Parasite-Host Coevolution

TREE vol. 5, no. IO, October 1990 ParasitbHost Coevolution Catherine A, Toft and Andrew J. Karter Parasite-host coevofution can have many different endpoints, not simply the commensafism of ‘conventional wisdom’. Empirical studies and mathematical models are elucidating the conditions under which parasite-host systems can coevolve to intermediate and high levels of parasite virulence - and when they can coevolve to commensalism and mutualism. The conventional wisdom of parasitology and medicine is that parasites evolve to do little or no harm to hosts. While this view is still prevalent in many circles, it has been repeatedly challenged in the last dozen years’-7. Although the conventional wisdom appeals to common sense and is supported by examples, recent efforts’,5,R,9 have explored mechanisms beyond the naive group-selectionist arguments that have satisfied earlier authors. Meanwhile, the study of coevolution has made us moreaware of the costs, benefits and trade-offs involved in all coevolved relationships, including both parasitism and mutualisml~9~‘0. Lately, ecologists and evolutionary biologists have considered a wider range of orthan have traditional ganisms parasitologists8,“,‘2, yielding additional insights about the many pathways that coevolution can take. In sum, these studies reveal that many coevolutionary outcomes are possible, mainly because of constraints specific to the organisms involved that direct or stop the trajectories of coevolutionlO. By ‘coevolution’, we mean that two species undergogenetic change in response to the interaction between them13, and here we will specifically consider only the coevolution of virulence. Virulence is a complex feature of parasite-host interactions. It may appear to be solely an attribute of the parasite, but, in fact, virulence and resistance are each the net effect of the physiological, morphological and behavioral interactions between parasite and host. Virulence, then. can be conCatherineToft is at the Dept of Zoology,University of California,Davis,CA 95616, USA;Andrew Karter is at the Dept of Epidemiology and Preventive Medicine, School of Veterinary Medicine, University of California, Davis, CA 956 16, USA 326 sidered the net effect of parasites on their hosts, and can be measured in a number of ways. For example, it can be estimated by parasite reproduction, by parasite infectiousness or by the damage a parasite does to the host, i.e. the disease’“. In recent modeling efforts (see below), virulence often (but not always15l refers to host death caused directly by the parasite4-5. However, all studies emphasize that there are complex interrelations between pathology leading to parasite-induced host deaths and benefits accrued to the parasite from its interaction with the host - primarily transmission and reproduction5,9. These interrelations have been explored explicitly in only a few instances; unfortunately, we know all too little about how parasite virulence, transmission and fecundity interact with host resistance in real parasite-host systems’“. Evolutionary change in virulence A variety of examples demonstrate (or suggest) that virulence can change through coevolution. Importantly, examples exist for an array of evolutionary outcomes3~5 (Boxes I and 2). Coevolution has been clearly demonstrated in only a few empirical studies, the best being that of the Myxoma virus infecting rabbits in Australia and Britain17. While many other documented cases provide evidence of evolutionary change3,7,‘b, we often do not know the physiological mechanisms for virulence or resistance, much less the details of coevolutionary change. The discrepancy between parasite and host generation times has suggested to some that coevolution is not as important as the parasite’s adaptations to the host. The Myxoma-rabbit story contradicts this reasoning, however, because in less than 20 years rabbits showed a clear evolutionary change in resistance17, albeit not as much as that in the virus’s virulence. (Note that real changes in virulence and resistance in the field were estimated from reference test stocks kept in the laboratory.) Thus we assume for other examples that coevolutionary change may well have occurred and that virulence and resistance are not sharply separable. Nevertheless, from here on, we will for simplicity emphasize virulence (taking the parasite’s point of view), but readers should keep these caveats in mind. We now review case studies under the three qualitative outcomes of evolution of virulence: virulence decreases to ‘intermediate’ levels; virulence increases from some starting point; and ‘virulence’ decreases to zero (commensalism) or even becomes positive lmutualism I. Virulence settles to ‘iNtermediate’ levels The best-documented cases so far fall under this evolutionary outcome Imyxomatosis; avian malaria, Box I ; but see Box 2). We put quotes around ‘intermediate’ because we will be emphasizing relative rather than absolute measures of virulence. ‘Intermediate’ is appropriate to describe these examples because virulence decreased over time but did not decrease to zero lthe commensalism of conventional wisdom I. The Myxoma-rabbit system, familiar by now to most ecologists and evolutionary biologists, settled into intermediate levels of virulence within a year or so and has remained roughly steady for two decades. However, an equilibrium may not yet have been reached, and some of the fluctuations in prevalence of various strains may represent evolution of increased resistance in rabbits, or introduction of new vector+“. Less well-studied but nonetheless documented examples in humans are diseases, such as smallpox and measles, that are much more virulent in populations to which they have been recently inwhere troduced than in populations there has been long exposureb. Similarly, ‘zoonoses’ (diseases introduced to humans from wild and domestic animals) are often severe or lethal in humans and milder in the ‘reservoir’ (animal) host, although much of the evidence comprises anecdotes from the medical literature (e.g. rabies, Lassa fever, bubonic plague, and perhaps HIV; see also Box 21. These diseases generally are not completely benign in the animal, i.e. more coevolved, hosts. For none of these examples besides the Myxoma-rabbit case is it known what constrains the viru- rREE vol. 5, no. 10, October 1990 lence in the low direction, i.e. preventing it from reaching commensalism. However, the dependency Df transmission on factors leading to host pathology and death is a likely explanation, and one that has rezeived most attention. Virulence settles to ‘fiig& levels Once again, ‘high’ is a relative neasure; we refer here to cases Nhere virulence increased over :ime. Ewald3 argues that in vector3orne parasites - including malaria disease Plasmodium), Chagas’ Trypanosoma I, Leishmania, relapsng fever, Rickettsia and yellow ,‘ever (but see Box I I - the cost of :3athogenicity causing host immolbility is removed. He argues that *:here is no penalty (and perhaps tzven an advantage) for these para&sites in increasing their exploitation of the host until it is immobilized, because a vector can still find the host, unlike in directly transmitted parasites. However, some examples I including the Myxoma-rabbit sysI em15; see also Box 2 I do not corroborate this idea, and we might expect each vector-primary host-parasite system to be slightly different, depending on biological details. Nevertheless, in some host-paraGte systems, the upper constraint IO virulence might be removed, and in those instances, virulence could ,:ontinue to increase. ‘lirulence goes to zero: tommeflsalistic ,rnd mutualistic endpoints Alternatively, the lower conr-,traint to virulence can be removed, ‘:lnd those parasite-host systems evolving lower virulence or greater resistance have no barrier along the parasitism-commensalismmutualism continuum’. As Thomp:.on’O has pointed out, mutualisms itIre not the happy, ‘peaceful’ arrangements they are conventionally thought to be. Many are so full of manipulation, costs and even antagonism that they are suspected to have arisen evolutionarily from parasitism. These include the fig wasp pollination system, lichens, 2nd mycorrhizal fungi. Similarly, c.ommensalisms may not represent ‘peaceful’ coexistence either, but rather a stand-off between parasite ii ttack and host counterattack; in few instances, however, have costs to Posts and parasites been estimated. Evidence from the new molecular and other experimental techniques unequivocally demonstrates that mitochondria, chloroplasts and bacterial plasmids are associations between organisms of different speciesls. Mitochondria and chloroplasts may have arisen from originally parasitic relationships18, although tests of this postulate are difficult to imagine. Studies on bacteria and their phages and plasmids, however, have been quite fruitful, because of their short generation times and evolutionary plasticity’9-2’. In bacteria and their viruses, evidence suggests that evolution has occurred independently in both directions a number of times’9-2’. Thus, perhaps ironically, the conventional wisdom now under attack may be correct about the evolution of the association between such microorganisms, which was responsible for the evolution of eukaryote@ and indeed life as we know it on this planet. Because the bacterial phage-plasmid pathway can take place in a few days in the laboratory, it may represent the best experimental model to determine what conditions can overrule the ‘lower’ constraint to parasitehost coevolution i9-21 (inasmuch as these prokaryote systems can be generalized to multicellular, eukaryote systems). Experiments in progress suggest that the key lies in the nature of transmission (R. Lenski, pers. commun.1, just as models assert. Models of parasite-host coevolution Models of parasite-host coevolution have provided significant insights into the constraints that direct and impede the coevolutionary trajectories of virulence and resistance, and their results in turn guide further empirical study. These early efforts corroborate the examples we have provided above: multiple coevolutionary endpoints are possible. In model systems, any of the following conditions can (theoretically) result in the reduction of virulence to commensalism. First, if parasite-induced host mortality, transmission, host recovery and perhaps other factors are not interrelated, then there is no theoretical lower constraint on virulence. Because the basic parasite reproductive rate, R,, is inversely related to parasite-induced host mortality (virulence), R, is maximized by reducing virulence to zero - assuming that there are no interactions between virulence and other parameters4,5. Second, if resistance has no cost to the host, it can counter the parasite’s attack (virulence) with no limit, and thus the parasite’s net effect on the host is negligible9,22. Examples of situations matching these conditions may include some gut symbionts. Third, in certain modes of transmission, such as vertical transmission (i.e. from parent to offspring), large benefits accrue to the parasite by increased host reproduction, and this will select for lower virulence in model systems7. Fourth, if group, or perhaps more selection accurately interdemic, should predominate over individual selection, then the lower constraint on virulence is removed or lessened; i.e. parasites can be prudent” , as the conventional wisdom holds them to be. lnterdemic selection is not improbable in parasites. Structured habitats with limited immigration can lead to group-type selection in model systems2?, which could theoretically result in lowered virulence. However, others have postulated the opposite outcome patterns of increased virulence with periodic disease outbreaks from structured habitatsI (see also Box 21. If any of the above conditions do 327 TREE vol. 5, no. 10, October 1990 no t a p p ly, virule nc e will b e c o nstra ine d fro m re a c hing ze ro . Exa c t p re d ic tio ns on whe re virule nc e will se ttle a re p o ssib le fro m se ve ra l o f the a b o ve mo d e ls. Two c o nstra ints o n d e c re a sing virule nc e a re mo st c o mmo nly inve stig a te d in mo d e l syste ms, a nd ind e e d a re like ly to b e c o mmo n in re a l syste ms. The first is whe n virule nc e is a func tio n o f e ithe r tra nsmissio n or re c o ve ry ra te . Virule nc e a nd re c o ve ry ra te we re e stima te d in the Myxo ma -ra b b it syste m a nd fo und to b e no nline a rly re la te d” . The e stima te s we re the n p ut into a simp le mo d e l to d e te rmine the virule nc e le ve l tha t the o re tic a lly ma ximize s p a ra site re p ro d uc tive ra te . This le ve l wa s re ma rka b ly c lo se to the p re va le nt virule nc e le ve l o f the myxo ma virus in Austra lia a nd Brita in4, p ro vid ing stro ng e vid e nc e fo r suc h a c o nstra int. Se c o nd , the costs o f virule nc e a nd re sista nc e o fte n le a d to inte rme d ia te le ve ls o f virule nc e in mo d e l syste ms9,22: the c o sts p la c e a n up p e r c o nstra int o n virule nc e , a nd a n up p e r c o nstra int o n re sista nc e (whic h tra nsla te s into a lo we r ‘ c o nstra int’ o n virule nc e ). To te st the se id e a s, c o sts c o uld b e e stima te d fro m la b o ra to ry stud ie s a nd use d to c a lc ula te o p timum inve stme nts in virule nc e a nd in re sista nc e , fro m the p a ra site ’ s a nd ho st’ s p o ints o f vie w re sp e c tive ly. Suc h c a lc ula tio ns mig ht re ve a l tra d e -o ffs tha t c o uld re sult in intermediate levels of virusyslence in so me p a ra site -ho st te ms, suc h a s in the Myxo ma -ra b b it e xa mp le . Ma ny o f the mo d e ls me ntio ne d a b o ve c o uld be used to estimate the value that virulence will reach whe n p a ra me te rs e stima te d fro m re a l syste ms a re p ut into the mo d e ls. Whe the r virule nc e is ‘ lo w’ , ‘ inte rme d ia te ’ o r ‘ hig h’ wo uld d e - p e nd o n the p a rtic ula rs. Othe r mo d e ls a sk whe the r g e ne tic p o lymo rp hisms in virule nc e a nd re sista nc e c an be ma inta ine d 4,5,9,24, a s o p p o se d to a sking wha t the a ve ra g e le ve l o f virule nc e mig ht b e fo r a g ive n p o p ula tio n the se a re d iffe re nt b ut re la te d q ue stio ns. Whe n g e ne tic p o lymo rp hism in virule nc e / re sista nc e oc c urs, the n susc e p tib ility is no t fixe d (virule nc e ma ximum), no r is re sista nc e fixe d (virule nc e minimum I. Po p ula tio ns o f p a ra site s ma y b e mixture s o f c lo ne s o f d iffe re nt viru328 ‘FREE vol. 5, no. 70, Ocrober 1990 ience levels, as in the Myxomarabbit case4. If any polymorphism exists in host resistance, we may assume that total resistance doesn’t pay evolutionarily, perhaps because of costs of resistance. At i he same time, the costs of excessive virulence accrue to parasites, usually in reduced transmission. Hence, polymorphisms are more likely when both virulence and re!;istance have some kind of cost9,22. modeling Thus, efforts have revealed a variety of conditions directing the trajectories of coevolution between parasite and host. .rheir predictions are easily testable (at least in principle), and c;hould help us to understand the evolutionary dynamics of many parasite-host systems. Importantly, commensalism is not the only out,;:ome predicted by models. I:uture directions Lastly, we briefly mention some obvious next steps to increase (:)ur understanding of parasite-host interactions. First, we need a family of theoretical models that bridge the interface’, r)arasitism-mutualism ,:Icross which parameters can change. -*bus, parasite-host systems may be ,:lble to reach commensalistic and rnutualistic endpoints even if par,rlmeters are linked, but linked in ‘ways different from those leading to i:ln endpoint of intermediate viruience. Work on bacterial plasmids and phages may inspire the first &tempts in this area, because I:hese viruses evolve quickly backand-forth across the parasitismmutualism interface19. Second, we need more work on coevolution of multicellular ‘nacroparasites’, such as helminths. Macroparasites are invariably ag6;regated in the host population; that is, most hosts have few or no parasites and relatively few hosts carry high parasite burdens16. This aggregated distribution, which has not yet been fully explained, probably derives from heterogeneity in the parasite and host populations, ii attributes such as transmission rates, host immunity and host susc.eptibility, as well as in temporal and spatial patterns. Because variability in host susceptibility is at Ilzast partly genetic, the aggregated distribution bears directly on coc,volution between macroparasites and hosts, and constitutes a major unexplored area. Third, coevolutionary models so far have typically taken the simplest form, lacking heterogeneity in time (i.e. age structure) and in space. As we have already mentioned, spatial structuring is crucial to whether group selection can occur15, and the role of group selection is still an open question in parasite-host coevolution9,‘9. Also, spatially complex patterns in virulence, such as in Trypanosoma (Box 21, suggest that (group selection or not1 conditions affecting coevolution of virulence vary spatially and this variation is worth pursuing in modeling and empirical studies. Such efforts have been initiated for plant-funga125 and the Myxom+rabbit15 systems, and reveal that temporal and spatial structuring was important in their coevolution. Fourth, interactions among mortality factors are of potential importance in parasite-host systems, and such interactions have received little attention. For example, individuals weakened by disease might be easier for predators to capture2h, and studies in humans have linked resistance to host nutritional state. Interactions among parameters can generate complicated population behaviors2’, and would surely affect selection pressures on parasitehost interactions. Also, effects are likely to be different in intermediate and definitive hosts (depending on mode of transmission). Further study explicitly exploring the effects of interactions among mortality factors is warranted. Finally, far more empirical work on parasite-host associations is needed. In particular, collaboration among specialists in ecology, physiimmunology, systematics, ology, epidemiology and medicine, including laboratory, field and theoretical approaches, is necessary to understand parasite-host coevolution in any detail’QR. Acknowledgements T. Carlton helped extensively in finding references on Trypanosoma. 0. Halvorsen. S. Levin. R. May, A. Skorping and 1. 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