y- ela ed diseases [2]. Fi s ly based on candida e gene app oaches,
immunogene ics has now mo ed owa ds genomics wi h he ad en o new echnologies including
DNA mic oa ays and nex -gene a ion sequencing. Whole genome sequencing o indi iduals wi h
ex eme pheno ypes o in ec ious diseases and subsequen genome-wide associa ion s udies a e now
con ibu ing o e eal he gene ic bases o human suscep ibili y o pa icula in ec ious diseases and
o deciphe he immunological mechanisms unde lying he pa hogenesis o hese diseases see o
e iews [1,3,4]. Al hough simila esea ch has been ca ied ou on in ec ious diseases o domes ic
animals e.g., [5,6], he applica ion o immunogene ics o wild animals, which cons i u e a la ge pa o
he ec o s/ ese oi s o agen s o zoono ic diseases [7], emains sca ce. I mainly ocused on genes o
he majo his ocompa ibili y complex (Mhc, equi alen o Hla—human leukocy e an igen—in humans)
un il he need o mo e candida e immune a ge genes had been poin ed ou [8]. Fo example, gene
candida e app oaches ela ed o inna e immuni y e.g., oll-like ecep o s o cy okines, [9,10] as well as
genomic app oaches [11–13] ha e ecen ly been de eloped on wild bi ds, ishes and oden s o
e alua e he in luence o molecula mechanisms on suscep ibili y o in ec ious diseases. In es iga ing
spa io- empo al a ia ions o allele/single nucleo ide polymo phism (SNP) equencies a hese
genes/loci p o ided u he insigh in o he po en ial ole o hese polymo phisms in he suscep ibili y
Vi uses 2014, 6 2216
o in ec ious diseases [14], he epidemiological consequences o his a iabili y [15] and he e olu iona y
mechanisms (selec ion, mig a ion, d i ) main aining immune gene di e si y [16,17]. S ikingly, only
ecen ly has his e olu iona y pe spec i e been explo ed in human s udies [18].
1.2. Han a i us In ec ion and Disease
Humans a e ―inciden al hos s‖ o han a i uses and a e ypically in ec ed ia con amina ed ae osolized
sec e ions ( eces, u ine, sali a) o he ese oi animals, which mainly include oden s, bu also sh ews,
moles and ba s hough no human connec ion has been es ablished ye wi h han a i uses om he h ee
la e hos g oups. The clinical cou se o human han a i al in ec ions a ies g ea ly acco ding o he
di e en han a i uses, anging om no disease o mild cou se and low case- a ali y a e (0.1% in
Puumala i us –PUUV– in ec ion) o se e e cou se up o 40%–50% in Sin Nomb e –SNV– and Andes
–ANDV– i us in ec ions [19,20]. In addi ion, la ge a ia ion in clinical se e i y exis s among pa ien s
o a gi en han a i us species. Se ological su eys conduc ed in Eu ope and in he Ame icas ha e
demons a ed he p esence o an ibodies in humans who had no his o y o clinical disease
wi h hemo hagic e e wi h enal synd ome (HFRS) o han a i us ca diopulmona y synd ome
(HCPS) [19,21]. This sugges s ha e en o some human pa hogenic han a i uses, some in ec ions
could be subclinical. Mo e speci ically, i is known ha he cou se o neph opa hia epidemica (NE),
a mild o m o HFRS in pa ien s in ec ed wi h PUUV is highly a iable, anging om asymp oma ic [22]
o occasionally a al disease [23]. Hypo ension up o clinical shock a e o example p esen in less
han 10% o he hospi alized pa ien s, 5% may equi e dialysis, while some a al ou comes ha e been
epo ed less han 0.1% [24,25]. Al hough complex in e ac ions a e likely o unde lie his a iabili y,
he impo ance o hos gene ics in he suscep ibili y o han a i us in ec ions and in he se e i y o he
disease has begun o gain e idence.
In oden s, which a e he ese oi s o pa hogenic han a i uses, in ec ion is pe sis en [26,27] and
mainly asymp oma ic bu see [28–30]. Ne e heless oden s di e in hei p obabili y o being in ec ed
wi h hei associa ed han a i us e.g., [31]. Expe imen al in ec ions ha e con i med ha he ou come o
a gi en han a i us in ec ion could a y among oden s [32,33]. As in humans, he gene ic backg ound
o he ese oi s could media e his a iabili y.
1.3. Po en ial Applica ions
We e iew he s udies on associa ions be ween immuni y- ela ed gene a ia ion (coding sequence
and le els o ansc ip ion) and he ou comes o han a i us in ec ion, conside ing bo h he p obabili y
o ge ing in ec ed and he se e i y o he diseases, in humans and oden s. These esul s a e o majo
medical impo ance because hey can help p edic ing disease p og ession in hospi alized pa ien s and
can lead o be e he apeu ics and accines. Fu he mo e, hey may imp o e ou unde s anding o he
epidemiology o han a i uses, by p o iding a mo e p ecise comp ehension hos swi ching and ul ima ely
han a i us ansmission om ese oi s o humans.
Vi uses 2014, 6 2217
2. Impac o Gene ic Fac o s in Human Han a i us In ec ions
2.1. Sequence Polymo phism o Immuni y-Rela ed Genes and he Se e i y o Human Han a i us In ec ions
Gene candida e app oaches ha e been de eloped o emphasize associa ions be ween human
geno ypes and he clinical se e i y o han a i us in ec ions, wi h he aim o deciphe ing he gene ic
ac o s ha ha e a majo in luence on he ou come o hese in ec ions. Immunogene ic in es iga ions
ha e mainly ocused on he human leukocy e an igen (HLA) sys em, and on genes encoding molecules
associa ed wi h his complex such as he C4A componen o he complemen sys em. Few o he
addi ional genes ha e been in es iga ed. We de ail he esul s o hese s udies below (see Table 1
o a summa y).
HLA sys em. I encompasses 224 genes in a 3.6-Mb egion o ch omosome 6 in humans [34]. I is
an essen ial componen o he immune sys em wi h abou 39.8% o hese genes being immuni y- ela ed
ones. Fo y o he o al genes belonging o he HLA sys em encode leukocy e an igens. The ole o
hese cell-su ace an igens is o p esen pa hogen-de i ed an igens o T cells and o ini ia e acqui ed
immune esponses [35]. Some o hese genes (i.e., class I and class II genes) a e among he mos
polymo phic in humans. Fo example, mo e han 100 allelic a ian s ha e been iden i ied in human
popula ions a he HLA-B and HLA-DRB1 loci (IMGT/HLA da abase, [36]). Many associa ions
be ween alleles o combina ions o alleles and suscep ibili y o in ec ious and au oimmune diseases
ha e been desc ibed in humans e.g., [4,37].
Fo HFRS and HCPS, isk HLA haplo ypes ha e been iden i ied acco ding o he ollowing clinical
and labo a o y pa ame e s o disease se e i y: ea men ime a hospi al (o e all se e i y), weigh
change du ing hospi al ca e (amoun o luid e en ion du ing oligu ic phase), need o dialysis, lowes
sys olic blood p essu e, p esence o shock, inc ease o plasma c ea inine and u ea (se e i y o acu e
kidney inju y—AKI), dec ease o pla ele s ( h ombocy openia) and inc ease in blood leukocy e coun
(leukocy osis) [19]. The e is a g ea geog aphic a iabili y in he HLA alleles and haplo ypes associa ed
wi h han a i us disease se e i y, bo h o HLA class I (HLA-B) and class II (HLA-DRB) genes.
In Finland, he indi iduals wi h HLA alleles HLA-B*08 and DRB1*0301 a e likely o ha e he
mos se e e o m o he PUUV in ec ion wi h lowe blood p essu es, highe c ea inine [38] and mo e
i us exc e ion in o he u ine and in o he blood [39]. On he con a y, indi iduals wi h HLA-B*27
ha e a benign clinical cou se [40]. In Slo enia, he HLA-DRB1*15 haplo ype was mo e equen in
pa ien s wi h se e e PUUV-HFRS p og ession han in pa ien s wi h a mild cou se o he disease [41].
In China, he mos se e e HFRS cases due o Han aan i us (HNTV) we e associa ed wi h he
p esence o HLA-B*46 allele and HLA-B*46–DRB1*09 o HLA-B*51–DRB1*09 haplo ypes [42].
In con as , he HLA-DRB1*12 allele was mo e equen in pa ien s wi h a mild o m o he disease
bu his ela ion was only ma ginally signi ican [43].
In he USA, he HLA-B*3501 and HLA-DRB1*1402 alleles a e associa ed wi h inc eased isk o
se e e Sin Nomb e (SNV)-induced HCPS [43–45]. In ano he s udy, HLA-B*35- es ic ed memo y
T-cell esponses we e ela ed o mild disease ou come in HCPS due o Andes i us [46]. In he Chilean
popula ion, HLA-DRB1*15 was associa ed wi h a mild o m o HCPS due o Andes i us whe eas
HLA-B*08 was again co ela ed wi h he se e e cou se o his disease [47].
Vi uses 2014, 6 2218
Table 1. Immuni y- ela ed genes associa ed wi h he se e i y o han a i us disease in humans.
Gene
Coun y
Haplo ype
Exp ession
Han a i us
Rele ance wi h Disease Se e i y
(−: Mild o m; +: Mo e Se e e)
Rele ance wi h In ec ion
(P: P o ec i e; R: Risk)
HFRS
HLA
Finland
HLA-B*08
PUUV
+
HLA-DRB1*0301
PUUV
+
HLA-B*27
PUUV
−
Slo enia
HLA-DRB1*15
PUUV
+
HLA-DRB1*13
PUUV & DOBV
+ (PUUV)
PUUV > DOBV
HLA-B*35
PUUV & DOBV
+ (DOBV)
DOBV > PUUV
HLA-B*07
PUUV
P
China
HLA-B*46
HTNV
+
HLA-B*46/DRB1*09
HTNV
+
R
HLA-B*51/DRB1*09
HTNV
+
HLA-DRB1*12
HTNV
−
P
TNF
Finland
−308
PUUV
+
Belgium
−238
PUUV
+
C4A
Finland
Dele ion
PUUV
+
HPA-3
China
3b
HTNV
+
R
PAI-1
Finland
GG
PUUV
+
Gp1A
Finland
C
PUUV
+
VE-CDH5
Russia
*T/*T
PUUV
+
GATA-3
Finland
Highe
PUUV
+
IL1-RA
China
*/*
HTNV
R
IL1-1b
China
−511
HTNV
R
IL1
Finland
x
PUUV
None
HPA-1
China
x
HTNV
None
CD3e
Finland
x
PUUV
None
T-BET
Finland
x
PUUV
None
HCPS
HLA
US
HLA-B*3501
SNV
+
HLA-DRB1*1402
SNV
+
HLA-B*35
ANDV
−
Chile
HLA-B*08
ANDV
+
HLA-DRB1*15
ANDV
−
TNF
B azil
−308G/A
ARAV
+
+ and − espec i ely indica e ha se e e o mild o ms o han a i us disease a e associa ed wi h gene ic a ia ions; P and R espec i ely indica e ha gene ic a ia ions
con e p o ec ion o a e associa ed wi h highe isk o han a i us in ec ion.

Vi uses 2014, 6 2219
Thus, di e en han a i uses seem o be p ocessed di e en ly h ough he same HLA molecules
esul ing in mild o se e e ou comes o he disease. S udies on he gene ic ac o s associa ed wi h
disease se e i y due o di e en sympa ic han a i uses con i m his s a emen . In Slo enia o
example, bo h PUUV and Dob a a i us (DOBV) a e p esen and cause HFRS. PUUV-in ec ed
pa ien s end o ha e mo e equen ly (32%) HLA-DRB1*13 haplo ype han DOBV-in ec ed pa ien
(18%), especially in he se e e o m o PUUV disease [41]. Fu he mo e, DOBV-in ec ed pa ien s
ha e a signi ican ly highe p e alence o HLA-B*35 han PUUV-in ec ed pa ien s This allele was
ma ginally associa ed wi h a a al ou come o he DOBV-in ec ed pa ien s [41].
I is in e es ing o no e ha mos o hese alleles/haplo ypes associa ed wi h se e i y o han a i us
disease a e linked o abno mal immune esponses o au oimmune diseases see e e ences in [38,48].
Indi iduals wi h he haplo ype HLA-B*08–HLA-DRB1*0301 a e p one o no mal o inc eased
humo al immune esponse and a low T-cell immune esponsi eness [49]. In con as , he HLA-B*27
allele is associa ed wi h dec eased p oduc ion o TNF and IFN-γ by T cells [50]. These immunogene ic
s udies hus p o ided he i s lines o e idence ha he pa hogenesis o han a i us in ec ion is likely
o imply he immune sys em o he hos . Fu he in es iga ions a e equi ed o deciphe he
mechanisms linking HLA class I and class II gene polymo phism, T cell esponses and he se e i y o
han a i us in ec ion.
The umo nec osis ac o (TNF) clus e belongs o he class III egion o he HLA complex and
con ains genes ha encode wo cy okines, TNF and LTA, and LTB, a ecep o ha o ms he e o ime s
wi h LTA [34]. An allele associa ed wi h high p oduc ion o TNF (polymo phism a posi ion −308)
co ela es wi h he se e e clinical cou se o PUUV in ec ion in Finnish pa ien s [51] and is s ongly
exp essed in kidneys o PUUV-in ec ed humans [52]. TNF gene is pa ly in ol ed in se e e PUUV
disease bu is a less impo an isk ac o han he HLA-B*08–HLA-DRB1*0301 haplo ype [23].
In Belgium, pa ien s wi h he low-p oduce allele o TNF (polymo phism a posi ion −238) had a mo e
se e e clinical cou se [53,54]. In B azil, he high-p oducing TNF-a 2 allele (−308G/A) was mo e
equen in HCPS pa ien s han in indi iduals wi h an ibodies bu wi hou a his o y o HCPS,
sugges ing ha his allele could ep esen a isk ac o o de eloping HCPS [55]. In B azil, his TNF-a
2 allele associa ion, unlike in Finland, was independen o he HLA-B*08–HLA-DRB1*0301 linkage
disequilib ium. In he same s udy, no associa ion was ound be ween TNF alleles and he se e i y o
case- a ali y- a e o HCPS [55].
C4A. Dele ion wi hin he C4A gene encoding he C4A componen o he complemen sys em is
in a iably associa ed wi h he HLA-B*08–HLA-DRB1*0301 haplo ype [56,57]. This is o in e es
since he e is good e idence ha complemen ac i a ion con ibu es o he pa hogenesis o PUUV
in ec ion [56]. Le els o he soluble e minal SC5b-9 complex we e highe , and C3 le els we e lowe
du ing he acu e s age han du ing con alescence, especially in pa ien s wi h ches x- ay abno mali ies.
These changes had a signi ican co ela ion wi h clinical and labo a o y pa ame e s o disease se e i y.
Polymo phism wi hin genes encoding cy okines may modula e cy okine p oduc ion du ing
in lamma ion and he e o e in luence he ou come o han a i us in ec ions. Only ew s udies ha e
add essed his ques ion. Mäkelä e al. [58] ha e analyzed polymo phism o he IL-1 amily genes.
They did no ind any e idence o allele equencies o geno ypes a ec ing he clinical cou se o
PUUV in ec ions.
Vi uses 2014, 6 2220
Polymo phisms o pla ele glycop o ein IIb/IIIa alloa igen (HPA1/HPA3) ha e been in es iga ed
and HPA-3, bu no HPA-1, was mo e equen in Chinese pa ien s wi h se e e han mild HFRS [59].
In Finland, plasminogen ac i a o inhibi o (PAI-1) and pla ele GP1a we e associa ed wi h se e e
PUUV in ec ion [60].
Finally, he p e alence o he VE-cadhe in CDH5 geno ype *T/*T was signi ican ly highe in
Russian pa ien s wi h he se e e o m o HFRS due o PUUV han in o he pa ien s. Missense mu a ion
c.1550T > C wi hin he VE-cadhe in gene could inc ease he desquama ion p ocess o endo helial cells
and lead o a se e e o m o HFRS wi h complica ions [61].
2.2. Va iabili y in Immuni y-Rela ed Gene Exp ession and Se e i y o Human Han a i us In ec ions
Se e al associa ions be ween se um le els o cy okines TNF IL-6, IL-2, IL-8, IL-10, IFN-γ,
see [62–66] o he in ensi y o pla ele β3 in eg in [67] and disease se e i y ha e been shown o
PUUV, HTNV and DOBV in ec ions. Gene ic de e minisms modula ing he mRNA exp ession le els
o he genes encoding hese molecules could ep esen impo an isk ac o s o han a i us disease
se e i y. Ne e heless, only a single s udy has compa ed he le els o mRNA exp ession o some o
hese genes among pa ien s exhibi ing di e en p og essions o han a i us disease. B ie ly,
Lib a y e al. [63] ollowed he mRNA exp ession le els o a T-cell associa ed gene (CD3e), a ype 1
cy okine ansc ip ion ac o (T-BET) and a ype 2 cy okine ansc ip ion ac o (GATA-3) in daily
u ine samples o iden i y isk ac o s o se e e PUUV HFRS du ing acu e illness (AKI). They ound
ha only GATA-3 mRNA exp ession was highe in pa ien s de eloping se e e AKI han in hose wi h
mild AKI. They concluded ha his clinical se e i y could be explained by excessi e ype 2 T-cell
esponses compa ed o ype 1 T-cell esponses in he kidneys. Al e na i ely, GATA3/Th2 esponse
may be a nega i e eedback o empe immunopa hology. In he nea u u e, simila s udies in o he
coun ies, o o he genes and o he han a i us species, could help iden i ying a la ge a ay o
immunogene ic ac o s modula ing he se e i y o human han a i us in ec ions.
2.3. Polymo phism o Immuni y-Rela ed Genes and Human Suscep ibili y o Han a i us In ec ions
As shown abo e, mos o he immunogene ic s udies on human han a i us in ec ions ha e looked
o associa ions be ween human immunogene ics and disease se e i y. Only ew o hem in es iga ed
ac o s ha could con ibu e o suscep ibili y o han a i us in ec ion. Thei esul s ha e shown ha all
gene ic a ia ions modula ing han a i us in ec ion isk we e also in ol ed in disease clinical se e i y.
Hence, HLA-DRB1*09 and HLA-B*46–DRB1*09 we e mo e common in Chinese pa ien s wi h
HTNV-induced HFRS han in heal hy indi iduals [48,68]. Mo eo e , non-ca iage o he in e leukin-1
ecep o an agonis (IL-1RA) allele 2 and he IL-1b (−511) allele 2 [58] as well as HPA-3 b allele [59]
we e mo e equen in HFRS pa ien s han in se onega i e con ols. These alleles/haplo ypes could
hus be iden i ied as gene ic isk ac o s associa ed wi h he suscep ibili y o han a i us in ec ions [59].
In u n, HLA-B*07 and HLA-DRB1*12 could ha e a p o ec i e ole, espec i ely, agains PUUV
in ec ion in Slo enia [69] and HTNV in ec ion in China [68].
Vi uses 2014, 6 2221
3. Impac o Immuni y-Rela ed Genes on he Risk o Han a i us In ec ion in Roden s
3.1. Kine ics o Immuni y-Rela ed Gene Exp ession Du ing Han a i us In ec ion in Roden s
The kine ics o immuni y- ela ed gene exp ession has been analyzed du ing expe imen al han a i us
in ec ion o se e al oden /han a i us models. As he cou se o in ec ion may di e among
indi iduals [32,33,70], compa ing hese dynamics u ned ou o be ele an o he iden i ica ion o
immunogene ic a ia ions unde lying hese di e ences. Fo now, wo main ques ions ha e been
in es iga ed and a e summa ized below: do a ia ions in immuni y- ela ed gene exp ession media e
sex di e ences in han a i us in ec ions? Do hey explain he pe sis ence o he clea ance o han a i uses in
oden ese oi s?
3.1.1. Immuni y-Rela ed Gene Exp ession and Sex Di e ences in Han a i us In ec ions
Longi udinal s udies in ese oi s o han a i uses ha e highligh ed ha in wild oden popula ions,
mo e males han emales a e in ec ed in ma u e animals only, bu no in subadul , i.e., non-b eeding
ones e.g., [71–74]. Sex-based di e ences in gene exp ession could modula e hese pa e ns in ma u e
oden s. Klein e al. [75] e ealed ha abou 1800 genes wi h known unc ion we e di e en ially
exp essed be ween sexually ma u e male and emale No way a s (Ra us no egicus) a e
expe imen al Seoul (SEOV) in ec ions. Up o 180 we e immuni y- ela ed genes ha showed a pa e n
o up- egula ion in o he lungs o emales compa ed o males. Associa ed unc ions included
in lamma o y (e.g., TNF-α, TNF-αR, IL-1R, IL-1RAcP) and an i i al (eIF-2α, IFN-γR, STAT-6,
(IRF)-1) esponses as well as MHC, Ig and T cell ma ke p o eins [75,76]. In addi ion, gene exp ession
o hea shock p o eins was highe in SEOV in ec ed males han in emales, indica ing a mo e ele a ed
cellula s ess [75]. These s udies he e o e sugges ha bo h di e ences in inna e and acqui ed
immuni y- ela ed gene exp ession could media e dimo phic esponses in oden ese oi s o
han a i us in ec ions.
3.1.2. Immuni y-Rela ed Gene Exp ession and Pe sis ence/Clea ance o Han a i us In ec ions
Han a i uses o en cause an acu e in ec ion ollowed by a pe sis en phase in ese oi oden s.
Howe e , a iable pa e ns o in ec ion ha e been obse ed among in ec ed indi iduals, e en wi hin a
gi en ese oi species. Fo example, Bo en e al. [77] e ealed wo dis inc pa e ns o in ec ion
(based on he le els and he dis ibu ion o i al RNA) du ing he pe sis en phase o SNV in ec ion in
dee mice. Some indi iduals exhibi ed a ― es ic ed‖ pa e n o i al eplica ion and an igen exp ession
(an igen exp ession was o example de ec ed in ewe han h ee o he issues examined), while
o he s showed a ―dissemina ed‖ pa e n o in ec ion (an igen exp ession was obse ed in i e o nine o
he issues examined). S udying he kine ics o oden gene exp ession ollowing han a i us in ec ion
has helped unde s anding hese phenomena. In pa icula , i allowed disc imina ing se e al mechanisms
explaining han a i us pe sis ence, including immune e asion, di ec supp ession o modi ica ion o hos
immune esponses.
The compa ison o cy okine gene exp ession p o iles be ween T cell lines in acu ely and
pe sis en ly in ec ed dee mice e ealed an inc ease o TGF-β and FoxP3 mRNA exp ession and a
Vi uses 2014, 6 2222
dec ease o IL-10 and IL-4 exp ession du ing he pe sis en phase o SNV in ec ion in mos o he lines
s udied [78]. Simila esul s we e ob ained by Eas e b ook e al. [79,80] based on he s udy o he
pe sis en phase o SEOV in ec ion in male No way a s. Inc eased le els o FoxP3 and TGF-β mRNA
exp ession we e obse ed in he lungs o SEOV in ec ed a s compa ed o unin ec ed ones. In con as ,
he le els o IL-10, IL-1b, IL-6 and TNF gene exp ession we e educed. Eas e b ook e al. [80] also
showed using SEOV in ec ed male No way a s ha p oin lamma o y esponses we e ele a ed
(e.g., high exp ession o IL-6, CCL2 and CCL5 genes) and ha egula o y esponses (e.g., exp ession
o TGF-β and Fox-P3) we e no induced in spleens, an immuni y- ela ed o gan whe e han a i us
eplica ion is low. Simila esul s we e obse ed ollowing immuni y- ela ed gene exp ession in spleen
o dee mice in ec ed wi h ANDV [33], al hough esponses we e mo e he e ogeneous among
indi iduals. This was p obably due o he ac ha oden s we e mo e inb ed in his expe imen han in
he one desc ibed abo e. These common modi ica ions o immuni y- ela ed gene exp ession du ing he
pe sis en phase seemed o depend on a concomi an inc ease o egula o T cells. By supp essing
p oin lamma o y esponses, hey could on one hand con ibu e o he ole ance o ese oi s o
han a i us in ec ion and hei associa ed pa hogenesis, and on he o he hand, lead o han a i us
pe sis ence in he hos .
3.2. Immunogene ics and Roden Suscep ibili y o Han a i us In ec ions
3.2.1. Sequence Polymo phism o Immuni y-Rela ed Genes be ween Rese oi and Non-Rese oi
Species and Thei Associa ion wi h Suscep ibili y o Han a i us In ec ion
Roden species exhibi di e en capaci ies as ese oi s o han a i uses. Fo example, han a i us
in ec ions a e supposed o be asymp oma ic and ch onic in hei oden ese oi s, howe e some
oden species a e known o be non- ese oi s o han a i uses. The Sy ian hams e s (Mesoc ice us
au a us) and he house mice o example do no ca y any han a i us in he wild and a e known o
mimic human pa hogenesis o o die when being in ec ed espec i ely wi h ANDV and HTNV see
e e ences in [81]. The ac ha phylogene ically ela ed oden species sha e simila p ope ies
allowing a gi en han a i us o eplica e compa ed o dis an ela ed ones [82] is a i s a gumen
indica ing ha gene ics migh modula e hese a ia ions. In e -speci ic molecula di e ences in he
genes encoding p o eins in ol ed in i us en y in o hos cells a e good candida es o es his
hypo hesis see o example [5].
To da e, no ecep o o han a i uses has been de ined no sugges ed in animal hos species.
Ou cu en knowledge is based on in i o o in i o analyses conduc ed on labo a o y oden species
ha a e no ese oi s o han a i uses. The e o e, mechanisms o i al en y in ese oi animals
emain unknown. Ne e heless, i could be in e es ing o analyse he polymo phism and he
phylogenies o he genes encoding hese ecep o s o o he p o eins. Se e al candida e genes can be
iden i ied om he li e a u e. The gene agmen encoding he plexin–semapho in–in eg in (PSI)
domain o he α β3 in eg in is in ol ed in i al a achmen o se e al pa hogenic han a i uses in
humans [83–87]. Single amino acid changes pe o med h ough mu agenesis we e shown o modi y
han a i us ecogni ion and subsequen in ec ion o cul u e cells. Raymond e al. [86], hen Ma hys e al.
[88] showed ha mu agenizing he mu ine PSI domains o homologous human esidues (subs i u ing
Vi uses 2014, 6 2229
se op e alence) had lowe le els o Mx2 gene exp ession han oles li ing in agmen ed hedge
ne wo ks lowe PUUV se op e alence, highe gene ic d i , see [110]. Again, hese lowe le els o
exp ession may be conside ed o e lec ole ance mechanism agains pa hogens (including PUUV).
Applying immunogene ics o he s udy o M. gla eolus/PUUV in e ac ion in na u al popula ions has
p o ided new a gumen s in a ou o ole ance mechanisms e ol ing in bank oles, di ec ly o
indi ec ly media ed by PUUV. His o ies o hos -pa hogen co-adap a ion, di e ences in bio ic and
abio ic en i onmen al condi ions a e ac o s ha could main ain and shape a ia ion in he ampli ude
o ole ance among bank ole popula ions. These conclusions a e de i ed om co ela i e pa e ns
based on he s udy o ew immuni y- ela ed genes. Genomic app oaches o expe imen al app oaches
will help con i m hese esul s and de ail he mechanisms unde lying ole ance o PUUV and i s
a ia ion o e Eu ope. In u u e, simila s udies should be conduc ed on o he oden /han a i us
models o es i his phenomenon may be gene alized a a la ge e olu iona y scale.
4. Discussion: The E olu iona y Pe spec i es
4.1. Geog aphic Dis ibu ion o Suscep ible Haplo ypes and he Risk o Han a i us Eme gence
As de ailed abo e, he analyses o gene ic a ia ion modula ing he suscep ibili y, han a i us
eplica ion o se e i y o disease, ha e usually been pe o med a he popula ion le el (one locali y o
one coun y) in ese oi s o in humans. Cong uen o incong uen pa e ns may exis when esul s a e
compa ed be ween popula ions. Ne e heless, no o ew lessons ha e been lea ned om hese
compa isons bu see in oden s, [16,104]. To ou knowledge, he e is no eal wish o conduc a
wo ldwide human case s udy. Un il now, esea ch ocused on a single coun y o on a speci ic han a i us.
Including a wide ange o popula ions conce ned wi h one o se e al speci ic han a i uses could p o ide
mo e gene ic conclusions on he ole o immunogene ics on human suscep ibili y o han a i uses.
Fu he mo e, such esea ch would ha e impo an consequences in e ms o public heal h.
In humans, allele equencies a e now a ailable o se e al millions o single nucleo ide
polymo phisms (SNPs) in wo ldwide popula ions [111,112]. These da a ha e been used o e alua e
genome-wide associa ion s udies o many diseases 250 s udies e e enced in 2012, see [18]. I would
be wo h exploi ing hese genomic da a o e alua e he gene ic basis o human suscep ibili y o
han a i us in ec ion a a la ge genomic scale, and o explo e po en ial geog aphic a ia ions
(e.g., be ween he New and Old Wo lds, o be ween Eu opean and Asian coun ies). Ul ima ely, i
could be en isaged o map gene ic isks o HFRS ac oss Eu ope and Asia o HCP in he Ame icas.
These dis ibu ion maps could help a ge ing egions whe e HFRS isk is high bu s ill unde es ima ed
o un ecognized. Such egions would be he i s p io i y o in o ming heal h p o essionals and
de eloping communica ion s a egies o he gene al public.
Compa ison o he geog aphic dis ibu ion o allele equencies o ―neu al‖ SNPs and SNPs ha
a e associa ed wi h suscep ibili y o han a i uses o se e i y o han a i al disease may highligh he
his o ical and selec i e e olu iona y o ces ac ing on hese candida e SNPs and shaping he obse ed
dis ibu ion o polymo phism. Se e al s udies ha e been conduc ed in his amewo k o di e en
immuni y- ela ed genes. Ba ei o e al. [113] conside ed wo inna e immuni y- ela ed genes sha ing
e y close physical icini y (Cd209 and Cd209l). They emphasized ha his o y and selec ion had lead

Vi uses 2014, 6 2230
o di e en ou comes o inna e immuni y- ela ed gene polymo phism. T aces o ancien popula ion
s uc u e in A ica and s ong unc ional cons ain s explained he di e si y o Cd209 gene while
balancing selec ion was likely o gene a e he high le el o di e si y obse ed a he Cd209l gene.
A majo di icul y may eside in he iden i ica ion o he selec ion p essu e ac ing on candida e genes
and shaping he dis ibu ion o hei polymo phism a la ge geog aphical scales see o example in
mammals [96]. Ne e heless, some signi ican examples exis , including he compa a i e e olu iona y
his o ies o halassemia and mala ia [114]. The applica ion o concep s o e olu iona y biology o he
s udy o immunogene ic ac o s a ec ing suscep ibili y o han a i uses o clinical cou se o han a i al
disease in humans should be p omising app oaches in he nea u u e.
4.2. E olu ion o Tole ance in Roden s and I s Epidemiological Consequences
Se e al s udies ha e emphasized he high le el o a iabili y in ese oi suscep ibili y o a gi en
han a i us o in hei abili y o limi han a i us eplica ion [16,104,115]. These esul s may be
in e p e ed in e ms o ole ance o han a i us as some o he molecules in ol ed in his p ocess can
lead o immunopa hologies when o e -p oduced (e.g., TNF-α, Mx2). In u n, his indi idual a iabili y
o ole ance can s ongly impac han a i us epidemiology. Indi iduals exhibi ing high le els o
ole ance will play a majo ole in han a i us pe sis ence, dissemina ion and ansmission dynamics.
Tole ance has neu al o posi i e e ec s on pa hogen i ness [106,116]. Tole an indi iduals may hence
suppo highe i al loads, leading o highe quan i ies o i al pa icles po en ially exc e ed in o he
en i onmen . Such indi iduals migh he e o e be conside ed as supe -sp eade s o han a i us [117].
I appea s impo an o iden i y hese supe -sp eade s wi hin and be ween ese oi popula ions/species.
This would imp o e ou knowledge abou han a i us eco-epidemiology, and ul ima ely would allow o
adap public heal h p e en ion s a egies. I is he e o e c ucial o e alua e he e aci y o ese oi
ole ance o han a i uses and supe -sp eading e en s, o iden i y i s gene ic bases as well as i s
pheno ypic plas ici y. In pa icula , he ole o co-in ec ion has been emphasized o explain some cases
o supe -sp eading see examples in [118]. How and which addi ional in ec ions modula e he quan i y
o han a i us pa icles exc e ed in he en i onmen , and how ese oi immunogene ics migh
in luence he p obabili y o such co-in ec ions h ough an agonis ic pleio opy (i.e., gene ic ade-o s)
a e impo an ques ions o add ess in u u e esea ch.
4.3. Di icul ies o De ine Wha Is a Non-Rese oi Species o Han a i uses
The no ion o non- ese oi species is di icul o de ine because he absence o e idence
(i.e., de ec ion o a i us) is no e idence in i sel .
Non- ese oi species may co espond o species ha ha e ne e been exposed o he i us o
species ha ha e ne e been concei ed as po en ial ese oi s (because o hei axonomic ank o
because o he egions hey inhabi ). Un il ecen ly, han a i uses we e hough o be main ained in
na u e in oden ese oi s om Eu asia and Ame icas solely. Howe e , new han a i us species ha e
been desc ibed in A ican oden s e.g., Sangassou, [119] bu also in small mammals o he han oden s
e.g., Talpidae, So icidae, Chi op e a, see o a ecen e iew [20]. Non- ese oi species may also be
hose ha die ex emely quickly upon in ec ion hence limi ing he p obabili y o de ec ing posi i e
indi iduals in wild popula ions. Finally, non- ese oi species may also conce n hose in which
Vi uses 2014, 6 2231
han a i us could no be able o en e and/o eplica e wi hin cells. In hese wo la e cases, no
han a i us would be de ec ed and he e m ―non- ese oi ‖ would emb ace species highly suscep ible
and highly esis an o he i us.
A las bu no leas di icul y a ises om he ac ha di e en han a i uses may p oduce opposi e
e ec s acco ding o he hos species conside ed. Fo example, Mapo al i us (MAPV), a han a i us
ha was o iginally isola ed om an a bo eal ice a , Oecomys bicolo , causes disease in he Sy ian
golden hams e , Mesoc ice us au a us, ha is clinically and pa hologically ema kably simila o
HCPS [120]. No e ha he e is p esen ly no e idence ha MAPV is pa hogenic in humans.
A e in ec ion wi h ANDV, hams e s also de elop HCPS-like disease ha ai h ully mimics he
human condi ion wi h espec o incuba ion pe iod and pa hophysiology o disease. On he con a y,
he closely ela ed human pa hogen SNV can eplica e in hams e s bu does no cause o e disease
while Old Wo ld han a i uses such as PUUV, HTNV, SEOV, and DOBV only p oduce subclinical
in ec ions [121]. Thus disease and in ec ion ou comes do no seem o co ela e in his animal model
wi h human disease-causing po en ial.
Un il now, oden models such as he golden hams e o he labo a o y mouse a e conside ed as
use ul ones o s udy he pa hogenesis o han a i us disease in humans and o assess he ole o
po en ial he apeu ic agen s. In pa allel, i would be wo h compa ing immunology in ese oi and
non- ese oi species o which oden hos /han a i us in e ac ions lead o adically di e en ou comes.
I could help emphasizing mechanisms and gene ic cha ac e is ics unde lying such di e ences. In
pa icula , un a eling he p ocesses go e ning pe sis en in ec ion and clea ance o he i us in he
na u al hos s could open new a enues o human medical esea ch.
4.4. Di e ences in Han a i us Vi ulence
This e iew delibe a ely ocused on oden ese oi and human immunogene ics. Compa a i e
genomics o han a i uses is an obliga o y coun e pa o ully unde s and ese oi o human/han a i us
in e ac ions and co-adap a ion. Such app oach coupling han a i us sequencing om in ec ed wild
animals and humans could help o sol e some o he un esol ed ques ions conce ning han a i uses,
including he de e minan s o pa hogenici y o hos swi ching, he ecep o o en y in o ese oi cells, e c.
Gene ically and an igenically closely ela ed han a i uses can show la ge di e ences in i ulence.
Recen ly a subdi ision o he DBV in o ou closely ela ed geno ypes was p oposed [119]—Dob a a,
Sochi, Ku kino, and Saa emaa. These geno ypes co espond o di e en phylogene ic lineages, and
display speci ic hos ese oi s, geog aphical dis ibu ion, and pa hogenici y o suckling mice and
humans. Mo e de ailed s udies o hese closely ela ed han a i us geno ypes, causing ei he li e- h ea ening
(Dob a a, Sochi), ela i ely mild in ec ion (Ku kino) o possibly only subclinical human in ec ions
(Saa emaa), could e eal he gene ic de e minan s o i us-hos in e ac ion mechanisms leading
o i ulence.
In addi ion, in i o han a i us in ec ions o cul u ed cells (e.g., Ve o E6, CHO, HUVECs) ha e
sugges ed ha non-pa hogenic han a i uses use β1 in eg in as ecep o o cell en y while he
pa hogenic ones use β3 in eg in [123]. Han a i uses ca ied by he Mic o us- oles, such as Tula i us
(TULV), o Sangassou, which is ha bo ed by he A ican wood mouse, Hylomyscus simus, we e
demons a ed o in ec humans, al hough his seems o be a e [124–126], bu o use β1 in eg in, a leas
Vi uses 2014, 6 2232
in cell cul u e models. This highligh s he needs o be e unde s and he ecep o s used by pa hogenic
o non-pa hogenic han a i uses and he po en ial links be ween hese ecep o s and han a i us
pa hogenici y in humans. Whe he he newly ound sh ew-, mole- and ba -bo ne i uses in ec o he
animals including humans, and i so wi h which consequences, also emains o be elucida ed. By his
way, han a i us compa a i e genomics would help o e eal some o he gene ic de e minan s o
human pa hogenici y.
5. Concluding Rema ks
In summa y, his e iew aimed a highligh ing a numbe o impo an immuni y- ela ed genes ha
seem o be associa ed wi h he clinical cou se o han a i al disease in humans, and he suscep ibili y o
humans and oden s o han a i uses. Beyond his lis , we wan ed o emphasize he necessi y, in he
e y nea u u e, o ―in ec ‖ he classical human immunogene ics app oach bo h wi h e olu iona y
biology and wi h he da ase s p oduced by he human genome p ojec s. This combina ion o
app oaches, he u u e accumula ion o gene ic da a using new gene a ion sequencing echnologies and
genome-wide associa ion s udies, as well as close collabo a ions be ween esea ches de eloped on wild
ese oi s and humans, should ul ima ely imp o e ou knowledge o han a i us isk and epidemiology.
Acknowledgmen s
The au ho s o iginal s udies ha e been pa ly suppo ed by he Eu opean p og ams GOCE-CT-
2003-010284 EDEN and FP7-261504 EDENex , and he pape is ca alogued by he EDENex S ee ing
Commi ee as EDENex 191 (h p://www.edenex .eu). O he suppo s o his wo k include g an s om
The Academy o Finland; Sig id Jusélius Founda ion; Helsinki Uni e si y Hospi al, Hospi al dis ic
o Helsinki and Uusimaa (TYH-2011305) Resea ch Funds; The Compe i i e S a e Resea ch Funding
o he Expe Responsibili y A ea o Tampe e Uni e si y Hospi al; Tampe e Tube culosis
Founda ion; Heal h/Na ional Ins i u e o Alle gy and In ec ious Diseases (NIH/NIAD, U19 AI57319),
INRA-EFPA p oje s inno an s. MP is cu en ly unded by an FRS-FNRS ellowship (Belgian Fund o
Scien i ic Resea ch).
Con lic s o In e es
The au ho s decla e no con lic o in e es .
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