The Zoonosis and Mutation of Malaria

Featuring: Plasmodium knowlesi

Jingyi Jiang
April 21, 2014
MICRB 201H
Porter
Malaria is one of te !iggest pu!li" ealt "on"erns in te #orl$% Classifie$ as one of te
&Big 'ree( infe"tions tat togeter a""ount for one out of e)ery ten $eats #orl$#i$e, tis
parasite infe"ts appro*i+ately 200 +illion people ea" year an$ lea)es so+e ,%4 !illion oters at
ris-% 'e C.C esti+ates tat o)er /00,000 people, +ost of #o+ are young "il$ren less tan
fi)e years ol$, $ie fro+ tis $isease e)ery year% Resear" is un$er #ay to fin$ out +ore a!out
!ot te !iologi"al +e"anis+s an$ te e)olution of +alaria in opes of e)entually $e)eloping
+ore effe"ti)e +eto$s of figting it%
Malaria Pathogenesis
It #oul$ !e unfair to #rite a paper a!out +alaria #itout first a"-no#le$ging its long an$
"o+ple* life "y"le0 parasites in te genus Plasmodium a)e tree $istin"t stages tat ta-e pla"e
in $ifferent lo"ations% In 1114, .r% 2ouis H% Miller su++ari3e$ te patogenesis of +alaria an$
$es"ri!e$ te tree life stages: te sporogoni" "y"le, e*o4erytro"yti" "y"le, an$ te erytro"yti"
"y"le% .uring te sporogoni" "y"le, +alaria ga+eto"ytes tat are ingeste$ !y a +os5uito
"o+!ine an$ se*ually repro$u"e in te gut to +a-e ollo# oo"ytes fille$ #it sporo3ites% 'e
sporo3ites are release$ fro+ sali)ary glan$s #en te +os5uito fee$s on a ne# ost% 'ese
sporo3ites ten ta-e up resi$en"e in te li)er, #ere tey stay insi$e epato"ytes 6li)er "ells7 an$
+ultiply ase*ually to !e"o+e s"i3onts, #i" later release +ero3oites% .uring tis "y"le te
patogen $oes not "ause any sy+pto+s%
After an in"u!ation perio$ of aroun$ one #ee-, tousan$s of tese organis+s !urst out of
te li)er "ells an$ !egin te erytro"yti" "y"le in te !loo$strea+% 8en tey "o+e into "onta"t
#it erytro"ytes, ligan$s tat are use$ for !in$ing erytro"yte re"eptors are release$ fro+ t#o
types of organelles in te patogen: roptries an$ +i"rone+es% 'e +ero3oites +ay +ature into
tropo3oites after entering te re$ !loo$ "ells, #i" #oul$ "ause te "ell to rupture an$ release
+ore of te +ero3oites% 'e patogens "oul$ also $e)elop into ga+eto"ytes #itout lysing te
"ell an$ !e "onsu+e$ !y +os5uitoes #ere tey #oul$ start te "y"le again 6Miller, et al%, 11147%
All spe"ies of +alaria follo# so+e )ersion of tis "y"le, altoug tere are so+e sligt
)ariations tat $istinguis one strain fro+ anoter%
Fig% 1: A grapi" representation of te +alaria parasite9s life "y"le 68in3eler 200:7
P. knowlesi
;ne of te "o+pli"ations of fin$ing a "ure for +alaria is te seer $i)ersity of te
Plasmodium genus% 'ere are o)er one un$re$ spe"ies of tis proto3oa tat infe"t !ir$s, reptiles
an$ +a++als% ;nly fi)e +ain spe"ies of +alaria are -no#n to infe"t u+ans: Plasmodium
falciparium 6#i" "auses infe"te$ erytro"ytes to sti"- to !loo$ )essel surfa"es until tey
e*plo$e7, P. vivax 6#i" as a latent li)er stage, allo#ing it to stay i$$en longer7, P. ovale, P.
malariae, and P. knowlesi.
Altoug tis +ay not see+ li-e +u", ne# e)i$en"e of e+erging 3oonoti" +alaria,
along #it te $is"o)ery of $rug4resistant proto3oan strains, +ay in$i"ate tat te parasite is
e)ol)ing an$ !e"o+ing +u" +ore patogeni"% P. knowlesi 6te fift u+an Plasmodium
spe"ies7 #as re"ently $is"o)ere$ to !e a signifi"ant "ause of +alaria in u+ans% It #as originally
tougt tat its +ain osts #ere M. fascicularis an$ M. nemestrina +on-eys an$ tat it "oul$
only infe"t u+ans un$er spe"ifi" e*peri+ental "on$itions% 'e first natural o""urren"e of P.
knowlesi in u+ans #as reporte$ in 11/<, an$ a se"on$ "ase #as suspe"te$ in 11=1 in te sa+e
region 6>antele an$ Jo-iranta, 20117% ?o oter "ases #ere reporte$ until Bal!ir @ing $is"o)ere$
in 2004 tat <:A of te "ases of +alaria in te Malaysian Borneo #ere a"tually "ause$ !y tis
strain% 'is parasite is no# !e"o+ing espe"ially "o++on in @outeast Asia !e"ause
$e)elop+ent an$ $eforestation are !ringing u+ans into "loser "onta"t #it +a"a5ue +on-eys%
Interestingly, a u+an4to4u+an infe"tion pat#ay as not yet !een esta!lise$ an$ it see+s tat
u+ans "an only "ontra"t tis strain if tey are !itten !y +a"a5ues or !y +os5uito )e"tors tat
"arry te +on-ey parasite 6Antinori, et al%, 201,7% P. knowlesi is terefore "onsi$ere$ a
&3oonoti"( $isease%
'is proto3oan $istinguises itself fro+ oter pri+ate strains of +alaria !e"ause it as a
)ery fast 244our ase*ual erytro"yti" "y"le 6Antinori, et al%, 201,7% 'is results in ig $ensities
of parasites in te !loo$ in a )ery sort ti+e i++e$iately after its in"u!ation perio$, #i" "oul$
!e $ea$ly if not treate$ 5ui"-ly%
P. knowlesi is also te first +alaria proto3oan in #i" antigeni" )ariation #as foun$%
'is +a-es it parti"ularly pro!le+ati" !e"ause re$ !loo$ "ells typi"ally "ange teir antigeni" or
a$esi)e properties in "ertain #ays #en tey !e"o+e infe"te$ so tey "an !e $ispose$ of !y
#ite !loo$ "ellsB o#e)er, tis strain of +alaria "an )ary te +e+!rane proteins of infe"te$
erytro"ytes to a)oi$ i++une $ete"tion 6@u, et al%, 111<7%
'e "o+plete P. knowlesi geno+e #as se5uen"e$ 200: 6Antinori, et al%, 201,7% 'is
pro)i$e$ enoug infor+ation for resear"ers to "on"lu$e tat its "losest relati)e is P. vivax% It
#as also $is"o)ere$ tat tis parasite is $ifferent fro+ oter +alaria proto3oans !e"ause it as
+any C4C repeats in its nu"lei" .?A 6Pain, et al%, 200:7% 'ese regions "ontain
intra"ro+oso+al telo+eri" se5uen"es 6I'@s7, #i" are tougt to ser)e as re"o+!ination
te+plates for gene "on)ersion 6#en one gene repla"es a o+ologous se5uen"e so tat te
se5uen"es !e"o+e i$enti"al7 a+ong "ertain antigen genes% 'ey +ay also elp #it
trans"riptional "ontrol% 'ere are se)eral oter pe"uliarities spe"ifi" to te P. knowlesi geno+e
a!out #i" little is -no#n, sin"e s"ientists a)e only re"ently !egun to stu$y te+ in $etail%
It is also si+ilar to P. vivax in tat it atta"es to te .uffy !loo$ group antigen on te
surfa"e of erytro"ytes in or$er to in)a$e te "ells% Its .uffy4!in$ing $o+ain in"lu$es "ystein
resi$ues an$ a C<4C: region tat !in$s #it re$ !loo$ "ells0 all of tis is "on"eale$ insi$e an
api"al organelle "alle$ a +i"rone+e so it is not e*pose$ to i++une "ells in te !loo$strea+, an$
is release$ only #en te +ero3oite "o+es into "onta"t #it an erytro"yte 6Miller, et% al, 11147%
8itout te gene tat "o$es for te .uffy4!in$ing proteins, te parasite is "o+pletely una!le to
in)a$e u+an "ells 6Antinori, et al%, 201,7% It is interesting to note tat P. knowlesi is responsi!le
for te +aDority of +alaria "ases in @outeast Asia !ut is al+ost "o+pletely a!sent in Afri"aB
tis +ay !e !e"ause +ost people in te "ontinent are .uffy4negati)e0 tey $o not a)e te .uffy
antigen tat !in$ P. vivax an$ P. knowlesi.
'e fa"t tat P. knowlesi "an Du+p fro+ one spe"ies to anoter e)en toug it #as
originally tougt to rarely infe"t u+ans, is rater "on"erning !e"ause of te potential for it to
$o a &ost4s#it"( 6Antinori, et al%, 201,7 an$ !e"o+e trans+issi!le a+ong u+ans% If tis
parasite gains te a!ility to perfor+ u+an4+os5uito4u+an trans+ission, it is )ery li-ely tat it
#oul$ no longer re+ain lo"ali3e$ an$ #oul$ sprea$ into ig4touris+ areas in Asia 6>antele an$
Jo-iranta, 20117% 'ere is also te possi!ility tat strains #i" "urrently infe"t oter apes, "oul$
$e)elop te a!ility to Du+p to u+ans% In fa"t, analysis of o)er 1,000 gene se5uen"es fro+
)arious apes $e+onstrate$ tat P. falciparum 6te +ost se)ere for+ of +alaria, a""or$ing to te
8orl$ Healt ;rgani3ation7 a$ originate$ in gorillas !efore it infe"te$ u+ans 62iu, et al%,
20107% 'ese apes +ost li-ely ser)e$ as reser)oirs for u+an P. falciparum until se)eral un$re$
tousan$ years ago, #en one strain of tis parasite $i)erge$ an$ #as a!le to !e trans+itte$ fro+
one u+an to anoter troug a +os5uito )e"tor%
Fig% 2: Bot P. falciparum an$ P. knowlesi +ost li-ely originate$ fro+ non4u+an pri+ate reser)oirs% 6Hall 20127
But o# "an a $isease !e"o+e trans+issi!le to +ore tan one spe"iesE ?ot +u" is
-no#n a!out te +ole"ular +e"anis+s tat allo# +alaria to "ross spe"ies !arriers0 o#e)er, it
as !een foun$ tat +os5uitoes play a large role in $eter+ining #i" ost te parasite #ill
infe"t% Mos5uitoes ser)e as &!ri$ge )e"tors( of +alaria !et#een u+an an$ non4u+an pri+ates
6Ferulst, et al%, 20127% Certain spe"ies of +os5uitoes "oul$ !e infe"te$ #it P. knowlesi
ga+eto"ytes in te !loo$strea+, #ile oters are refra"toryBte parasite $oes not repro$u"e
insi$e te+% 'e sus"epti!le +os5uitoes also a)e "ertain preferen"es 6!ase$ on !o$y o$or,
"ar!on $io*i$e pro$u"tion, s#eat glan$ $istri!ution, et"%7 for te apes tey fee$ on% In te en$,
te "o+!ination of +os5uito sus"epti!ility an$ fee$ing preferen"es "oul$ result in "ertain spe"ies
of pri+ates !eing infe"te$ !y "ertain spe"ies of +alaria%
Treatments and Resistance
Rigt no#, te +ost effe"ti)e treat+ents for P. knowlesi are te sa+e $rugs tat are use$
for P. falciparum $uring teir erytro"yti" stageB"loro5uine an$ pri+a5uine% 'e e*a"t
+e"anis+ of te "loro5uine4proto3oan intera"tion is un-no#n, !ut a stu$y #as $one in 11=2
to i$entify te #ays tat "loro5uine affe"t te parasites% It #as foun$ tat te "on"entration of
te $rug in solution $e"rease$ #en it #as e*pose$ to +alarial .?A, an$ tat te presen"e of
"loro5uine prote"te$ .?A fro+ $egra$ing at ig te+peratures 6suggesting tat tere #as
!in$ing going on7% 'e resear"ers "on"lu$e$ tat tis $rug ten$e$ to target te .?A of P.
knowlesi% Gpon furter in)estigation, it #as foun$ tat as "loro5uine #as in"orporate$ into te
geno+e, it $isrupte$ te !in$ing of ,H4a$enosine into .?A an$ R?A, as #ell as te
in"orporation of 14C4isoleu"ine into protein an$ te for+ation of la"tate $uring "ellular
respiration 6Cutteri$ge, et al%, 11=27% Ho#e)er, te +ain effe"t of "loro5uine still see+s to !e
$ue to its intera"tion #it .?ABall te oter pro"esses #ere affe"te$ to te sa+e e*tent an$
#ere +ost li-ely results of te geneti" +o$ifi"ation%
'is treat+ent #or-s #ell for P. knowlesi an$ +ost for+s of P. falciparum0 o#e)er, it9s
un-no#n if tis #ill "ontinue to !e true in te long run% 'ere a)e !een +any "ases of
"loro5uine4resistant P. falciparum an$ tis is !e"o+ing +ore "o++on as te $rug is !eing
pres"ri!e$ +ore% ?on4resistant proto3oans ten$ to a""u+ulate large a+ounts of "loro5uine tat
later intera"t #it teir .?A% Resistant patogens a)e !een foun$ to release te $rug as it is
a!sor!e$B tey re+o)e it 40 to <0 ti+es faster tan te sus"epti!le parasite "an 6>rogsta$, et
al%, 11:=7%
It as !een foun$ tat resistant proto3oans a)e a +utant "loro5uine resistan"e
transporter 6PfCR'7, #i" allo#s te +ero3oites to pu+p te $rug out of teir $igesti)e
)a"uoles 6H"-er, et al%, 20127% Cal"iu+ "annel !lo"-ers, o#e)er, a)e !een so#n to interfere
#it te a"tion of tis transporter, slo#ing te release an$ in"reasing te a""u+ulation of te
$rug !y resistant 6!ut not sus"epti!le7 P. falciparum 6>rogsta$, et al%, 11:=7% 'is ser)es as +ore
e)i$en"e tat te +utant transporter is not present in te original +alaria strain, !ut e+erge$
troug so+e sort of "ange in its geno+e%
But #y $oes tis +atterE Mutations in +i"roorganis+s "an often +a-e te+ +ore
patogeni" an$ !etter suite$ to teir en)iron+ent% Gn$erstan$ing te 3oonosis of +alariaBo#
it +utates to !e a!le to sur)i)e in a $ifferent ostB+ay elp us learn +ore a!out o# te
parasite a$apts an$ !e"o+es resistant to $rugs% P. falciparum +utate$ in or$er to $o a ost4
s#it" fro+ gorillas to u+ans, an$ is no# +utating to !e"o+e resistant to one of our +ost
po#erful anti4+alarial $rugs% As of no#, tere as !een no e)i$en"e for $rug resistan"e in P.
knowlesi% But is possi!le tat tis e+erging $isease "oul$ follo# a si+ilar pat, $rasti"ally
e*pan$ing its geograpi"al range an$ !e"o+ing a +u" !igger pu!li" ealt "on"ern 6Antinori,
et al%, 201,7%
Future Perspectives
@o far not +u" is -no# a!out te e*a"t +e"anis+s of sus"epti!ility to "loro5uine in
P. falciparum% Resear"ers are trying to fin$ out o# "ertain strains of +alaria first !e"a+e
resistant to "loro5uine0 tis +igt !e applie$ to oter spe"ies of +alaria to try to pre)ent $rug
resistan"e in te future% 'ere is also resear" !eing $one on te purpose of intra"ro+oso+al
telo+eri" se5uen"es an$ oter uni5ue aspe"ts of te P. knowlesi geno+e% 'ese se5uen"es "oul$
pro)i$e "lues a!out te 3oonosis or patogeni"ity of tis parasite%
In a$$ition, it see+s rater $iffi"ult to fin$ resear" a!out te spe"ifi" +utations in te
+alaria proto3oa tat allo# "ertain strains to "ross spe"ies !arriers% 8at is te pysiologi"al
$ifferen"e !et#een te preistori" P. falciparum tat "oul$ only infe"t gorillas, an$ te "urrent
P. falciparum tat affe"ts !ot gorillas an$ u+ansE Ho# $oes P. knowlesi "ange, on a
+ole"ular le)el, to !e a!le to sur)i)e in u+ans after a)ing li)e$ in +a"a5ues for so longE
Ans#ering tese 5uestions "oul$ elp us un$erstan$ elp us not only +alaria !ut also +any
oter +aDor patogens tat "oul$ a)e non4u+an reser)oirsBin"lu$ing te oter t#o &Big
'ree( $iseases% 'ere is no $ou!t tat +utations in +alaria proto3oa tat allo# te+ to !e"o+e
3oonoti" or $rug resistant a)e signifi"ant i+pli"ations for pu!li" ealt, an$ #oul$ !e an
i+portant area to resear" in te future%
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