Trade-offs, conflicts of interest and manipulation in Plasmodium–mosquito interactions

TRENDS in Parasitology Vol.17 No.4 April 2001

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189ReviewReview

Alex Schwartz

Dept of Zoology, AarhusUniversity,Universitetsparken B135,DK-8000 Aarhus,Denmark.e-mail: [email protected]

Jacob C. Koella*

Laboratoire d’Ecologie,Université P. & M. Curie,CNRS UMR 7625, 7 quaiSt. Bernard, F-75252 Paris,France.*e-mail:[email protected]

Evolutionary forces tend to increase the reproductivesuccess of any organism – in the case of mosquitoes,this means that we expect fecundity per gonotrophiccycle and adult lifespan (and thus, the number ofgonotrophic cycles) to be maximized. However,mosquito fecundity and lifespan will generally not beable to evolve independently of each other, but ratherwill be negatively correlated. Thus, mosquitoevolution is constrained by a trade-off between thesetwo parameters1, resulting in a life-history strategythat is close to the optimal compromise between highfecundity and long life (Box 1).

One trade-off between reproduction and survivalresults from the requirement of blood for eggdevelopment, and particularly from the strongcorrelation between the amount of blood imbibed by amosquito and its fecundity. Bloodfeeding, however,increases the risk of mortality in at least two ways.First, the act of feeding is itself a risk, as irritationfrom the mosquito bite might elicit defensivebehaviour by the host, with the result that mosquitoesare killed while feeding or trying to feed2,3. Second,blood-fed mosquitoes are obvious, nutritious andclumsy prey, and are therefore more likely to be killedby predators than are unfed mosquitoes. Althoughdata on mosquitoes are lacking, the predation rate byinsectivorous birds on engorged and on unfed tsetsefollows this expected pattern4. Either of these costs ofbloodfeeding implies that increased fecundity, whichcan only be achieved by increased bloodfeeding, willincur a higher risk of mortality.

Such trade-offs impose a constraint on theevolution of the bloodfeeding strategy of mosquitoes

(Box 1). Because of the host’s defensive response, amosquito can spend only a limited time on any givenhost before it is scared away, and will therefore notalways be able to complete its bloodmeal. How muchshould it risk in its attempt to obtain a full bloodmeal?Obviously, it will return for a second bite only if theadditional fecundity it gains from doing so more thancompensates the risk of being killed in the attempt.Therefore, if the mortality associated with feeding islow or fecundity increases strongly with additionalblood, mosquitoes should tend to obtain multiplemeals5. Indeed, multiple meals are quite often foundin natural mosquito populations6–8, includingAnopheles9. (The factors responsible for multiplefeeding were not investigated in these studies. Otherecological or physiological factors, such as proximityto potential hosts10 or a circadian biting rhythm11,might also contribute to the frequency of multiplefeeding.)

Manipulation of the host by the parasite

How will these trade-offs affect a malaria parasitedeveloping within its mosquito vector? One mightassume that the biting rate that is optimal for themosquito is also optimal for the parasite, as theparasite shares some interests with the mosquito. Itis in the interests of both partners that the mosquitosurvives for a long time (at least until infectioussporozoites have developed) and that it then bitesfrequently. However, because of the trade-offsbetween feeding behaviour, fecundity and mortality,some of the parasite’s interests conflict with those ofthe mosquito. Therefore, the parasite should try tomanipulate the mosquito’s feeding behaviour and lifehistory to increase its transmission.

Oocysts decrease mosquito biting and fecundityAt the oocyst stage, the sole interest of the parasite isthe mosquito’s survival, as the sporozoites that could betransmitted by the mosquito’s bite have not yetdeveloped. Because of the trade-offs alreadymentioned, this would mean that the parasites shouldtry to manipulate a mosquito in at least two ways.First, they should try to prevent the mosquito frombiting, as risky biting behaviour decreases thelikelihood that the mosquito will survive thedevelopmental period of the parasite, but does not yet

A long-held view among parasitologists is that infection by malaria parasites

does not harm the mosquito vector. One of the reasons for this belief is that the

two partners of the association share interests in the most important life-

history traits of the mosquito. Both partners benefit from increased survival

and an increased rate of bloodfeeding – the mosquito to increase its

reproductive success and the parasite to ensure its transmission. Problems

with this line of reasoning appear when one considers possible trade-offs

among the mosquito’s life-history parameters, which constrain the attempts by

the mosquito and the parasite to maximize their success. Could these

constraints differ between the two partners and thus lead to conflicts of

interest and what would be the evolutionary and epidemiological

consequences of conflicting interests? These questions will be investigated

below.

Trade-offs, conflicts of interest and

manipulation in

Plasmodium–mosquito interactions

Alex Schwartz and Jacob C. Koella


http://parasites.trends.com

190 Review

benefit the parasite in terms of transmission. In theonly published report of an experiment investigatingthis question, this is indeed what occurred: thepersistence with which Anopheles stephensimosquitoes attempt to feed on a human host isdecreased if they are infected with oocysts of theparasite Plasmodium yoelii nigeriensis12 (Fig. 1a). Ofcourse, one can argue that the decrease in persistenceis an accidental by-product of infection. It seems morelikely, however, that it is the result of activemanipulation by the parasite, as the effect ofsporozoites is in the opposite direction (see laterdiscussion). Second, the parasite should try to reducethe mosquito’s fecundity, as increased fecundity mightdrain resources that could otherwise be used forsurvival, and laying eggs might increase the risk ofmortality. Again, this prediction has been confirmedwith Aedes aegypti infected with Plasmodium

gallinaceum13, with An. stephensi infected withP. y. nigeriensis14,15 and with Anopheles gambiaeinfected with Plasmodium falciparum16. In all threesystems, infected individuals produce fewer eggs thanuninfected individuals (Fig. 1b). The mechanismbehind this phenomenon is not yet clear. Again, it ispossible that the reduced fecundity is an accidental by-product of infection. A further possibility is thatreduced fecundity is the result of a trade-off with theimmune response of the mosquito (see below). It is,however, attractive to speculate that the parasitesactively manipulate the vitello-endocrine system of themosquito to reduce its fecundity.

Sporozoites increase probing period and frequencyAt the sporozoite stage, the parasite appears morelikely to share its interests with the mosquito, as bothrely on the mosquito’s biting for their success.

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Trade-offs and constraints in the lifehistory of a mosquito can lead to a conflictof interest for the frequency ofbloodfeeding by the mosquito, as can beshown by a simple model of the host’sreproductive success and the parasite’stransmission successa. The question wefocus on here is the following: oncesporozoites have invaded the salivaryglands (and are thus infectious), what isthe optimal biting rate for mosquitoes andparasites? In other words, what is thebiting rate that maximizes thereproductive rate of the mosquito and thetransmission rate of the parasite over therest of the mosquito’s lifespan?

One of the most important constraintsis that biting is risky. Let us assume thateach biting attempt incurs the same risk ofbeing killed. Then, the mosquito’smortality increases with its biting rate as µ = µ0(1 + a) (i.e. the background mortalityis µ0 and the mortality induced by biting isµ0a), where a denotes the biting rate and µis the daily mortality of the mosquito.

Accordingly, an adult mosquito has anexpected lifespan of 1/µ0(1 + a) (Fig. Ia).

The mosquito’s reproductive successcan be written as the product of its lifespanand the number of eggs it lays per day. Thelatter is likely to be influenced by the bitingrate, as it is determined by the size of thebloodmeal, which will increase with thenumber of times the mosquito bites. Thefunction f (a) that relates fecundity andbiting rate is likely to increase less thanlinearly with biting rate (Fig. Ib), as fullyfed mosquitoes cannot increase theirfecundity by additional biting. The lifetimereproductive success:

then has an optimum at an intermediatebiting rate (Fig. Ic).

Similarly, the parasite’s lifetimetransmission success is given by theproduct of its transmission rate and themosquito’s life span. As each bite (oncesporozoites have invaded the salivary

glands) can be infective, transmission ratecan be expected to increase more or lesslinearly with biting rate (Fig. Id). Therefore,lifetime transmission success will beproportional to:

which is maximized at the highest possiblebiting rate (Fig. Ie).

The conclusion that the parasite’ssuccess is maximal at a higher biting ratethan is the host’s is rather robust tochanges in the assumptions about therelationship between biting rate, mortality,fecundity and transmission, as long astransmission increases more rapidly thanfecundity with biting rate.

Reference

a Koella, J.C. (1999) An evolutionary view of theinteractions between anopheline mosquitoesand malaria parasites. Microbes Infect. 1,303–308

Fig. I. Effects of biting rate on mosquito reproductivesuccess and parasite transmission success.

Box 1. Conflicts of interest between mosquitoes and malaria parasites

Bites per nightBites per night Bites per night Bites per night Bites per night

(a) (b) (c) (d) (e)

TRENDS in Parasitology

Tota

l tra

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issi

on

Life

spa

n

Fec

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ty

Tota

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n

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0 aaf

R m +µ=

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R m +µ=

[1]

[2]



191Review

However, the parasite places more emphasis onbiting, whereas the mosquito is more concerned withsurvival (Box 1). Two reasons are responsible for thisconflict. First, parasite transmission is likely to

increase more rapidly with biting frequency thanmosquito fecundity, because each bite imparts acertain probability of parasite transmission but willincrease fecundity only up to its asymptotic value(which depends, among other factors, on themosquito’s size). Second, transmission occurs duringbiting, whereas oviposition occurs several days afterbiting, so that the mosquito must place moreemphasis on survival than the parasite.

Thus, as a sporozoite, the parasite is more likely tobenefit from a higher biting rate than the mosquito isand it should therefore try to manipulate the mosquitoto bite more frequently. Such manipulation has beenobserved several times in laboratory situations. In oneexperiment, sporozoite-infected An. stephensi weremore persistent than uninfected controls or oocyst-infected mosquitoes12 (Fig. 1a). Other experimentshave shown that P. gallinaceum sporozoites lower theapyrase activity in the salivary glands of infectedAe. aegypti; as a result, an infected mosquito hasdifficulties in obtaining blood and it probes for a longertime than an uninfected female does17. In naturallyinfected An. gambiae, sporozoites of P. falciparumincrease not only the duration of probing, but also thenumber of probes and the likelihood that themosquitoes begin to probe18. Similar manipulation hasalso been observed in a natural situation, where

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00 2 4 6 8 10

Pro

port

ion

givi

ng-u

p

Time (min)

None Low High

0

10

20

30

40

% m

ultip

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edin

g

Level of sporozoite infection

(a)

(c) (d)

(b)

Control infected Control infected0

20

40

60

Mea

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cund

ity

Oocyst burden

Low High

Evening: before biting Morning: after biting0

5

10

15

% w

ith s

poro

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s

Time of sample

0.2

0.4

0.6

TRENDS in Parasitology

Fig. 1. (a) Effect (in the laboratory) of Plasmodium yoelii nigeriensisonbiting persistence of Anopheles stephensi, defined as the amount of time(up to a maximum of 10 min) that a hungry (unfed) mosquito continues toland and attempts to probe if it is interrupted during each attempt withouthaving obtained any blood. The percentage of mosquitoes giving up theirfeeding attempts after the amount of time given on the X-axis is shown.Uninfected controls are represented by the green line, oocyst-infectedindividuals by the red line, and sporozoite-infected individuals by the blueline. Modified from Ref 12. (b) Effect (in the laboratory) of low (mean 4.4 ± 0.4oocysts per midgut) and high (>75 oocysts per midgut) oocyst burdens ofthe parasite P. yoelii nigeriensison the fecundity of An. stephensi. A differentcontrol was used for comparison of the mosquitoes differing in oocystburdens. The bars show the mean number of eggs per mosquito and thevertical lines show the standard errors of the mean. Modified from Ref. 14.(c) Effect (in the field) of Plasmodium falciparumon the biting rate of An.gambiae, defined as the probability that a mosquito obtains its bloodmealfrom more than one human host. The bars show the percentage ofmosquitoes with multiple meals when they are caught early in the morning(after having completed their biting activity) for different levels of sporozoiteinfections, and the vertical lines show the 95% confidence intervals of thebinomial distribution. (Modified from Ref. 9.) (d) Effect (in the field) of P. falciparumon the risk of feeding-associated mortality of An. gambiae. A sample of mosquitoes was caught early in the evening (before theystarted to bite), and a second sample of the same population was caught the following morning (after they had completed their biting activity). A decrease in prevalence implies that more sporozoite-infected thanuninfected mosquitoes died during the observation period of one night, i.e.that sporozoites increase mortality rate. Modified from Ref. 24.



192 Review

sporozoite-infected An. gambiae are more likely to biteseveral humans and to obtain a full bloodmeal duringany given night than are uninfected mosquitoes9

(Fig. 1c). This was suggested to result from thereduction of apyrase activity: in order to obtain a fullbloodmeal, an infected mosquito with reduced apyraseactivity and hence reduced blood uptake must bitemore often than an uninfected mosquito with normalapyrase activity.

Thus, sporozoites appear to increase theirtransmission by increasing the biting rate of their mosquito vectors. As biting is a major risk for the mosquito, this manipulation is expected toincrease mosquito mortality. Indeed, although severalstudies (mostly performed in laboratory situations)could not find an effect of Plasmodium on mosquitosurvival19,20, some laboratory studies21,22 and, moreimportantly, several field studies, suggest thatsporozoites shorten the lifespan of their mosquitovectors23,24 (Fig. 1d).

The fact that parasites manipulate mosquitoes toincrease the biting rate despite risking an increase inmortality might seem counter-intuitive. It can beexplained however, by the conflicts of interest imposedby the trade-offs intrinsic to the mosquito’s life history,as shown in Box 1. This explanation is very similar tothe one that is widely used by evolutionary ecologistsin their attempts to understand the evolutionarypressure on parasite virulence25–27. A parasite willmaintain a high level of virulence over evolutionarytime if its virulence is more than balanced by acorresponding increase in transmission rate.

Manipulation of biting behaviour in an attempt toincrease transmission appears to be a recurrenttheme among parasites that use haematophagousinsects as vectors. A common mechanism appears tobe that the parasite impairs the ability of its vector toobtain a full bloodmeal, and therefore induces thevector to bite several times before it is fully engorged.Leishmania-infected sandflies for example, havedifficulty obtaining a full bloodmeal, probablybecause of impaired blood flow through the foregut28.Therefore, infected sandflies probe more often thanuninfected flies and, as probing is infectious, severalhosts can be infected by one fly29. The plaguebacterium Yersinia pestis, transmitted by the tropicalrat flea Xenopsylla cheopis, blocks the proventriculusof the flea and causes regurgitation when the flea isbloodfeeding30. Trypanosomes can affect themechanoreceptive sensilla of their tsetse hosts, sothat infected flies probe more frequently thanuninfected flies31,32 (although not all experimentshave found this behavioural change33). As parasitesare frequently transmitted during probing,transmission is likely to be increased.

Why don’t mosquito vectors evolve to be more

refractory?

Thus, it appears that malaria parasites can takeadvantage of the trade-offs intrinsic to the mosquito’s

life history and manipulate its behaviour andfecundity, thereby reducing its reproductive success.One would therefore expect the mosquito to respondto the selective pressure of the parasite with aresistance mechanism. Several lines of defenceagainst Plasmodium infections are indeed possible:An. gambiae can destroy ookinetes by anintracellular, lytic response in the midgut34, and alsoby a humoral, melanotic response35; mosquitodefensin, an antimicrobial peptide, might destroy themalaria parasite if a concurrent bacterial infectionprimes the immune system36, and some defensins killmalaria sporozoites37; and An. stephensi mightdeactivate sporozoites by synthesizing nitric acid38. Atleast some of these responses have a geneticbasis39–41, so that one would expect resistance tospread in a mosquito population infected by malariaparasites. In general, however, the proportion ofmosquitoes (of vector species) that can encapsulateoocysts is believed to be very low to non-existent42 (theprevalence of other responses in natural populationshas never been investigated).

The reason for this lack of resistance againstmalaria parasites in natural mosquito populationsmight lie in yet another trade-off: one betweenimmune function and life-history traits. The immuneresponse in insects incurs reproductive costs43; thisincludes the immune response of mosquitoes againstmalaria parasites. Thus, selection for refractorinessagainst malaria incurs changes in several life-historytraits of Ae. aegypti. Refractory mosquitoes are, forexample, smaller as adults, obtain smallerbloodmeals, lay fewer eggs and have shorter lifespanscompared with susceptible mosquitoes44. By contrast,An. stephensi that have been selected for a higherlevel of refractoriness digest their bloodmeal morerapidly than do sensitive mosquitoes45; however, it isnot clear whether this is an evolutionary advantageor not, because it is not an isolated physiologicalprocess but reproductive success that determinesevolutionary pressure. If we look at fecundity as afactor that is nearer to reproductive success thandigestion, there does seem to be a cost ofrefractoriness in Anopheles. In at least one naturalpopulation of An. gambiae, most blood-fed mosquitoesthat are inoculated with a sephadex bead are able tomount an encapsulation response against the bead(A. Schwartz and J.C. Koella, unpublished). However,the mosquitoes that mount the most effectiveencapsulation response lay the fewest eggs(A. Schwartz and J.C. Koella, unpublished),suggesting a trade-off between the encapsulationresponse and fecundity.

Therefore, the level of refractoriness in a mosquitopopulation will be determined by a balance betweenthe benefit of resisting infection (and thus reducingthe cost of being manipulated) and the cost ofmounting an adequate immune response. Becausethe parasite, and in particular the sporozoite, greatlyincreases the mortality rate of the mosquito by

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193Review

manipulating its biting behaviour (Fig. 1d), thebenefit of resistance would appear to be great.However, this potential advantage must beconsidered together with the risk that a mosquitobecomes infected with sporozoites. This, indeed, isvery low (generally, prevalence ranges between <1and 10%, even in areas highly endemic formalaria46,47), so that, overall, there is littleevolutionary pressure to increase refractoriness; thecost of immunity is likely to outweigh its benefits.

There could be several other reasons for theapparent lack of refractoriness in naturalpopulations. First, the melanization response isgenerally strongest in very young48 mosquitoes. Theolder mosquitoes in field samples thus bias theobservations. Second, other forms of resistance mightbe less costly than an encapsulation and melanizationresponse. Therefore, natural selection should favourthese refractory mechanisms. To date, however, therehave not been any field reports of anophelineimmunity to Plasmodium. Finally, it is perhaps theparasite that is downregulating the mosquito’s

immune system, in yet another demonstration of itsability to manipulate its host.

Concluding remarks

Although the malaria parasite is certainly among themost extensively studied parasites that infecthumans, scientists have only touched on the trade-offs and conflicts of interest involved in theinteractions between the parasite and its hosts. Whatis known suggests that they set the stage for a co-evolutionary race between the parasite’s ability tomanipulate its mosquito vector and the ability of themosquito to resist, if not infection, then at leastmanipulation. The complex and subtle interactionsbetween life-history traits, refractoriness and theeffects of parasite infection (and many other traits) allcontribute to the evolutionary pressures on hosts andparasites and, thus, ultimately on the epidemiology ofmalaria. Neglecting any of these factors mightpresent a warped picture, not only of theepidemiological patterns, but also of the success offuture control strategies.

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Acknowledgements

Financial support for A.S.was provided byDANIDA/RUF, Journal nr.90968.


http://parasites.trends.com 1471-4922/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0169-4758(00)01837-8

194 Review

Early1 and recent2,3 experiments have establishedthat passively transferred antibodies reduceparasitaemia associated with the human malariaparasite Plasmodium falciparum. Inhibiting theinvasion of red blood cells (RBCs) through binding tomerozoite antigens is one way in which antibodiesagainst parasites can exert their effects. Antibodies toproteins on the merozoite surface [e.g. the 185–200-kDa merozoite surface antigen 1 (MSA1) (Ref. 4) andthe 40–50-kDa MSA2 (Refs 5,6)], rhoptries andmicronemes7,8, parasitophorous vacuoles (e.g. theserine-rich antigen (SERA)9 and the heat-stable S-antigen10) and other merozoite proteins whoselocations have not been established definitively11

have been reported to inhibit P. falciparum growthand multiplication in vitro.

Antibodies use several mechanisms that canprevent merozoites from invading RBCs.• causing complement-mediated damage to

merozoites (e.g. antibodies binding to α-galactosylepitopes12)

• sterically interfering with the recognition of RBCligands and other molecules involved in theinvasion process [e.g. antibodies to theerythrocyte-binding antigen13 (EBA)]

• preventing the appropriate maturation orprocessing of merozoite surface proteins needed for

the invasion process [e.g. antibodies to the 19 kDaC-terminal fragment of MSA1 (Ref. 4)]

• preventing merozoite release by causingagglutination of merozoites in rupturing schizonts(e.g. antibodies in immune Aotus monkey serum14

and antibodies to a 140-kDa Plasmodium knowlesimerozoite surface protein15).

However, merozoite reinvasion occurs within a fewminutes of release and therefore antibodies againstmerozoites have to be present at high concentrationsand/or possess sufficient affinity to bind rapidly andstably in sufficient numbers to merozoites to generatethese effects16. This is supported by observations thatthe degree of protection induced by immunization ofmice with the 19-kDa fragment of Plasmodium yoeliiMSA1 depends on the level of specific antibody17,18.

Polyclonal antibodies to MSA2 promote multiple

invasion of RBC by merozoites

An IgG2b monoclonal antibody (mAb) directedagainst an epitope in the 32 residue, twice repeated,allele-specific flanking sequence of the FC27 MSA2molecule, produced 96% inhibition of 3[H]-hypoxanthine incorporation, at 121 µg ml−1 in anin vitro growth and invasion inhibition assay5. In thecommon version of the 3[H]-hypoxanthineincorporation assay, 3[H]-hypoxanthine added to ring-stage parasites is used through the purine salvagepathway and incorporated into newly synthesizedDNA in mature parasites. The assay is thereforefrequently used to estimate the numbers of viablering stages produced during invasion fromsynchronized cultures of schizonts. An IgG3 mAb

There is considerable interest in using merozoite proteins in a vaccine against

falciparum malaria. Observations that antibodies to merozoite surface proteins

block invasion are a basis for optimism. This article draws attention to

important and varied aspects of how antibodies to Plasmodium falciparum

merozoites affect red blood cell invasion.

Antibodies and Plasmodiumfalciparum merozoites

Ranjan Ramasamy, Manthri Ramasamy and Surangi Yasawardena

36 Lowenburger, C.A. et al. (1999)Mosquito–Plasmodium interactions in response toimmune activation of the vector.Exp. Parasitol. 91,59–69

37 Shahabuddin, M. et al. (1998) Plasmodiumgallinaceum: differential killing of some mosquitostages of the parasite by insect defensin.Exp.Parasitol. 89, 103–112

38 Luckhart, S. et al. (1998) The mosquito Anophelesstephensi limits malaria parasite development withinducible synthesis of nitric acid.Proc. Natl. Acad.Sci. U. S. A. 95, 5700–5705

39 Feldmann,A.M. et al. (1986) The selection ofAnopheles stephensi for refractoriness andsusceptibility to Plasmodium falciparum.Trop.Geogr. Med. 38, 317–318

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Review

Ranjan Ramasamy*

Dept of Genetics,University of Groningen,Kerklaan 30, 9751 NNHaren, The Netherlands.*e-mail: [email protected]

Manthri Ramasamy

Surangi Yasawardena

Institute of FundamentalStudies, Kandy, Sri Lanka.

Trade-offs, conflicts of interest and manipulation in Plasmodium–mosquito interactions

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