saccharomyces as vaksin candidiasis

8/15/2019 Saccharomyces as Vaksin Candidiasis

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Immunological Investigations, 2012; 41(8): 847-855 ¡nf OriTlí)Copyright © Informa Healthcare USA, Inc. ISSN: 088!0"#$ print % "!'#"( online ) — **)

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Soccharomyces as a VaccineAgainst Systemic Candidiasis

Min LiuJ'^'^ Karl V. ClemonsJ'^'^ Maria E. JohansenJ Marife

Martinez,^ Vicky ChenJ and Daid !. "teens ^'^'^

^California Institute for Medial !esear"# $an %ose# California &5128# '$e*art+ent of Mediine# i,ision of Infetious iseases# $anta Clara alle. MedialCenter# $an %ose# California# &5128 '$^e*art+ent of Mediine# i,ision of Infetious iseases and /eora*"iMediine# $tanford 'ni,ersit.# $tanford# California &405 '$

e "a,e s"o3n "eat-illed Saccharomyces (6) is a *roteti,e ,aine aainst as*er-illosis and oidioido+.osis 9o test t"e ".*ot"esis t"at t"e effia. of 6- indued *rotetion +a. e due to t"e ross-reati,e antiens in t"e ell 3alls oft"e differentfi+i# 3e studied t"e effet of 6 aainst s.ste+i andidiasis Male C-I +ie 3ere

i,en different rei+ens of 6 suutaneousl. *rior to intra,enous "allene 3it"Cania al/icans. Co+*ared to 10^ i,en 4 ti+es *roloned sur,i,?il ( @ 002)# uts"o3ed dose-li+itin to>iit. 6 i,en . an oral route# or . a suutaneous route3it" alu+ as an adAu,ant# did not i+*ro,e sur,i,al B,erall# 3e found t"at 6 *rotets+ie fro+ infetion . Cania al/icans in a dose-and rei+en-de*endent +anner 9ounderstand t"e *rotetion indued . 6 aainst different funal s*eies# additionalstudies of e*ito*e +a**in are 3arranted

2ey3ors antifunal ,aine# andidiasis# Saccharomyces.

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Cania al/icans is t"e +ost o++on ause of in,asi,e funal infetion in "u+ans$.ste+i andidiasis an e let"al and "as inreased sinifiantl. o,er t"e *ast t3odeades due to t"e risin nu+ers of i++unoo+*ro+ised *atients and in,asi,e+edial *roedures (aAAe" et al# 2004) lt"ou" anti-funal drus are enefiial intreat+ent of andidiasis# t"e e+erene of resis-tane and t"e side effets of so+eantifunal drus +ae t"era*. less t"an ideal

A//reviations: 6: "eat-illed .east# : .east e>trat# *e*tone# de>trose# $M:


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9"us# t"ere re+ains a need to de,elo* ,aines# 3it" +ini+al side effets to *atients at ris of de,elo*in s.ste+i andidiasis# 3"i" 3ill indue *rotetion efore t"e disease ours

Bur *re,ious studies s"o3ed t"at ,aination 3it" "eat illed Saccharomycescerevisiae (6) e>"i"ited a ross-*roteti,e effet aainst s.ste+i as*erillosis($te,ens et al# 2010; Eiu et al# 2011a) and oidioido+.osis (Ca*illa et al# 200&)Bur onoin 3or "as *ointed to3ard e. ell 3all l.an o+*onents# ie# luanand +annan# and "o+oloous *roteins# s"ared et3een funi# as i+*ortanto+*onents res*onsile for t"e ross-*rotetion (Eiu et al# 2010; Eiu et al# in *ress;$te,ens et al# 2010; iaF-re,alo et al# 2011) 9"e ross-reati,ities raise t"e

*ossii"t. of stud.in t"e ross *rotetion a+on ot"er funal s*eies and t"usde,elo*in road-s*etru+ ,aine andidates aainst +an. se,ere funalinfetions Indeed# +ost reentl. 3e "a,e also s"o3n 6 *roteti,e aainstr.*tooosis (MaAi+ider et al# 2011) 9"e ai+ of t"is stud. 3as to e>a+ine t"eeffia. of 6 as a ,aine aainst e>*eri+ental +urine s.ste+i andidiasis

MATERIALS AND METHODS

Heat!2ille 4east 5accineseat-illed# endoto>in-free (Eiu et al# 2011a) S. cerevisiae ,aine *re*ara-

tions 3ere +ade as *re,iousl. desried (Ca*illa et al# 200&) and e*t at 4GC 10^ or 12 > 10^ illed .easts 6 3as i,enon a s"edule of da. 28# 21# and 14 (6 >); 5# 28# 21# and 14 (6 4>); or 4 42# 5# 28# 21# and 14 (6 =>) da.s efore "allene 3it" Cania


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"accharomyces Protection Versus Candidiasis )*+

InfectionMie 3ere infeted 3it" C. al/icans strain L5# as desried *re,iousl.

(Morrison and $te,ens# 1&&0; anson et al# 1&&1; Cle+ons and $te,ens# 2001)9"e froFen strain 3as re,i,ed on $ and a sinle olon. 3as inoulated into$M "rot" ($.nt"eti +ino id Mediu+-unal)(oe*ri" and inn#1&72) as desried (Morrison and $te,ens# 1&&0; anson et al# 1&&1; Cle+onsand $te,ens# 2001) Cells 3ere 3as"ed . entrifuation at 200 > g t"ree ti+es3it" saline# ounted and ell nu+ers 3ere adAusted to t"e desired nu+ere*endin on t"e stud.# ea" +ouse 3as "allened intra,enousl. 3it" 2 >

10^ to 575 10^ ,iale Cania in saline

Survival Analysis

Mie 3ere "eed for sur,i,al dail. for 14 or 1= da.s after infetion 9oassess se,erit. of infetion in sur,i,ors# tissue urdens in all sur,i,in +ie3ere deter+ined on da. 14 or 1= as *re,iousl. desried (anson et al# 1&&1;Cle+ons and $te,ens# 2001) $tatistial o+*arisons of sur,i,al 3ere *er-for+ed . lo ran test unal tissue urden 3as anal.Fed . a non*ara+etriMann-"itne. '-test usin /ra*"ad 0 for indo3s or statistial o+*ar-

isons of C'# an aritrar. ,alue of loio 75 C' 3as assined to data *oints+issin due to t"e deat" of an ani+al fro+ infetion (Ea"in# 1&&&; $"i"# 2002)9"is ,alue is "i"er t"an t"at reo,ered fro+ an. sur,i,in +ouse# assures deat"is assined a 3orse outo+e t"an sur,i,al 3it" an. urden# and a**ro>-i+atest"e C' *resent in t"e oran Aust *rior to deat"# as deter+ined *re-,iousl.(Morrison and $te,ens# 1&&0; anson et al# 1&&1; Cle+ons and $te,ens# 2001)In so+e e>*eri+ents no C' 3ere deter+ined eause t"e +aAorit. of +ie diedafter infetion; t"us# t"e nu+er of sur,i,in +ie 3as not lare enou" to eale to detet sinifiant differenes in funal load

RESULTS

Preliminary Studies

In t3o initial studies# +ie 3ere "allened 3it" onl. (2—24) > 10^ C.al/icans ells *er +ouse Co+*ared to o+*ared 3it"


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+odel 3ere neessar. to +ore learl. deter+ine 3"et"er 6 ,ainationindued *rotetion

i/h Lethality "tudies

*roloned sur,i,al ( @ 0028 and 0005# res*eti,el.)(i l) C'reo,ered fro+ t"e idne.s of sur,i,in 6 4> ,ainated +ie 3ere redued,ersus


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) M. Liu et al.

6 s"o3s +ore effeti,e *rotetion *er ,aine dose aainst t"e latter infe-tions# 3"ere doses of = > 10^ *ro,ide near +a>i+al *rotetion (Ca*illa et al#200&; Eiu et al# 2011a) 6 ,aination aainst andidiasis usin = > 10^.easts i,en => resulted in etter outo+e t"an t"e sa+e dose i,en or 4 ti+esin *rolonin sur,i,al# ut did not indue a le,el of *rotetion suffiient to

*re,ent deat"s or e urati,e 9"is dis*arit. on ,aine effia. +a. suestt"at t"e ross-reati,e *roteti,e o+*onents et3een Saccharomyces andCania +a. e less aundant t"an et3een Saccharomyces and Aspergillus or Cocciioies, andor "ost reonition and defense +e"anis+s aainst andi-diasis +a. e different fro+ t"at of as*erillosis and oidioido+.osis efound in t"ese studies t"at inreasin t"e dose of 6 t3ofold to 12 > 10^ ellsi,en 4> +a. i+*ro,e ,aine effia.# ut also +a. e an u**er li+it of doseand lose to t"e t"res"old of to>iit. urt"er+ore# a "i"er dose of 12 > 10^6 i,en 4> s"o3ed e,en reater let"al to>iit. *rior to infetion In ontrast#all ot"er s doses of 6 i,en 4 or +ore ti+es 3ere effeti,e in reduinC' in o+*arison to t"e *eri-+ental andidiasis (9orosantui et al# 2005; Cassone# 2008; er3erda et al#2010) lt"ou" "ost defense aainst andidiasis is de*endent on 3"ere t"einfetion ours (idel et al# 1&&7; Conti et al# 200&)# 9"l7 ells and IE-17 arei+*liated in *roteti,e res*onses aainst +uosal andidiasis and in t"e,aine-indued res*onse to s.ste+i andidiasis# . en"anin *"ao^osisand illin . neutro*"ils (uan et al# 2004; Conti et al# 200&; Ein et al#200&) Bur results fro+ +ulti*le .toine sreenin s"o3ed t"at 6 ,aina-tion triered *rodution of t"e *roinfla++ator. .toines# inludin IE-17(Eiu et al# 2011)# 3"i" +a. in turn +ediate a s*eifi ada*ti,e i++uneres*onse leadin to "ost defense aainst s.ste+i andidiasis (Ein et al# 200&)

9"us 3e "a,e found t"at 6 ,aination indues an antiod. res*onse


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"accharomyces Profecfion Versus Candidiasis )<

aainst s.ste+i andidiasis 9"ese *re,ious studies (Eiu et al# 2011) 3ere *erfor+ed 3it" t"e less intense ,aine rei+ens useful for a+elioratin as*er-illosis or oidioido+.osis# and as an altered i++une *rofile +a. "e enen-dered 3it" +ore intense rei+ens# and t"ere +a. e differenes in t"e different+ouse strains studied# re*eated i++unoloial studies in t"e *resent stud.onditions ould i,e additional insi"ts into t"e +e"anis+s of resistane

B,erall# t"ese studies de+onstrate t"at "eat-illed .east of Saccharomycescerevisiae ad+inistered as a ,aine is *roteti,e for C-I +ie aainst e>*eri-+ental s.ste+i andidiasis; it 3ould e of interest to deter+ine 3"et"er ,aination 3it" 6 3ould also *rotet aainst +uosal infetion 3it"Cania, sine t"is is anot"er i+*ortant linial entit. (e# ,ainitis) 9"eseresults# in o+ination 3it" t"ose fro+ studies 3it" as*erillosis# oidioido-+.osis (Ca*illa et al# 200&; $te,ens et al# 2010; Eiu et al# 2011a) and studiesalso indiatin effia. aainst r.*tooosis# suests t"e *ossiilit. of a

*anfunal ,aine andidate aainst funal infetion usin 6 or . enerat-in a deri,ati,e of 6# *artiularl. a l.an-onAuated *rotein ,aine t"at+i+is 6 ation it" reard to furt"er use of 6 itself# .east-ased,aines are safe in +an (iMieli et al# 200=)# and initial studies 3it" "eat-illed Saccharomyces "a,e s"o3n tolerane to t"is ,aine in aner *atients

(Eu et al# 2004; ranFusoffet al# 2005; Munson et al# 2008)

Declaration of Interest: Wo e>ternal fundin 3as reei,ed for t"ese studies 9"eaut"ors "a,e no onflits of interest 9"e aut"ors alone are res*onsile for t"eontent and 3ritin of t"e *a*er

&EPE&E$CE"


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Cutler# % ?# ee*e# / $# %r# 6lein# ev. 6icro/iol. 5:1—28

iaF-re,alo# # on# 9 trat-*rotein

onAuates indue a *roteti,e i++une res*onse aainst e>*eri+ental andidiasis ;. Infect. +is. 17&:1477-1484

anson# E # erl+an# M# Cle+ons# 6 # $te,ens# (1&&1) $A+er. et3eenilofunin and a+*oteriin < in a +urine +odel of andidiasis Antimicro/. AgentsChemother. 5:14-17

oe*ri# # inn# (1&72) Bfusation ofte ati,it. of antifunalinti+irois . ulture +edia ;. Infect. +is. 12=:5-=1

uan# # Wa# E# idel# E# $"3arFenerer# (2004) !eNuire+ent of interleuin-17 for s.ste+i anti!Cania al/icans ost defense in +ie % Infect. +is. 1&0:

=24-=1Ea $ala# # 'rani# # 9orosantui# # Cassone# # usiello# C M (1&&=)

Manno*roteins fro+ Cania al/icans eliit a 9"-tr*e-l .toine *rofile in "u+anCania s*eifi lon-ter+ 9 ell ultures ;. ?iol. >egul. Homeost. Agents 10:8-12

Eain# % M (1&&&) orst-ran sore anal.sis 3it infor+ati,el. +issin oser,ationsin linial trials Control Clin. @rials 20:408-422

Ein# E# Ira"i+# $# u# # Yrer# % M# ,anesian# #


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*er+ission o3e,er# users +a. *rint# do3nload# or e+ail artiles for indi,idual use

saccharomyces as vaksin candidiasis

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