- Email: [email protected]
The evolution of parasitic diseases
high which
voltage-activating, TEA-sensitive, maps to chromosome 1 band
type-A K ’ channel ~21. 1. Nw-o~~~i. Kw 39,
41~1-412
23 Kumar. A. and hi, KS. (1990) Chromosoma! copy number of 18s + 26s ribosomal RNA
lticalization and genes in evolu-
tionarily diverse mosquitoes (Diptera, 113 277-289 24 M&hi, A. and i’ili, E. (1994) Ribosomal quitoes: locnlizatiorl by fluorescence (FISH). ~hwf~fy 72 SN-605
Culicidae). RNA in situ
H~~ditu~
genes in moshybridization
D. Ebert and EA. Herre reduction in potential reproduction (neither ear destroyed) and, thus, transmission. By sparing one ear, D. yhahcmlvctrs has evolved a strategy of intermediate virulence. Genetic correlations maintain virulence
The conceptual
framework of this review is best introduced with an example illustrating that I!2 level of severity of a parasitic disease, ie. ‘r irulence, GUI be adaptive for the parasite. The p:lrasitic ear-mite i3ic~t~cMcs~lllf7Inc~r1clllcctcs USC-111~infeh:ts and destroys only one car of its hosts (some species of noctuid moths)‘, A one-c)arcd moth may hvc its (ici:ustic detenccs somewhat impaired, but it is still J safer mite v~hiclc and habitat than a moth that is dtlafcncd .\ltsgcthcr. Rcgardlcss of how crow&d the infcchi car may bccotnc, the other ear is left undisturbed and can function to dctcct pr4hry b,lts, which W~NIIC,kill host and pdrasitc, Dcstrnying ncithr ear would make the moth an 6vc’n safer mitt vchiclc, but space around the oirtcr p&u++of the ear is rcstrictcd and the additional utilizath~ of the inner parts of the car allows the mite to produce more offspring. Other, closely rclatcd ear-mites that do not destroy ears (family Qtophcidon~enidae, the ‘ear-sparing’ mites) can occupy both ears, but apparently cannot build up in as large numbers as D. pludnrrtodcctc~sand therefore have a transmission disadvantagcl. This example illustrates a key point in much current thinking on the evolution of virulence: virulence can be maintained by genetic correlations with other fitness traits of the parasitez-5. In the ear-mite example, the crucial relationship is the correlation between the number of destroyed ears and the potential of the parasik to reproduce. A decrease or increase in virulence is associated with a loss of fitness, either in the fbrm of a disproportionately large increase in mortality (both ears destroyed) or a disproportionately large Dieter Ebert was at the NERC Centre for- Population BIOIOQ, lmwal Collegeat Sllwood Patk. Ascot, UK SL5 7PY and IS cumently at the Zoologlsches lnstltut Unlversit;it Basel, Rheinsprung 9, -105 1 Basel, Switzerland. E. Allen Herre IS at the Smithsonian Tropical Research Station, Unit 0948, APO AA 34002-0948, USA. Tel: +41 61 267 3488, Fax: +41 61 267 3457, e-mail: [email protected] 96
Copqh!
0
1996. Elsewt
kcr~e
I td
‘hllc-c$$. A genetic correlation can be seen as an evolutionart/ trade-off, ie. a linkage between traits that constr,rin their simultaneous evolution. A fitnessincreasing change in one trait is accompanied by a fitness rt.duction in a different trait”. In these cases, selecticn is expected to favour the combination of traits that results in the highest fitness. It is important :U emphasize that selection can only act on genetic correlations. In the case of the ear-mite example, selection could oniy change virulence when a mite shows up with a heritable character to infect either both ears or neither ear. In an environment in which hearing is not of great significance for moth survival (eg. in the absence of bats), selection might fnvour mitt genotypes that utilize both host ears, and by this means incrcasc reproduction and transmission rate. In tlh cast, an cnvironmcntnl chongc would nltcr thtl c;hpc of lhc trade-off and thus sc?lc~ction~w~ld shift the optimal l~~vc4of virulcncc. hts ‘~1 as an c~xtvrn;ll constraint influmcing tl~ ivolution of viruhcc). In gt‘nerill, little is known Jwtlt trcldc-h hctwcw virulcncc and other fitness components of parasites, and so far most arguments rely on plausible suggestions rather than on data. A few empirical studies have addressed genetic correlations: across different strains of the myxoma virus in Australiac rabbit populations, a negative relationship was found between the host recovery rate and the virus-induced host mortality rate~~~P”.For a microsporidian gut parasite of the planktonic crustacean Dqd~~~in, a positive genetic correlation between sporcload and host mortality has been found”. The bacteriophage fl shows a positive correlation between transmission and virulence 1”. Other trade-offs involving virulence have been suggcstcd, for example with multiplication rate of parasites of lni~iian~~~~~,with infectivity of mocisc plague and mouse typhoid’, with nuclear polyhedrosis virus production? and with fecundity of parasitic nematodes of fig wasps13. However, good data are rare, apparently because few systems have been investigated in which host and parasite traits in different strains can be measured conveniently. Pmnsite fihess. We use a standard epidemiological equation to illustrate the role of trade-offs for parasite fitness. The fitness of a horizontally transmitted parasite in a completely uninfected host population can be All I s$:ht; rc .et\ed
0 I69
4758/96/$
I5 00
Pcmtology
7-o&/y, vol. 12, no. 3.’ I 416 .
described by the parasites’ life-time reproductive success, R,,. R,, can bc calculated using the I*elationship: R,,=
PtN) p+a+v
(1)
where p is the rate at which an infected host transmits the parasite
believed to favour the evolution of higher virulence. In such cases, a more virulent strain might dominate, even if its R,, is lower than that of a less-virulent s~rainl5,l9-21. Based on a trade-off between parasite reproduction and virulence, Antia and co-worker9 have developed the hypothesis that it is the immune systein of vertebrates that might be responsible for the maintenance of virulence in those microparasites it controls and clears. In their model, highly virulent parasites kill their hosts, and themselves, too early; and avirulent strains contribute iittle to parasite transmission before they are cleared ‘y the immune system. As a result, selection favours parasites of intermediate virulence. A different set of predictions results from the suggestion that aity iitcrease in transmission rate allows for the evolution of higher levels of viruleitce12. On tlte basis of this argument, vector- , air- and water-borne parasites have been predicted to have higher levels of virulence than those transmitted directly from host to hosP’Pl’. Likewise, low host density favours IOM virulence, whereas high host density favours higher virulencei. So far, no experimental tests have been published for any of these predictions. The use of a comparative approach lo test these predictions is difficult because of confounding epidemiological effects. Increased transmission enables parasites to persist that would otlterwise be too virulent and therefore too unfit (R,, cl) lo silrvive. For example, in dense ltost populations one can expect lo find more virulent parasite species than in less dense populations 14.Consequently, tltr average viruience across parasite species recorded from areas with high host densities shouid be higher tltan the mean virulcncc from low density areas. Titereforc, this finding does not support the prcldiction that
b
-0.4 Residuals
0.0 of parasite-induced
Po~~s,to/ogyToday, vol. 12, no. 3. I996
0.4 mortality
Natural mortality
Parasite-induced
mortality (0~)
Box 2. How Useful is R, as a Pacxite Fitness Estimator? Eqllilib~illrl! cclrltjitic)rls: The use of R,, generally assumes !!?at t!le uninfected population is at it5 equilibrium and regulated by something other than rhe parasite14,Hence, R,, is the number of secondary infections produced by a single infection in ‘1x1uninfected host populatio:?. Once J parasite spreads, the host population is not at its equilibrium any more, and R,, loses accuracy as a predictor of parasite fitness. This is important in the early stages of an epidemic. In suc11 cases,the parasite strain with the highest growth rate (Malthusian fitness) has the highest fitness, and this may not be the one with of the uninfected host the hi,ghest life-time reproductive success2’,h7.However, although R,, is defined for the equilibrium population, it allows us to predict competitive t~xclusion at the equilibrium of the infected population. This is because the ‘effective reproductive rate’, R,, scales linearly with the host density. Thus, when R,, of Strain A is larger than R,, of Strain B, then R,. of Strain A = 1, when R, for Strain B is Cl. Strain B will be ou:competedl-‘. Vcrficul fmzsrrrissic~n: R,, has only limited use in the study of vertical transmitted parasites. It can be used to obtain a par‘lsite fitness estimate, ie. it gives the number of scLondary infections produced by a single infection in an mlinfected succes+. This is host population. However, R,, of a vertically transmitted parasite does not determine competition because the contribution of vertical and horizontal transmissions to R,, relate in different ways t:: density. Wifhirz-hosf ezwlufiorc In its most simple form, R,, is calculated undr>r the assumption that no within-host evolution occurs. Multiple infections and competition between parasites within hosts can select for levels of virult:,lce that are higher than those predicted on the basis of R,, alone. In such cases, a more virulent strain might dcminate, even if its RC,is lower than that of a less virulent strain l’QI. Likewise, parasite mutants, which evolve during the course ,~f an infection, can dominate the expressed level of virulence, although their long-term fitness is reduced (+-I . The IIUII III k~~~nlunodeficit~lcy virus (HIV) is a good example of rapid within-host evolutionh“. W/I!/ IISCR,,? The outlined limitations do not refute the concept of R,,. As a first approximation, R,, gives a fair estimate of parasite fitness in most cases. Further, it is a very convenient parameter, since it is much easier to quantify than the Malthusian parameter and because a large set of mathematical tools is available to place R,, in a meaningful epicicmiological and evolutionary framework 1-I.The limitations of R,, (listed above) indicate situations in which a closer exCmiination of a particular case might result in a better understanding of parasite fitness than the simple application of R,, becomes an even more powerful tool to stud!’ the the R,, concept would suggest. Thus, knowing its limitations, ecology and evolution of parasites.
increased transmission selects for higher levels of optimal virulence. Frankzl noted that it is important to distinguish bctwcen epidemic and cndcmic discascs. In epidemics, host density and transmission cfficicncy strongly infhncc the evolution of virulcncc’, while the duration of the infection is less importdnt, In contrast, sndcmic infections phcc a premium on durdtion of infection, and virulsncc is not ii~flucnccd by opportuiritics for transmissions Ch/jidi/i(tll fi)r*I*(~oII~(*~*s. In its most simplistic form, cl p‘\r‘Mc takes resources from its host to support its own grcn44h, rq~roduction, trdnsinission dnd/or survivd, Compclition over limild rb’sourccs, such ds body fdt, food dnd vitamins, crcdtcs a conflict tht is often the ccIiiseof disease. If gcnctic variation for competitive ability exists, resource competition gcncratcs the type of trade-offs that can maintain virulence. Pdrasitc strains that monopolize fewer resources will cause less damage to their host, but will grow less or produce less propagules. Thus, a genetic \I’ ~rrclation exists hetwccn parasites’ within-host fitness and their virulcncc, An rxtrcme co~~scquc~~ce of rcsourcc competition is parasitic castration of hosts. In one of the first models on the evolution of virulence, ObrcbskP proposed that host castration is adaptive for horizontally transmitted parasites because the consumption of the ov+ rics by the parasite is the Ieast likely to reduce host life span. Organs not involved in host reproduction might play some vital role for the host, and thus for the parasite, and therefore should be destroyed last. Thus, host castration can maximize parasite fitness, by freeing host resources without reducing host life span. Castration is most commonly found among either large parasites, or small parasites that reach large biomasses inside their hosts (see Ref. 25 for review), ie. parasites that need large amounts of resources to maintain growth and reproduction. However, the question 98
remains: why do not all horizontally transmitted parasites (in particular those with large biomass) castrate their hosts? Competition over resources has gained some attcntion with respect to alteration in the host resource allocatid~~. Life history theory predicts that rcsourccs sl~cwlci bc shifted from late to early reproduction in hosts which arc cithcr infcctecl or are likely to become iiIfcctcd’7~ZH.I-lowc’vc’r, dcspitc some encouraging cvi‘~~~~C(?2”, ‘I), otlicr cxamplcs arc’ suggc’stivc mtlrcr than conr*lttsivC~,and so 1’ijrarc’ ~~ltogcthcr r;\r~?(PJH.ll.FC~CIIIdity compensation might hid to some interesting cvdutioih~rv conflictsQ, For hlxilmp1c’, by incrc\asing its curly fc~:uidily, a host miglil shorten its life span and conscqucntly the life sy;m of the parasite. This would select for parasites that gain more-rapid control over rcsourcc’s and, in turn, select for hosts which utilize their resources even earlier. Host-parasite conflict over resources is likely to be important in many parasitic discascs, and deserves more attention by evolutionary biologists. Vertical transmission What we have said SOfar applies mainly for horizontally transmitted parasites. For parasites that are also transmitted from parents to offspring (vertically), the optimal level of virulence is strongly influenced by the dative opportunities for vertical and horizontal transmission. All else being equal, an exclusively vertically transmitted parasite sliouid not harm its host, because the number of new infections depends on the fecundity of the host?J~-“‘. Bull and co-worke@ tested this prediction by manipulating transmission in a bacteria-pllage system. By eduding horizontal transmission experimentally, they were able to select for a benevolent interaction. In contrast, predominantly horizontal transmission resulted in the evolution of increased virulence. Further support comes from observations on an initially virulent parasitic Parc~srtologyToday, vol. 12, no. 3, I996
-Box 3. Opportunity for Transmission The number cf secondary infections a parasite produces in a 1.0 --population of uninfected hosts can be written as the sum of I the contributions from horizontal CR,,-,,)and vertical (R,,-,) z .g o 8 \ Horizontal trans,nitL ion transmission: R,,-,,+ I<,,-, = R,,. From this condition, it becomes \ .-o .aUI ’ clear that a single ir ifected host must give rise to at least one c E F ! T new infection, through a combination of horizontal and ver-F 2~ 0.6 \ tical transmission to persist, ie. R,, >1 (Refs 44, 45) (see Fig. 02 right). In a spatially structured host population, the contri5% 0.4 bution of horizontal transmission to parasite fitness might [f be limited by a lack of opportunities. In these conditions the 8.’ O-2 - ’ ‘\___ Vertical transmission relative contribution of vertical transmission increases and & 2 It would pay for the parasite to minimize virulence, ie. the I I I I 0.0 reduction in host reproductive success. 0 5 10 15 20 Imagine a host with a strongly structured population, for Number of hosts in a patch example, fig wasps in figs or insects breeding in mushrooms. The number of hosts that meet at one time determines the relative contributions of R,,-,, and Roe,.to parasite fitness. The graph shows the proportions of vertical and horizontal transmission for an avirulent parasite (a virulent parasite would reduce the proportion of vertical transmission and increase the proportion of horizontal transmission further). If one host arrives at a breeding patch together with its parasite, 100% of the transrilission event will be vertical, while there is no opportunity for horizontal transmission. With two arriving hosts, half of the transmission events will be horizontal (assuming randomness within a patch). However, the parasite might not have produced enough offspring to utilize the larger host population. By stronger expl&?tion of the very host which brought the parasite to this patch, parasite offspring number might be increased at the exppnse of host offspring number (in the best case, without increasing host mortality). With more hosts meeting in one patch, the parasite should increase offspring production further to increase the number of secondary infections, thus becoming more virulent. With large numbers of hosts arriving at one patch, tlansmission is essentially horizontal and the evolution of virulence will be domiliated by the shape of t’le trade-off function (see Box l), and not by the lack of opportunity for transmission. Frank’” highlighted a second mechanism that can lead to an increased level of optimal virulence with increasing opportunities for horizontal transmission. Me argues that with increasing levels of horizontal transmi&on the likelihood increases that hosts are multiply infected with different, unrelated parasite genotypes. Reduced relatedness among parasites increases parasite competition for host resources and consequently increases virulence. Tl~us, increased opportunity for horizontal transmission is negatively correlated with the average relatedness of parasites and therefore could select for
increased L virulence.
-
bacterium in an amoeba. After five years of mainly vertical transmission, this bacterium evolved bencvo1(J,~(-p3”,7L’ . Not all cxclusivcly vertically transmitted parasites arc avirulent. Sex-ratio distortion or incompatibility of infcctcd malcs and uninfcctcd f~malcs are c’xamplcs whcrc virulcncc can bc mainlaincd in the abscilcc of horizontal trans1l7ission.‘“. The relationship bctwcen viruhce and rcbute of transmission can also bc seen in parasitic sex-ratio distorters. These parasites bias the sex ratio of their hosts such that the parasite-transmitting sex increases in number or quality*~~, as the other sex is usually a dead end for parasite transmission. The ‘late male killing’ microsporidians in some mosquitoes avoio this problem by evolving sex-specific virulence”. These microsporidians are transmitted transovarily from mothers to heir offspring. While daughters of infected females show no signs of disease and transmit the parasite vertically (and disperse them), male offspring are killed by the parasite once the larva has reached its maximum size. The microsporidian spores are released into the water and horizontal transmission occurs. Evolution has increased transmission by reducing virulence in the vertically transmitting sex, but has favoured virulence, and the correlated increase in parasite spore prodlrction, in the horizontally transmitting sex. Mixed trm-ks of trmsrnission mi pophtkm
stt’wt~~rc.
Increased opportunities for horizontal transmission would allow an otherwise vertically transmitted parasite to become more virulent. Within fig wasp species, the reproductive success of individual females can be related to the presence or absence of nematode infecParasrtology Today,vo’ 12,no. 3, I996
tions, thereby permitting the tastimation of nematode virulcncc~3. Across species, the characteristically different population structure exhibited by the host wasp species prcscnts different opportimitics for the transmisslon of the ncmatodc spccics that parasitize them. The nematode species with the greate:,t cstimatcd virulence arc associated will1 host wasp species hat are chractcrizcd by population structun3 that provide the most frequent opportunities for horizontal transmission. Moreover, pven though all of tl’rc pairs of species share the same basic natural history, the estimates of the nematodes effects on the rcproductivc success of the wasps define a continuum of rclationships ranging from commensal to parasitic’“. The fig wasps provide a nice example in which opportunities for horizontal transmission are well defined. The population structure of this system allows only a limited number of transmission events within one fig. The more foundress wasps meet, the more horizontal transmission is possible and the relative proportion of vertical transmission decreases. Other systelns where population structure might be a crucial de~crminant for the evolution of virulence include social insect populations (within and between colony transmissio#J and host species with short-living breeding patches, such as mosquitoes brreding in small water holes, fruit flies breeding in r( u:ting fruits or IIIUS~ImaV in their hosts (Box 3). rooms and gregarious parasitcb:_.. In unstructured host populations with vertically and horizontally transmitted parasih, predictions arc more difficult to make because tht opportuility for horizontal transmission depends on the parasite prevalence .I!.Js. A p arasite with horizontal and vertical 99
11rllsm$sion will benefit mainly from horizontal transmission while its prevalence is low. When prevalence increases, the opportunities for horizontal transmission decrease and the relative frequency of new infections through vertical transmission increases (assuming no multiple infection). The preferred level of virulence is very difficult to predict and cannot be inferred from a simple comparison of the relative proportions of vertical and horizontal transmission alon&“. Thus, opportunity for transmission has a different me;lning in structured and unstructured host population and can affect the evolution of virulence in different ways. ‘Novel’ host-parasite associations We have emphasized that the expression of disease symptoms and their severity is a consequence of selection to maximize parasite success. This is unlikely in the case of novel host-parasite combinations. Virulence expressed by an introduced ‘novel’ parasite can be below or above the level that presumably would I 2sult in the highest fitness. Although it was often suggcsttld that newly introduced parasites are more harmful than adapted parasites-‘+‘H, experimental evidence indicates that the opposite is usually true. Novel parasites are, on average, less harmful‘)J9,5(‘, less infectious“,il-5J and less fit”,55-i7 than the same parasite strain infecting the host it is adapted to. Some evidence indicates further that a parasite’s ability to infect and exploit a novel host decreases with decreasing geographic, and presumably genetic, distance from the host to which the parasite is adapted“. Local adaptation may thus b 2 seen as the extension of host specificity on a micro-evolutionary scalcqx. If parositcs in novel hosts arc, on avcragc, less virulent than adapted associations, then WC need to explain why some novsl associations have ncverthcless bee11 devastating, Many catastrophic cpidernics with high lcvcls of virulcncc (eg. the Grcnt Potato Blight in Ireland in the ‘184Os,and the Rindcr Pest in Africa in the late ‘19th century) rcsultcd from introduced diseases, Although there is a lack of clear data, it is increasingly accepted that these cases are exceptions that we have recordl:d because of their extreme effects, while numerous parasite introductions have remained unnoticed because they are avirulenP,5’). Given the massive increase in human mobility and the accompanied deliberate or accidental translocation of hosts and parasites, it is essential to lc?rn more about the expression of virulence in novel associations. Other examples of non-adaptive virulence are novel or accidental host-parasite associations in which the parasite cannot transmit. For example, virulence of TO.WCWfl cmis or Closlridim botrdirrtui~ infections in humans appears purely incidental. Likewise, nontransmissible parasite mutants that evolve within hosts and sometimes infect the ‘wrong’ organ, can cause severe damage but decrease the parasites’ longterm fitness(~“. Perspectives E~~pirlcal evidence in support of the presented concept for the evolution of virulence comes from a wide range of parasites, including bacterial phages, protozoa, nematodes and ectoparasitic arthropods. At present, 100
we are seeing only the tip of the iceberg, exemplified by the lack of empirical studies with horizontally transmitted parasites. Two important aspects in our understanding of the evolution and expression of virulence that have not yet gained much attention. are dose effects and coevolution. Dose effects, ie. increased parasite burdens coinciding with higher virulence, but with iower parasite fecundity per capuP, have not been considered in theoretical or practical studies. In many cases, dose effects seem to play a crucial role in the expression of virulence, not only in macroparasites, but also in microparasite+*. The second major gap concerns the co-evolution of hosts and parasites. Current knowledge of the evolution of diseases comes from systems in which host coevoh,tion appears to have played a minor role in the expression of virulence. However, it is likely that host evolution contributes to the evolution and expression of virulence as well. It is, for example, often foulld that the virulence of one parasite strain varies across different host genotypes from the same population. In the absence of parasite evolution such variation could rapidly select for reduced virulence. Given the high evolutionary rate of parasites h2-h*,1~0st evolution might be ignored in a first approximation’rs, but for a better understanding of the evolution of diseases it is essential to understand the role played by host evolutionh”,“h. Acknowledgements DIscussions with Bob May, Mat-c Lipsitch, Sebastian Bohnhoeffetand MattIn Nowak Influenced out- wntq. Mat-c LIpsItch, Katt-ina MangIn, Chnstlnc Mtillct-, Alex Kl;?qeveld and, In patilculat; Judy Wearing-Wilde Improved CNICI- VWIO~I~ of the manuscript.
Rcfcrences
4 I&\d, A.F. (I9941 The evolution of virulence. T~rrrls Micx~l~i~~l. 1, 73-7Cl
5 C,,II, ,I.].(1994) Virulence. EW/II/~IW48, 1423-1337 6 Sterlrns, SC. (1992) T/w Ezwlrrtic~l 0f I,$* Histc~rks, Oxford Uniwrsi ty Press 7 Fanner, F. and RatclifQ, F.N. (I%51 M!y.wrrrdosis, Cnn~briclp Uniwrsi ty Press H b!r:\f, KM. and Anderson, R.M. (1983) Epidemiology and
genetics in the coevolution of parasites and hosts. /‘WC. R. SIR*. /Mlil0l/
SW. 13219, 281313
9 Ebcrt, D. ( 199~) Virulence and local adaptation of a horizontally transmitted ldSlrasite. Sdwcv 265, 1084-10H6 It1 Uull, J.J. and Molincux, I.:. ( 1992) Molecular genetics of adaptation in an erperimental mode1 of cooperation. E;d~rfic)rr 46, 882-89s 1 I Ewald,
Host-parasite relations, vectors, and the ot disease severity. ,4rrrr1r. k*il. Ecc~l.Sy~tww~ics 14,
I’ W. (1983)
evolution ‘46545
13 Herre, E.k. (1993) Population structure and the evolution of virulence in nematode parasites of fig wasps. Sci~rrcc~259, 1442-l 445 14 Anderson, R.M. and May, R.M. (1991) hfcctiom Dimes of ~UJr117119,Oxford University Press 15 Brernermann, H.J. anit Pickering, J. (1983) A game-theoretical model of parasite virulence. 1.Thor. Bid. 100,41 l-426 16 Lenski, R.E. and May, R.M. (1994) The evolution of virulence in
parasites and pathogens: reconciliation
between two com-
peting hypotheses. 1. Thor. Bid. 169,253-266 17 Kakehashi, M. and Yoshinaga, F. (1992) Evolution Parclotology
of airborne
Today, vol. 12, no. 3, I996
18 19
20 21 22 23 24 25 26 27 28 29
30 31 32 33 34 .+:‘, 36 37
3H 39 40 4I 42 43 44 4S
infectious diseases according to changes in characteristics of the host population. Ecol. Rcs. 7,235-243 Lipsitch, M. et n/. (1985) Host population structure and the evolution of virulence: a law of diminishing returns. Ezal~!tinr, 49, 743-748 Nowak, M.A. and Mav, R.M. (1994) Superinfection and the evolution of parasite virulence. Proc. R. Ser. London Ser. B 2S5, 81-89 Levin, S.A. and Pimentel, D (1981) Selection for intermediate rates of increase in parasite-host systems. Am. Nut. 117,308-315 van Baalen, M. and Sabelis, M.W. The dynamics of multiple infection and the evolution of virulence. Am. Nnt. (ir: press) Antia, R. ct nl. (1994) Within-host population dynamics and the evolution and maintenance of microparasite virulence. Am. Not. 144,457-472 Frank, S.A. Models of parasite virulence. Q. /&SIT.Bid. (in press) Obrebski, S. (1975) Parasite reproductive strategy and evolution of castration of hosts by parasites. Sri~~~lcc 188,1314-l 316 Baudoin, M. (1975) Host castration as a parasitic strategy. Ezd~~tioi~ 29,335-352 Minchella, D.J. (1985) Host life-history variation in response to parasitism. Pw&o/o~J/ 90, 205-216 Hochberg, M.E. ct nl. (lP92) Parasitism as a constraint on the rate of life history evolution. 1. E~ol. Bid. 5,491-503 Michalakis, Y. and Ho&berg, M.E. (1994) Parasitic effects on host life-history traits: a review of recent studies. Pmmitcp 1, 291-294 Minchella, D.J. and Loverde, P.T. (1981) A cost of increased early reproductive effort in the snail Bioqh?/nrin glnbrntn. Am. Nd. 118,876-881 Lafferty, K.D. (1993) The marine snail, Cmllzidcn cnliforaicrr matures at smaller size where parasitism is high. Oih 68,3-l 1 Ebert, D. (1994) Genetic differences in the interactions of a microsporidian parasite and four clones of its cyclically parthenogenetic host. P~7m~ito/o,q/ 108, 1l-l 6 Forbes, M.R.L. (1993) Parasitism and host reproductive effort. OikIJS 67,444-450 Fine, l’.E.M. (1975) Vectors and vertical transmission: an epidemiologic perspectivr. ./\rrrl. NY Ad. SC;. 266, 173-194 Axclrod, R. and Hamii:on, W.D. (19X1) The evolution of cooperat’on. S~kwc 211, 1390-l 396 Anclcrson, R.M. and May, R.M. (IYXI) The population dynamics of microparasites and their invertebrate hosts. Pltih. Trr7e. R .LSOL.UCFTi,‘S 6 R 391 - , 451-524 . c Bull, J.J. 1’1 ril. (IYY’I 1 Selection of benevolence in a host-parasite system. Ez~~drrriorr 4S, X75-882 Clnytcrn, D.H. and Tompkins, D.M. (1YYd) Ectoparasite virulence is linked to mode of transmission. I’II~I*. I<. %I.. I IUI~/~UI s[v*. /I 9% a.,- 7 I I-’ h I7 Jcon, K.W. (11,721 lhvclopmcnt of cellular dcpcndcncc on infcctivc organisms: micrurgic,ll studies in amoebas. .C;C~UC18 176, I 122-l I23 Jcon, K.W. (l9H3) lntcgratrnn of bactcri,rl endosymbionk. in amoebae. /M. Kw. Cytol. (SuppI.) 14, 2947 Wcrrcn, J.H. (I\ r7/. (lY)H61 Male-killing bacteria in a parasitic wasp. Sci~wc~~ 231, Yr)O-9Y2 Hurst, L.D. (‘199.3) The incidences, mechanisms and evolution of cytoplamic sex ratio distorters in animals. Bird. Rf’il. 68, 121-l‘,.? Hurst, L.D. (19Ylj The incidences and evolution of cytoplasmic male killers. Proc. R. Sot. Lorrdo~~ Ser. B 244, 91-99 S&mid-Hcmyel, P. and Schmid-Hempcl, R. (1993) Transmissidn of a pathogen in Bo~rrbrrs fcrrcstris with a note on division of labour in social insects. Brh7v. Ecol. Sociobic~/. 33, 31Y-327 Mnngin, K.L. ct n/. (1995) Virulence and transmission modes of two microbporidia in Daphnia magna. Pm~r7~ilo/o,q1~ 111, 133- l-l2 Lipsitch, M. 1’1 nl. (199% The population dynamics of vertically
Are you organizing a meeting that is of interest to parasitologists? If so, please supply Parasitology Today with the details (dates, title, location) and a contact name, and we will include your meeting in our Diary page, without charge. Please make sure we receive the details at least 10 weeks prior to the meeting dates. -1
Pa,nsltolog~ Today, vol. 12, no. 3, I996
and horizontally
transmitted
parasites.
Proc. R. SW. Lorzh~z $I..
B 260,321-327
46 Ailison.
A.C.
(1982)
in Pophfiorl
Bbh~~~
(f /II~L’c~;~JZ[.SD;w~~~P.~
(Anderson, R.hl. and May, R.M., cds), pp 245-267,
Springer
47 Busvine, J-R. (1993) Dis~sc~ Trmswissior~ hy /rlqq t.s: /ts ~iq~~qyry U/UI Nkf!/ YMW (of Effort to Proilrrlt It, Springer 48 Alexander, M. (1981) Why microbial predators and pardsites do not eliminale their prey and hosts. Amu. Rw. Micr&io/. 35, 113-133 49 Dawson, J.R.O. (1967) The adaptation of tomato mosaic virus to resistant tomato plants. Awl. A,@. Bid. 60,209~214 50 Ballabeni, W. and Ward, P.I. (1993) Local adaptation of a trematode, Diplostorrwm yhoxirri to the European minnox P/loxiIu~s yhoxitms, its second intermediate host. Fwc. Ed. 7, ~4-90 51 Parker, M.A. (1985) Local population differentiation for compatibility zn an annual legume and its host-specific fungal pathogen. Eu~/u:~o;I 39, 713-723 52 Files, V.S. and Cram, E.B. (1949) A study on the comparative susceptibility of snail vectors to strains of ~clzistoso~~ra nsnnsorri. 1. Pmnsitol. 35, 555-560 53 Manning, S.D. ct al (1995) Geographic compatibility of the freshwater snail Bzrlirr~s globoszrs and Schistosomes frcm the Zimbabwe highveid. /jr!. 1. Prrmifo/og/ 25, 37-42 54 Lively, C.M. (11,891 Adaptation by a parasitic trematode to local populations of its snail host. Endufiw 13, 1663-1671 55 Edmunds, G.F. and Alstad, D.N. (1978) Coevolution in ir:sect herbivores and conifers. Scirucr lY9,94 l-945 56 Wainhouse, D. and Howell, R.S. (1983) Intraspecific variation in beech scale populations and in susceptibility of their host Fqqrs s~yfutrficn. Ed. E~rtorrrt~/. 8, 351-359 57 Karhan, R. (1989) Fine-scale adaptation of herbivorous thrips to individual host plants. Ahfwc 340,60-61 S8 Thompson, J.N. (1994) T/t,> C c,(~rlo/lrfic,ffr7I.l/ Pmws, Chicago Univcrsi tv I’rcss SY Burden, J.J. (1991) Fungal pathogens as selective forces in plant populations and communities. Austr. /. ELII/. 16,423-432 60 Levin, B.R. and Bull, J.J. (1994) Short-sighted evolution and the virulence of phathogenic microorganisms. Trcr~tl; Micw/ id. 2, 7h-81 61 H&berg, M.E. (1991) Intra-host interactions between a braconid endoparasitoid, Apmtclcs g/omwtus, and a baculovirus for larvae of Picris brnssicl1c. /. Auirn. Ecd. 60, Sl-63 62 Fcnncr, F. and Myers, K. (lY7ti) in Virrr.v’s rlrd Eiri’ir’~~r/rrr~‘r/f (Kur&ik, E. ,lnd M~~r,~m~,rosch, K., ads), pp 43Y-570, Academic I ‘rc’55 h3 IIonIingc,, I-. ,~ncl I loll,ind, 1.1. (1YY-l) in ‘/%I@I:cdflliculrrrt/ llicdc~~~l/(II \/ir~+ (M~brslt, S.S., c~l.1, pp I(, I-I X1, li,i\‘tbn I’rcss (~.i I I,ifncr, RI1.S. cf II/. ( IYYJ) Disparate rates of molecular evolution in cospeciating ho+, and parasites. Scir*rrt~r 2h5, IOS7- IINO 05 I I,iniill(Jq W.I 1. (IUHO) Sex versus non-sex versus parasite. (1llicf.G
35,
2H2-290
60 I+,lnk, S.A. ( l9Y.3) Evolution of host-parasite diversity. /‘i~hl~~w 47,1721-1732 (77 I,ipit&, M. ,md Novak, tv1.A. ( IYIU) The evolution of virulcncc in sexually transmitted HIV/AIDS. I. ‘/‘/Iw. /h/. 174, ~27-UO (1~ Nowalk, N. (1YYl) The evolution of viruses. Compctitioll between horizontal and vertical trancmission of mobile genes. 1. r/r1vr. Rid. 150, 330-347 69 Now&, M.,I. cf r7/. (lY91) Antigenic diversity thresholds dnd the development of AIDS. ,Sj ~CWCC354, %3--W) U.A. (1YYJ) Intra-host and intcr70 Bonhocffer, S. and Nowak, host selection: viral evolution of immune function impairment. /ht~. M7tl ,I\r-rd. S1.i. 1/S:\ 9 I, ~O(lZ-HO6h 71 l$~)llh~,c+fcq-. S. ‘UI~ Naw,lk, M.A. (I+)-!) Mutation and the evolllti(jn of virulence. /‘l’rh . I<. SOi’. Lltl/l/c)ll Sl’J*. I{ 2.48, 13:~~-14()
Are you going to attend a meeting that is of interest to parasitologists? If so, perhaps :lou would like to consider writing a short report of the meeting, capturing its main messages and the future directions indicated for the topic. Please contact the Editor of Parasitology Today st Elsevier Trends Journals, 68 Hills Road, Cambridge, UK Cl32 I LA. J IO1
voltage-activating, TEA-sensitive, maps to chromosome 1 band
type-A K ’ channel ~21. 1. Nw-o~~~i. Kw 39,
41~1-412
23 Kumar. A. and hi, KS. (1990) Chromosoma! copy number of 18s + 26s ribosomal RNA
lticalization and genes in evolu-
tionarily diverse mosquitoes (Diptera, 113 277-289 24 M&hi, A. and i’ili, E. (1994) Ribosomal quitoes: locnlizatiorl by fluorescence (FISH). ~hwf~fy 72 SN-605
Culicidae). RNA in situ
H~~ditu~
genes in moshybridization
D. Ebert and EA. Herre reduction in potential reproduction (neither ear destroyed) and, thus, transmission. By sparing one ear, D. yhahcmlvctrs has evolved a strategy of intermediate virulence. Genetic correlations maintain virulence
The conceptual
framework of this review is best introduced with an example illustrating that I!2 level of severity of a parasitic disease, ie. ‘r irulence, GUI be adaptive for the parasite. The p:lrasitic ear-mite i3ic~t~cMcs~lllf7Inc~r1clllcctcs USC-111~infeh:ts and destroys only one car of its hosts (some species of noctuid moths)‘, A one-c)arcd moth may hvc its (ici:ustic detenccs somewhat impaired, but it is still J safer mite v~hiclc and habitat than a moth that is dtlafcncd .\ltsgcthcr. Rcgardlcss of how crow&d the infcchi car may bccotnc, the other ear is left undisturbed and can function to dctcct pr4hry b,lts, which W~NIIC,kill host and pdrasitc, Dcstrnying ncithr ear would make the moth an 6vc’n safer mitt vchiclc, but space around the oirtcr p&u++of the ear is rcstrictcd and the additional utilizath~ of the inner parts of the car allows the mite to produce more offspring. Other, closely rclatcd ear-mites that do not destroy ears (family Qtophcidon~enidae, the ‘ear-sparing’ mites) can occupy both ears, but apparently cannot build up in as large numbers as D. pludnrrtodcctc~sand therefore have a transmission disadvantagcl. This example illustrates a key point in much current thinking on the evolution of virulence: virulence can be maintained by genetic correlations with other fitness traits of the parasitez-5. In the ear-mite example, the crucial relationship is the correlation between the number of destroyed ears and the potential of the parasik to reproduce. A decrease or increase in virulence is associated with a loss of fitness, either in the fbrm of a disproportionately large increase in mortality (both ears destroyed) or a disproportionately large Dieter Ebert was at the NERC Centre for- Population BIOIOQ, lmwal Collegeat Sllwood Patk. Ascot, UK SL5 7PY and IS cumently at the Zoologlsches lnstltut Unlversit;it Basel, Rheinsprung 9, -105 1 Basel, Switzerland. E. Allen Herre IS at the Smithsonian Tropical Research Station, Unit 0948, APO AA 34002-0948, USA. Tel: +41 61 267 3488, Fax: +41 61 267 3457, e-mail: [email protected] 96
Copqh!
0
1996. Elsewt
kcr~e
I td
‘hllc-c$$. A genetic correlation can be seen as an evolutionart/ trade-off, ie. a linkage between traits that constr,rin their simultaneous evolution. A fitnessincreasing change in one trait is accompanied by a fitness rt.duction in a different trait”. In these cases, selecticn is expected to favour the combination of traits that results in the highest fitness. It is important :U emphasize that selection can only act on genetic correlations. In the case of the ear-mite example, selection could oniy change virulence when a mite shows up with a heritable character to infect either both ears or neither ear. In an environment in which hearing is not of great significance for moth survival (eg. in the absence of bats), selection might fnvour mitt genotypes that utilize both host ears, and by this means incrcasc reproduction and transmission rate. In tlh cast, an cnvironmcntnl chongc would nltcr thtl c;hpc of lhc trade-off and thus sc?lc~ction~w~ld shift the optimal l~~vc4of virulcncc. hts ‘~1 as an c~xtvrn;ll constraint influmcing tl~ ivolution of viruhcc). In gt‘nerill, little is known Jwtlt trcldc-h hctwcw virulcncc and other fitness components of parasites, and so far most arguments rely on plausible suggestions rather than on data. A few empirical studies have addressed genetic correlations: across different strains of the myxoma virus in Australiac rabbit populations, a negative relationship was found between the host recovery rate and the virus-induced host mortality rate~~~P”.For a microsporidian gut parasite of the planktonic crustacean Dqd~~~in, a positive genetic correlation between sporcload and host mortality has been found”. The bacteriophage fl shows a positive correlation between transmission and virulence 1”. Other trade-offs involving virulence have been suggcstcd, for example with multiplication rate of parasites of lni~iian~~~~~,with infectivity of mocisc plague and mouse typhoid’, with nuclear polyhedrosis virus production? and with fecundity of parasitic nematodes of fig wasps13. However, good data are rare, apparently because few systems have been investigated in which host and parasite traits in different strains can be measured conveniently. Pmnsite fihess. We use a standard epidemiological equation to illustrate the role of trade-offs for parasite fitness. The fitness of a horizontally transmitted parasite in a completely uninfected host population can be All I s$:ht; rc .et\ed
0 I69
4758/96/$
I5 00
Pcmtology
7-o&/y, vol. 12, no. 3.’ I 416 .
described by the parasites’ life-time reproductive success, R,,. R,, can bc calculated using the I*elationship: R,,=
PtN) p+a+v
(1)
where p is the rate at which an infected host transmits the parasite
believed to favour the evolution of higher virulence. In such cases, a more virulent strain might dominate, even if its R,, is lower than that of a less-virulent s~rainl5,l9-21. Based on a trade-off between parasite reproduction and virulence, Antia and co-worker9 have developed the hypothesis that it is the immune systein of vertebrates that might be responsible for the maintenance of virulence in those microparasites it controls and clears. In their model, highly virulent parasites kill their hosts, and themselves, too early; and avirulent strains contribute iittle to parasite transmission before they are cleared ‘y the immune system. As a result, selection favours parasites of intermediate virulence. A different set of predictions results from the suggestion that aity iitcrease in transmission rate allows for the evolution of higher levels of viruleitce12. On tlte basis of this argument, vector- , air- and water-borne parasites have been predicted to have higher levels of virulence than those transmitted directly from host to hosP’Pl’. Likewise, low host density favours IOM virulence, whereas high host density favours higher virulencei. So far, no experimental tests have been published for any of these predictions. The use of a comparative approach lo test these predictions is difficult because of confounding epidemiological effects. Increased transmission enables parasites to persist that would otlterwise be too virulent and therefore too unfit (R,, cl) lo silrvive. For example, in dense ltost populations one can expect lo find more virulent parasite species than in less dense populations 14.Consequently, tltr average viruience across parasite species recorded from areas with high host densities shouid be higher tltan the mean virulcncc from low density areas. Titereforc, this finding does not support the prcldiction that
b
-0.4 Residuals
0.0 of parasite-induced
Po~~s,to/ogyToday, vol. 12, no. 3. I996
0.4 mortality
Natural mortality
Parasite-induced
mortality (0~)
Box 2. How Useful is R, as a Pacxite Fitness Estimator? Eqllilib~illrl! cclrltjitic)rls: The use of R,, generally assumes !!?at t!le uninfected population is at it5 equilibrium and regulated by something other than rhe parasite14,Hence, R,, is the number of secondary infections produced by a single infection in ‘1x1uninfected host populatio:?. Once J parasite spreads, the host population is not at its equilibrium any more, and R,, loses accuracy as a predictor of parasite fitness. This is important in the early stages of an epidemic. In suc11 cases,the parasite strain with the highest growth rate (Malthusian fitness) has the highest fitness, and this may not be the one with of the uninfected host the hi,ghest life-time reproductive success2’,h7.However, although R,, is defined for the equilibrium population, it allows us to predict competitive t~xclusion at the equilibrium of the infected population. This is because the ‘effective reproductive rate’, R,, scales linearly with the host density. Thus, when R,, of Strain A is larger than R,, of Strain B, then R,. of Strain A = 1, when R, for Strain B is Cl. Strain B will be ou:competedl-‘. Vcrficul fmzsrrrissic~n: R,, has only limited use in the study of vertical transmitted parasites. It can be used to obtain a par‘lsite fitness estimate, ie. it gives the number of scLondary infections produced by a single infection in an mlinfected succes+. This is host population. However, R,, of a vertically transmitted parasite does not determine competition because the contribution of vertical and horizontal transmissions to R,, relate in different ways t:: density. Wifhirz-hosf ezwlufiorc In its most simple form, R,, is calculated undr>r the assumption that no within-host evolution occurs. Multiple infections and competition between parasites within hosts can select for levels of virult:,lce that are higher than those predicted on the basis of R,, alone. In such cases, a more virulent strain might dcminate, even if its RC,is lower than that of a less virulent strain l’QI. Likewise, parasite mutants, which evolve during the course ,~f an infection, can dominate the expressed level of virulence, although their long-term fitness is reduced (+-I . The IIUII III k~~~nlunodeficit~lcy virus (HIV) is a good example of rapid within-host evolutionh“. W/I!/ IISCR,,? The outlined limitations do not refute the concept of R,,. As a first approximation, R,, gives a fair estimate of parasite fitness in most cases. Further, it is a very convenient parameter, since it is much easier to quantify than the Malthusian parameter and because a large set of mathematical tools is available to place R,, in a meaningful epicicmiological and evolutionary framework 1-I.The limitations of R,, (listed above) indicate situations in which a closer exCmiination of a particular case might result in a better understanding of parasite fitness than the simple application of R,, becomes an even more powerful tool to stud!’ the the R,, concept would suggest. Thus, knowing its limitations, ecology and evolution of parasites.
increased transmission selects for higher levels of optimal virulence. Frankzl noted that it is important to distinguish bctwcen epidemic and cndcmic discascs. In epidemics, host density and transmission cfficicncy strongly infhncc the evolution of virulcncc’, while the duration of the infection is less importdnt, In contrast, sndcmic infections phcc a premium on durdtion of infection, and virulsncc is not ii~flucnccd by opportuiritics for transmissions Ch/jidi/i(tll fi)r*I*(~oII~(*~*s. In its most simplistic form, cl p‘\r‘Mc takes resources from its host to support its own grcn44h, rq~roduction, trdnsinission dnd/or survivd, Compclition over limild rb’sourccs, such ds body fdt, food dnd vitamins, crcdtcs a conflict tht is often the ccIiiseof disease. If gcnctic variation for competitive ability exists, resource competition gcncratcs the type of trade-offs that can maintain virulence. Pdrasitc strains that monopolize fewer resources will cause less damage to their host, but will grow less or produce less propagules. Thus, a genetic \I’ ~rrclation exists hetwccn parasites’ within-host fitness and their virulcncc, An rxtrcme co~~scquc~~ce of rcsourcc competition is parasitic castration of hosts. In one of the first models on the evolution of virulence, ObrcbskP proposed that host castration is adaptive for horizontally transmitted parasites because the consumption of the ov+ rics by the parasite is the Ieast likely to reduce host life span. Organs not involved in host reproduction might play some vital role for the host, and thus for the parasite, and therefore should be destroyed last. Thus, host castration can maximize parasite fitness, by freeing host resources without reducing host life span. Castration is most commonly found among either large parasites, or small parasites that reach large biomasses inside their hosts (see Ref. 25 for review), ie. parasites that need large amounts of resources to maintain growth and reproduction. However, the question 98
remains: why do not all horizontally transmitted parasites (in particular those with large biomass) castrate their hosts? Competition over resources has gained some attcntion with respect to alteration in the host resource allocatid~~. Life history theory predicts that rcsourccs sl~cwlci bc shifted from late to early reproduction in hosts which arc cithcr infcctecl or are likely to become iiIfcctcd’7~ZH.I-lowc’vc’r, dcspitc some encouraging cvi‘~~~~C(?2”, ‘I), otlicr cxamplcs arc’ suggc’stivc mtlrcr than conr*lttsivC~,and so 1’ijrarc’ ~~ltogcthcr r;\r~?(PJH.ll.FC~CIIIdity compensation might hid to some interesting cvdutioih~rv conflictsQ, For hlxilmp1c’, by incrc\asing its curly fc~:uidily, a host miglil shorten its life span and conscqucntly the life sy;m of the parasite. This would select for parasites that gain more-rapid control over rcsourcc’s and, in turn, select for hosts which utilize their resources even earlier. Host-parasite conflict over resources is likely to be important in many parasitic discascs, and deserves more attention by evolutionary biologists. Vertical transmission What we have said SOfar applies mainly for horizontally transmitted parasites. For parasites that are also transmitted from parents to offspring (vertically), the optimal level of virulence is strongly influenced by the dative opportunities for vertical and horizontal transmission. All else being equal, an exclusively vertically transmitted parasite sliouid not harm its host, because the number of new infections depends on the fecundity of the host?J~-“‘. Bull and co-worke@ tested this prediction by manipulating transmission in a bacteria-pllage system. By eduding horizontal transmission experimentally, they were able to select for a benevolent interaction. In contrast, predominantly horizontal transmission resulted in the evolution of increased virulence. Further support comes from observations on an initially virulent parasitic Parc~srtologyToday, vol. 12, no. 3, I996
-Box 3. Opportunity for Transmission The number cf secondary infections a parasite produces in a 1.0 --population of uninfected hosts can be written as the sum of I the contributions from horizontal CR,,-,,)and vertical (R,,-,) z .g o 8 \ Horizontal trans,nitL ion transmission: R,,-,,+ I<,,-, = R,,. From this condition, it becomes \ .-o .aUI ’ clear that a single ir ifected host must give rise to at least one c E F ! T new infection, through a combination of horizontal and ver-F 2~ 0.6 \ tical transmission to persist, ie. R,, >1 (Refs 44, 45) (see Fig. 02 right). In a spatially structured host population, the contri5% 0.4 bution of horizontal transmission to parasite fitness might [f be limited by a lack of opportunities. In these conditions the 8.’ O-2 - ’ ‘\___ Vertical transmission relative contribution of vertical transmission increases and & 2 It would pay for the parasite to minimize virulence, ie. the I I I I 0.0 reduction in host reproductive success. 0 5 10 15 20 Imagine a host with a strongly structured population, for Number of hosts in a patch example, fig wasps in figs or insects breeding in mushrooms. The number of hosts that meet at one time determines the relative contributions of R,,-,, and Roe,.to parasite fitness. The graph shows the proportions of vertical and horizontal transmission for an avirulent parasite (a virulent parasite would reduce the proportion of vertical transmission and increase the proportion of horizontal transmission further). If one host arrives at a breeding patch together with its parasite, 100% of the transrilission event will be vertical, while there is no opportunity for horizontal transmission. With two arriving hosts, half of the transmission events will be horizontal (assuming randomness within a patch). However, the parasite might not have produced enough offspring to utilize the larger host population. By stronger expl&?tion of the very host which brought the parasite to this patch, parasite offspring number might be increased at the exppnse of host offspring number (in the best case, without increasing host mortality). With more hosts meeting in one patch, the parasite should increase offspring production further to increase the number of secondary infections, thus becoming more virulent. With large numbers of hosts arriving at one patch, tlansmission is essentially horizontal and the evolution of virulence will be domiliated by the shape of t’le trade-off function (see Box l), and not by the lack of opportunity for transmission. Frank’” highlighted a second mechanism that can lead to an increased level of optimal virulence with increasing opportunities for horizontal transmission. Me argues that with increasing levels of horizontal transmi&on the likelihood increases that hosts are multiply infected with different, unrelated parasite genotypes. Reduced relatedness among parasites increases parasite competition for host resources and consequently increases virulence. Tl~us, increased opportunity for horizontal transmission is negatively correlated with the average relatedness of parasites and therefore could select for
increased L virulence.
-
bacterium in an amoeba. After five years of mainly vertical transmission, this bacterium evolved bencvo1(J,~(-p3”,7L’ . Not all cxclusivcly vertically transmitted parasites arc avirulent. Sex-ratio distortion or incompatibility of infcctcd malcs and uninfcctcd f~malcs are c’xamplcs whcrc virulcncc can bc mainlaincd in the abscilcc of horizontal trans1l7ission.‘“. The relationship bctwcen viruhce and rcbute of transmission can also bc seen in parasitic sex-ratio distorters. These parasites bias the sex ratio of their hosts such that the parasite-transmitting sex increases in number or quality*~~, as the other sex is usually a dead end for parasite transmission. The ‘late male killing’ microsporidians in some mosquitoes avoio this problem by evolving sex-specific virulence”. These microsporidians are transmitted transovarily from mothers to heir offspring. While daughters of infected females show no signs of disease and transmit the parasite vertically (and disperse them), male offspring are killed by the parasite once the larva has reached its maximum size. The microsporidian spores are released into the water and horizontal transmission occurs. Evolution has increased transmission by reducing virulence in the vertically transmitting sex, but has favoured virulence, and the correlated increase in parasite spore prodlrction, in the horizontally transmitting sex. Mixed trm-ks of trmsrnission mi pophtkm
stt’wt~~rc.
Increased opportunities for horizontal transmission would allow an otherwise vertically transmitted parasite to become more virulent. Within fig wasp species, the reproductive success of individual females can be related to the presence or absence of nematode infecParasrtology Today,vo’ 12,no. 3, I996
tions, thereby permitting the tastimation of nematode virulcncc~3. Across species, the characteristically different population structure exhibited by the host wasp species prcscnts different opportimitics for the transmisslon of the ncmatodc spccics that parasitize them. The nematode species with the greate:,t cstimatcd virulence arc associated will1 host wasp species hat are chractcrizcd by population structun3 that provide the most frequent opportunities for horizontal transmission. Moreover, pven though all of tl’rc pairs of species share the same basic natural history, the estimates of the nematodes effects on the rcproductivc success of the wasps define a continuum of rclationships ranging from commensal to parasitic’“. The fig wasps provide a nice example in which opportunities for horizontal transmission are well defined. The population structure of this system allows only a limited number of transmission events within one fig. The more foundress wasps meet, the more horizontal transmission is possible and the relative proportion of vertical transmission decreases. Other systelns where population structure might be a crucial de~crminant for the evolution of virulence include social insect populations (within and between colony transmissio#J and host species with short-living breeding patches, such as mosquitoes brreding in small water holes, fruit flies breeding in r( u:ting fruits or IIIUS~ImaV in their hosts (Box 3). rooms and gregarious parasitcb:_.. In unstructured host populations with vertically and horizontally transmitted parasih, predictions arc more difficult to make because tht opportuility for horizontal transmission depends on the parasite prevalence .I!.Js. A p arasite with horizontal and vertical 99
11rllsm$sion will benefit mainly from horizontal transmission while its prevalence is low. When prevalence increases, the opportunities for horizontal transmission decrease and the relative frequency of new infections through vertical transmission increases (assuming no multiple infection). The preferred level of virulence is very difficult to predict and cannot be inferred from a simple comparison of the relative proportions of vertical and horizontal transmission alon&“. Thus, opportunity for transmission has a different me;lning in structured and unstructured host population and can affect the evolution of virulence in different ways. ‘Novel’ host-parasite associations We have emphasized that the expression of disease symptoms and their severity is a consequence of selection to maximize parasite success. This is unlikely in the case of novel host-parasite combinations. Virulence expressed by an introduced ‘novel’ parasite can be below or above the level that presumably would I 2sult in the highest fitness. Although it was often suggcsttld that newly introduced parasites are more harmful than adapted parasites-‘+‘H, experimental evidence indicates that the opposite is usually true. Novel parasites are, on average, less harmful‘)J9,5(‘, less infectious“,il-5J and less fit”,55-i7 than the same parasite strain infecting the host it is adapted to. Some evidence indicates further that a parasite’s ability to infect and exploit a novel host decreases with decreasing geographic, and presumably genetic, distance from the host to which the parasite is adapted“. Local adaptation may thus b 2 seen as the extension of host specificity on a micro-evolutionary scalcqx. If parositcs in novel hosts arc, on avcragc, less virulent than adapted associations, then WC need to explain why some novsl associations have ncverthcless bee11 devastating, Many catastrophic cpidernics with high lcvcls of virulcncc (eg. the Grcnt Potato Blight in Ireland in the ‘184Os,and the Rindcr Pest in Africa in the late ‘19th century) rcsultcd from introduced diseases, Although there is a lack of clear data, it is increasingly accepted that these cases are exceptions that we have recordl:d because of their extreme effects, while numerous parasite introductions have remained unnoticed because they are avirulenP,5’). Given the massive increase in human mobility and the accompanied deliberate or accidental translocation of hosts and parasites, it is essential to lc?rn more about the expression of virulence in novel associations. Other examples of non-adaptive virulence are novel or accidental host-parasite associations in which the parasite cannot transmit. For example, virulence of TO.WCWfl cmis or Closlridim botrdirrtui~ infections in humans appears purely incidental. Likewise, nontransmissible parasite mutants that evolve within hosts and sometimes infect the ‘wrong’ organ, can cause severe damage but decrease the parasites’ longterm fitness(~“. Perspectives E~~pirlcal evidence in support of the presented concept for the evolution of virulence comes from a wide range of parasites, including bacterial phages, protozoa, nematodes and ectoparasitic arthropods. At present, 100
we are seeing only the tip of the iceberg, exemplified by the lack of empirical studies with horizontally transmitted parasites. Two important aspects in our understanding of the evolution and expression of virulence that have not yet gained much attention. are dose effects and coevolution. Dose effects, ie. increased parasite burdens coinciding with higher virulence, but with iower parasite fecundity per capuP, have not been considered in theoretical or practical studies. In many cases, dose effects seem to play a crucial role in the expression of virulence, not only in macroparasites, but also in microparasite+*. The second major gap concerns the co-evolution of hosts and parasites. Current knowledge of the evolution of diseases comes from systems in which host coevoh,tion appears to have played a minor role in the expression of virulence. However, it is likely that host evolution contributes to the evolution and expression of virulence as well. It is, for example, often foulld that the virulence of one parasite strain varies across different host genotypes from the same population. In the absence of parasite evolution such variation could rapidly select for reduced virulence. Given the high evolutionary rate of parasites h2-h*,1~0st evolution might be ignored in a first approximation’rs, but for a better understanding of the evolution of diseases it is essential to understand the role played by host evolutionh”,“h. Acknowledgements DIscussions with Bob May, Mat-c Lipsitch, Sebastian Bohnhoeffetand MattIn Nowak Influenced out- wntq. Mat-c LIpsItch, Katt-ina MangIn, Chnstlnc Mtillct-, Alex Kl;?qeveld and, In patilculat; Judy Wearing-Wilde Improved CNICI- VWIO~I~ of the manuscript.
Rcfcrences
4 I&\d, A.F. (I9941 The evolution of virulence. T~rrrls Micx~l~i~~l. 1, 73-7Cl
5 C,,II, ,I.].(1994) Virulence. EW/II/~IW48, 1423-1337 6 Sterlrns, SC. (1992) T/w Ezwlrrtic~l 0f I,$* Histc~rks, Oxford Uniwrsi ty Press 7 Fanner, F. and RatclifQ, F.N. (I%51 M!y.wrrrdosis, Cnn~briclp Uniwrsi ty Press H b!r:\f, KM. and Anderson, R.M. (1983) Epidemiology and
genetics in the coevolution of parasites and hosts. /‘WC. R. SIR*. /Mlil0l/
SW. 13219, 281313
9 Ebcrt, D. ( 199~) Virulence and local adaptation of a horizontally transmitted ldSlrasite. Sdwcv 265, 1084-10H6 It1 Uull, J.J. and Molincux, I.:. ( 1992) Molecular genetics of adaptation in an erperimental mode1 of cooperation. E;d~rfic)rr 46, 882-89s 1 I Ewald,
Host-parasite relations, vectors, and the ot disease severity. ,4rrrr1r. k*il. Ecc~l.Sy~tww~ics 14,
I’ W. (1983)
evolution ‘46545
13 Herre, E.k. (1993) Population structure and the evolution of virulence in nematode parasites of fig wasps. Sci~rrcc~259, 1442-l 445 14 Anderson, R.M. and May, R.M. (1991) hfcctiom Dimes of ~UJr117119,Oxford University Press 15 Brernermann, H.J. anit Pickering, J. (1983) A game-theoretical model of parasite virulence. 1.Thor. Bid. 100,41 l-426 16 Lenski, R.E. and May, R.M. (1994) The evolution of virulence in
parasites and pathogens: reconciliation
between two com-
peting hypotheses. 1. Thor. Bid. 169,253-266 17 Kakehashi, M. and Yoshinaga, F. (1992) Evolution Parclotology
of airborne
Today, vol. 12, no. 3, I996
18 19
20 21 22 23 24 25 26 27 28 29
30 31 32 33 34 .+:‘, 36 37
3H 39 40 4I 42 43 44 4S
infectious diseases according to changes in characteristics of the host population. Ecol. Rcs. 7,235-243 Lipsitch, M. et n/. (1985) Host population structure and the evolution of virulence: a law of diminishing returns. Ezal~!tinr, 49, 743-748 Nowak, M.A. and Mav, R.M. (1994) Superinfection and the evolution of parasite virulence. Proc. R. Ser. London Ser. B 2S5, 81-89 Levin, S.A. and Pimentel, D (1981) Selection for intermediate rates of increase in parasite-host systems. Am. Nut. 117,308-315 van Baalen, M. and Sabelis, M.W. The dynamics of multiple infection and the evolution of virulence. Am. Nnt. (ir: press) Antia, R. ct nl. (1994) Within-host population dynamics and the evolution and maintenance of microparasite virulence. Am. Not. 144,457-472 Frank, S.A. Models of parasite virulence. Q. /&SIT.Bid. (in press) Obrebski, S. (1975) Parasite reproductive strategy and evolution of castration of hosts by parasites. Sri~~~lcc 188,1314-l 316 Baudoin, M. (1975) Host castration as a parasitic strategy. Ezd~~tioi~ 29,335-352 Minchella, D.J. (1985) Host life-history variation in response to parasitism. Pw&o/o~J/ 90, 205-216 Hochberg, M.E. ct nl. (lP92) Parasitism as a constraint on the rate of life history evolution. 1. E~ol. Bid. 5,491-503 Michalakis, Y. and Ho&berg, M.E. (1994) Parasitic effects on host life-history traits: a review of recent studies. Pmmitcp 1, 291-294 Minchella, D.J. and Loverde, P.T. (1981) A cost of increased early reproductive effort in the snail Bioqh?/nrin glnbrntn. Am. Nd. 118,876-881 Lafferty, K.D. (1993) The marine snail, Cmllzidcn cnliforaicrr matures at smaller size where parasitism is high. Oih 68,3-l 1 Ebert, D. (1994) Genetic differences in the interactions of a microsporidian parasite and four clones of its cyclically parthenogenetic host. P~7m~ito/o,q/ 108, 1l-l 6 Forbes, M.R.L. (1993) Parasitism and host reproductive effort. OikIJS 67,444-450 Fine, l’.E.M. (1975) Vectors and vertical transmission: an epidemiologic perspectivr. ./\rrrl. NY Ad. SC;. 266, 173-194 Axclrod, R. and Hamii:on, W.D. (19X1) The evolution of cooperat’on. S~kwc 211, 1390-l 396 Anclcrson, R.M. and May, R.M. (IYXI) The population dynamics of microparasites and their invertebrate hosts. Pltih. Trr7e. R .LSOL.UCFTi,‘S 6 R 391 - , 451-524 . c Bull, J.J. 1’1 ril. (IYY’I 1 Selection of benevolence in a host-parasite system. Ez~~drrriorr 4S, X75-882 Clnytcrn, D.H. and Tompkins, D.M. (1YYd) Ectoparasite virulence is linked to mode of transmission. I’II~I*. I<. %I.. I IUI~/~UI s[v*. /I 9% a.,- 7 I I-’ h I7 Jcon, K.W. (11,721 lhvclopmcnt of cellular dcpcndcncc on infcctivc organisms: micrurgic,ll studies in amoebas. .C;C~UC18 176, I 122-l I23 Jcon, K.W. (l9H3) lntcgratrnn of bactcri,rl endosymbionk. in amoebae. /M. Kw. Cytol. (SuppI.) 14, 2947 Wcrrcn, J.H. (I\ r7/. (lY)H61 Male-killing bacteria in a parasitic wasp. Sci~wc~~ 231, Yr)O-9Y2 Hurst, L.D. (‘199.3) The incidences, mechanisms and evolution of cytoplamic sex ratio distorters in animals. Bird. Rf’il. 68, 121-l‘,.? Hurst, L.D. (19Ylj The incidences and evolution of cytoplasmic male killers. Proc. R. Sot. Lorrdo~~ Ser. B 244, 91-99 S&mid-Hcmyel, P. and Schmid-Hempcl, R. (1993) Transmissidn of a pathogen in Bo~rrbrrs fcrrcstris with a note on division of labour in social insects. Brh7v. Ecol. Sociobic~/. 33, 31Y-327 Mnngin, K.L. ct n/. (1995) Virulence and transmission modes of two microbporidia in Daphnia magna. Pm~r7~ilo/o,q1~ 111, 133- l-l2 Lipsitch, M. 1’1 nl. (199% The population dynamics of vertically
Are you organizing a meeting that is of interest to parasitologists? If so, please supply Parasitology Today with the details (dates, title, location) and a contact name, and we will include your meeting in our Diary page, without charge. Please make sure we receive the details at least 10 weeks prior to the meeting dates. -1
Pa,nsltolog~ Today, vol. 12, no. 3, I996
and horizontally
transmitted
parasites.
Proc. R. SW. Lorzh~z $I..
B 260,321-327
46 Ailison.
A.C.
(1982)
in Pophfiorl
Bbh~~~
(f /II~L’c~;~JZ[.SD;w~~~P.~
(Anderson, R.hl. and May, R.M., cds), pp 245-267,
Springer
47 Busvine, J-R. (1993) Dis~sc~ Trmswissior~ hy /rlqq t.s: /ts ~iq~~qyry U/UI Nkf!/ YMW (of Effort to Proilrrlt It, Springer 48 Alexander, M. (1981) Why microbial predators and pardsites do not eliminale their prey and hosts. Amu. Rw. Micr&io/. 35, 113-133 49 Dawson, J.R.O. (1967) The adaptation of tomato mosaic virus to resistant tomato plants. Awl. A,@. Bid. 60,209~214 50 Ballabeni, W. and Ward, P.I. (1993) Local adaptation of a trematode, Diplostorrwm yhoxirri to the European minnox P/loxiIu~s yhoxitms, its second intermediate host. Fwc. Ed. 7, ~4-90 51 Parker, M.A. (1985) Local population differentiation for compatibility zn an annual legume and its host-specific fungal pathogen. Eu~/u:~o;I 39, 713-723 52 Files, V.S. and Cram, E.B. (1949) A study on the comparative susceptibility of snail vectors to strains of ~clzistoso~~ra nsnnsorri. 1. Pmnsitol. 35, 555-560 53 Manning, S.D. ct al (1995) Geographic compatibility of the freshwater snail Bzrlirr~s globoszrs and Schistosomes frcm the Zimbabwe highveid. /jr!. 1. Prrmifo/og/ 25, 37-42 54 Lively, C.M. (11,891 Adaptation by a parasitic trematode to local populations of its snail host. Endufiw 13, 1663-1671 55 Edmunds, G.F. and Alstad, D.N. (1978) Coevolution in ir:sect herbivores and conifers. Scirucr lY9,94 l-945 56 Wainhouse, D. and Howell, R.S. (1983) Intraspecific variation in beech scale populations and in susceptibility of their host Fqqrs s~yfutrficn. Ed. E~rtorrrt~/. 8, 351-359 57 Karhan, R. (1989) Fine-scale adaptation of herbivorous thrips to individual host plants. Ahfwc 340,60-61 S8 Thompson, J.N. (1994) T/t,> C c,(~rlo/lrfic,ffr7I.l/ Pmws, Chicago Univcrsi tv I’rcss SY Burden, J.J. (1991) Fungal pathogens as selective forces in plant populations and communities. Austr. /. ELII/. 16,423-432 60 Levin, B.R. and Bull, J.J. (1994) Short-sighted evolution and the virulence of phathogenic microorganisms. Trcr~tl; Micw/ id. 2, 7h-81 61 H&berg, M.E. (1991) Intra-host interactions between a braconid endoparasitoid, Apmtclcs g/omwtus, and a baculovirus for larvae of Picris brnssicl1c. /. Auirn. Ecd. 60, Sl-63 62 Fcnncr, F. and Myers, K. (lY7ti) in Virrr.v’s rlrd Eiri’ir’~~r/rrr~‘r/f (Kur&ik, E. ,lnd M~~r,~m~,rosch, K., ads), pp 43Y-570, Academic I ‘rc’55 h3 IIonIingc,, I-. ,~ncl I loll,ind, 1.1. (1YY-l) in ‘/%I@I:cdflliculrrrt/ llicdc~~~l/(II \/ir~+ (M~brslt, S.S., c~l.1, pp I(, I-I X1, li,i\‘tbn I’rcss (~.i I I,ifncr, RI1.S. cf II/. ( IYYJ) Disparate rates of molecular evolution in cospeciating ho+, and parasites. Scir*rrt~r 2h5, IOS7- IINO 05 I I,iniill(Jq W.I 1. (IUHO) Sex versus non-sex versus parasite. (1llicf.G
35,
2H2-290
60 I+,lnk, S.A. ( l9Y.3) Evolution of host-parasite diversity. /‘i~hl~~w 47,1721-1732 (77 I,ipit&, M. ,md Novak, tv1.A. ( IYIU) The evolution of virulcncc in sexually transmitted HIV/AIDS. I. ‘/‘/Iw. /h/. 174, ~27-UO (1~ Nowalk, N. (1YYl) The evolution of viruses. Compctitioll between horizontal and vertical trancmission of mobile genes. 1. r/r1vr. Rid. 150, 330-347 69 Now&, M.,I. cf r7/. (lY91) Antigenic diversity thresholds dnd the development of AIDS. ,Sj ~CWCC354, %3--W) U.A. (1YYJ) Intra-host and intcr70 Bonhocffer, S. and Nowak, host selection: viral evolution of immune function impairment. /ht~. M7tl ,I\r-rd. S1.i. 1/S:\ 9 I, ~O(lZ-HO6h 71 l$~)llh~,c+fcq-. S. ‘UI~ Naw,lk, M.A. (I+)-!) Mutation and the evolllti(jn of virulence. /‘l’rh . I<. SOi’. Lltl/l/c)ll Sl’J*. I{ 2.48, 13:~~-14()
Are you going to attend a meeting that is of interest to parasitologists? If so, perhaps :lou would like to consider writing a short report of the meeting, capturing its main messages and the future directions indicated for the topic. Please contact the Editor of Parasitology Today st Elsevier Trends Journals, 68 Hills Road, Cambridge, UK Cl32 I LA. J IO1