Host genes, parasites and parasitic infections

Inlernarional .loumolfor Prrnred in Grmt Briroin

Parasirology

Vol. 23, No 4. pp. 485-l94,

1993 0

HOST GENES, PARASITES AND PARASITIC G. D. GRAY and H.S. Department

of Animal

Science, University

00X&7519/93 56.00 + 0.M) Pergmon Press Lrd Societyfor Parasirology

1993 Auslralian

INFECTIONS

GILL

of New England,

Armidale,

NSW 2351, Australia

G. D. and GILL H. S. 1993. Host genes, parasites

and parasitic infections. International 23: 485494. Resistance to infection of mammalian hosts by parasites is under genetic control at many different levels: between species, between races, breeds and lines of single species and between individuals. These genetic effects have been described in many host-parasite systems. Here we review the interaction between three elements: host genes, parasites and the environment in which parasitic infections develop. Already livestock industries exploit genetic variation between breeds, particularly for the control of trypanosomiasis and tick infestation in cattle. In most populations, and to many diseases, resistance is heritable and selective breeding for resistance in commercial livestock species has been successful experimentally. Attempts at utilizing genetic variation are placed in the broad context of the coevolution of host and parasite, the limited knowledge we have of the mode of action of resistance genes and our ability to use genetic information to predict resistance to parasites.

Ab&aCt-GRAY

Journal

INDEX

for

Parasitology

KEY WORDS:

Genetics;

hosts; parasites;

breeding;

nematodes;

protozoa;

immunity.

in altered relationships between host and parasite, sometimes resulting in disease outbreaks. Monocultures of domesticated animals: sheep, goats, cattle, pigs, chickens and horses, are highly vulnerable to epizootics of protozoa, helminths and arthropods. In response to this threat there is the possibility of exploiting genetic variation in the host by increasing the frequency of resistance genes, to bring about a measure of disease control. This has been attempted successfully for trypanosomiasis (Trail, dIeteren & Murray, 1991) and ticks (de Castro, 1991) in cattle and nematodes in sheep (Gray, 1991) and goats (Gruner, 1991). These approaches are very promising but must be considered along with the unanswered question of why there is such diversity in resistance to disease in livestock species. What role, if any, does diversity in resistance per se have in the interaction between host and parasite? And what would be the consequences if loss of diversity in resistance was the outcome of artificial selection? There have been a number of comprehensive reviews of genetic variation in host response to parasites (Chandler, 1932; Hutt, 1958; Wakelin, 1978; 1985; 1988; 1989; Dargie, 1982; Mitchell, 1979; Albright & Albright, 1984; Barger, 1990; Grencis, 1990) and to infectious disease in general (Gowen, 1948; Gavora & Spencer, 1983; Templeton, Smith & Adams, 1988; Rothschild, 1989) to which the reader is referred. This brief review will focus on our current ability to predict the outcomes of parasitic infections, especially in outbred populations of commercial species, given only information about the genotype or genetic

INTRODUCTION MOST animal

species are naturally resistant to almost all species of parasites to which they are exposed and those parasites which do successfully establish and mature are then controlled to a greater or lesser extent by the genes of their hosts. These forms of genetic variation in host response have been found in almost all host-parasite systems and have been the subject of intensive study for diverse reasons: by evolutionary biologists seeking to understand the biodiversity of hosts and parasites, and by applied biologists attempting to make use of genetic variation to increase resistance to parasitic diseases of economically important hosts. For all these studies there is a need to understand how the host and parasite interact at the genetic and the phenotypic (anatomical, physiological and immunological) levels. Parasitism is the most common lifestyle among animals (‘All the wide world is little else, but parasites and sub-parasites’ Jonson, 1606) and may be responsible for speciation, sexual dimorphism, many social behaviours (Keymer & Read, 1990) and for generating and maintaining genetic diversity within species (Haldane, 1949; Clarke, 1976; 1979). Central to these arguments is that parasitic infections compromise the host in some way (Toft & Karter, 1990), even in the wild. Obvious as this may be to those of us who study parasites which cause disease in livestock and man, evidence that parasites harm their hosts in the wild has been obtained only with difficulty (Behnke & Barnard, 1990). But as hosts evolve, their parasites evolve with them. Domestication of livestock species has resulted 485

486

G. D.

GRAY and

background of the host. In view of the extensive literature on the subject it is our despondent view that our predictive ability is very limited.

H. S. GILL

requiring antigen specific antibodies. Variation

GENETIC

DIFFERENCES

BETWEEN

HOSTS

Variation between species

In the wild, parasites exert selection pressure on their hosts by reducing their fitness. The animal breeder must fulfil this same selective role from the perspective of productivity and profit. In addition to selecting from within a species, the breeder has the option of selecting other species which may meet his commercial objectives e.g. replacing goats with sheep, sheep with cattle, or pigs with chickens, or even mixing species that can be husbanded together. Host specificity of parasites can make this last option attractive. For example, strategies have been developed in which cattle and sheep are grazed alternately with the purpose of controlling sheep parasites which do not survive in cattle (Barger, 1978; Inderbitzen, Eckert & Hofmann, 1981; Reinecke & Louw, 1991). Such genetic differences can be broken down. Recently, for example, the cattle nematode Ostertagia ostertagi, was responsible for a rare outbreak of clinical disease in sheep (O’Callaghan, Martin & McFarland, 1992). Normally these interspecific barriers are very rigid and our knowledge of their nature is scant. For example, recent attempts to infect rabbits (Boisvenue & Novilla, 1992) and jirds (Conder, Johnson, Hall, Fleming, Mills & Guimond, 1992) with two species of nematodes of commercial importance resulted in pathological lesions which compare with those in the normal host and yet in these laboratory species the adult nematodes never mature-there is absolute “non-permissiveness”, the basis of which remains unknown. Further, removal of the spleen (Anderson, Cassaday & Healy, 1974) has resulted in human infections with Babesia microti, normally an exclusive parasite of mice. Later infections of healthy humans with B. microti were apparently the result of very high infection rates from close contact with the tick vector (Spielman, 1976). Thus, under extreme conditions, the species barriers can be broken down. The basis of host specificity has been explained in a few cases. Some non-(parasite) specific humoral factors have been identified which render hosts non-permissive: antibody-independent complement lysis of Trypanosoma cruzi in chickens (Kierszenbaum, Gottlieb & Budzko, 1981) and of Ascaris suum in guinea pigs (Leventhal & Soulsby, 1977). Human high density lipoprotein lyses some populations of the Trypanosoma brucei complex and protects humans from infection (Rifkin, 1978). These interspecific barriers have no recognition phase in the sense of

processing

or the production

of

within species

The importance of understanding intraspecific variation was stressed by Wakelin (1978): “It is probably not an exaggeration to say that failure adequately to recognise intraspecific variability in response to infection has hindered experimental investigation of the host-parasite relationship and may have delayed the development of effective control measures against economically important parasites.” Evidence acquired in the last 40 years has clearly shown that a significant proportion of intraspecific variation is genetically determined. Two examples of simple genetic control of variation have been demonstrated in Plasmodium falciparum infections of humans. It was established by Allison (1954) that the abnormal haemaglobin S, determined by a single gene, confers resistance to falciparum malaria. It is of major importance to the affected populations, and to the understanding of the possible maintenance of diversity of resistance genes, that individuals homozygous for the S allele do not survive, and therefore this lethal recessive gene is maintained in the human population by the advantage gained by heterozygous individuals exposed to infection. It cannot be inferred from this example, however, that resistance to disease necessarily has genetic disadvantages for the population. Indeed, generation of such diversity may have longterm advantages. Again using P.,falciparum, but this time in mice being vaccinated with a sporozoite vaccine, Good, Berzofsky, Maloy, Hayashi, Fujii, Hockmeyer & Miller (1986) have shown that the response to vaccination is restricted by MHC class 2 antigens expressed on the surface of T cells. As there is high diversity in the MHC antigens among humans these authors concluded that the prospects for large scale vaccination with this type of vaccine in humans were poor. T cells play a key role in the response to infection and vaccination and Mitchell (1979) argues that the T cell has also played an important role in the development of host-parasite systems, certainly at the intraspecific level. The lines of sheep successfully selected on the basis of the response to vaccination against Trichostrongylus colubriformis (reviewed by Windon, 1990) provide further evidence that there is genetic variation in the hosts ability to respond to vaccination as well as to infection. The genetic basis of resistance to Nematospiroides dubius infections in similarly selected lines of mice (Brindley, He, Sitepu, Pattie & Dobson, 1986) and to Haemonchus, in sheep (Woolaston, Gray, Albers, Piper, & Barker, 1990) was found to be polygenic, the consequence of

Host genes, parasites and parasitic infections the action of many genes rather major genes.

than one or a few

Variation amongpopulations Defining populations within species is difficult and controversial. Even distinct species as currently defined e.g. Bos taurus and Bos indicus, can interbreed. Below the species level there are a number of terms used to describe discrete populations: strain, race, breed, bloodline, or population and in each situation these terms need to be defined. Even when no distinctions can be easily drawn between different sections of the one population, it cannot be assumed that it is a single random-breeding, genetically homogeneous population. This is as true for domestic livestock as it is for humans: pedigrees in both cases can be misleading and inaccurate. The difficulties of distinguishing genetic from environmental sources of variation in disease resistance were described early by Chandler (1932) who cites a study which apparently showed “racial” differences between “Indian-whites” and “Indian-negros”, the latter showing greater resistance to hookworm (Cort, Stoll, Sweet, Riley & Schapiro, 1929, cited by Chandler, 1932). Later studies, reviewed by Cram (1943) showed Americans of African origin to have about one half to one third of the incidence of Enterobius vermicularis infection as their counterparts of Caucasian origin. This was a large study of over 4000 individuals yet it is conceded (Cram, 1940) that social and behavioural differences could not be eliminated as explanations of their findings. In animal studies it should be possible to make comparisons between populations within a species to eliminate all environmental influences. There are a number of criteria which have to be met, for example in the comparison of breeds: 1. Offspring born and reared together in the same environment. 2. Parents sampled from a wide, representative population of the target breeds. 3. Pedigrees recorded for appropriate statistical testing of breed effects. It is surprising (see Gray, 1991 and Gruner, 1991 for reviews) how often these conditions are not met. There are few good examples among ruminant breeds where knowledge of the breed has any predictive value for resistance to parasitic infection. It has been repeatedly shown that N’dama and West African Shorthorn cattle are more resistant to the effects of trypanosomes (Trail et al., 1991) and Bos indicus (species, breed, race?) are more resistant to tick infestation (Utech,. Wharton & Kerr, 1978; de Castro, 1991). In chickens (reviewed by Ackert, 1942) there is extensive variation among chicken breeds in resistance

487

to Ascaridia galli and inbred lines of chickens vary in their susceptibility to Eimeria infections (Bumstead & Millard, 1992). In the latter study seven Eimeria species were tested in eight strains of chickens and over all the lines there was an inverse relationship between resistance to the caecal species Eimeria tenella and the remaining six species. A comparable situation was described in pigs by Johnson, Stewart & Hale (1975): Hampshires were more susceptible than Duroc to infections with Strongyloides ransomi but more resistant to Ascaris suum. Such antagonistic effects have not been described in lines of sheep selected for resistance to gastrointestinal nematodes. Selection for resistance to Haemonchus confers resistance (although perhaps of lesser magnitude) to Trichostrongylus infections (Gray, Barger, LeJambre and Douch, 1992; Woolaston, Windon & Gray, 1991) and Ostertagia infections (Gill & Cruikshank, unpublished observations) and sheep selected for resistance to Trichostrongylus are also resistant to Ostertagia and Haemonchus infections (Windon 1991). Variation within populations Evidence for genetic control of resistance within human populations is difficult to obtain. Croll & Ghadirian (1981) identified a small proportion (l-3%) of the human population in Iran which carried between 11 and 84% of intestinal worm burdens but these “wormy persons” in 1 year were not the same in the next year suggesting there was a nongenetic reason for their worminess. In animal populations such overdispersed distributions of worms have been described by many authors (e.g. Crofton, 1971; Barger, 1985) and there is a better opportunity to distinguish between genetic and environmental effects since the development of computerised analysis and handling of large sets of data. To obtain accurate estimates of the genetic component it is usually necessary to perform large experiments. In the case of sheep producing one lamb per ewe, it is necessary to mate about 60 rams with 1500 ewes, with all the lambs being measured for the resistance traits of interest (Falconer, 1989). In almost all cases where genetic variation has been sought it has been found. For nematode infections of sheep, for example, the proportion of variation that can be attributed to genetic effects (the heritability) varies between 0.2 and 0.4 (Woolaston et al., 1991). Leighton, Murrell & Gasbarre (1989) and McKinnon, Meyer & Hetzel (1991) describe similar heritabilities for resistance to nematodes in calves. At such levels there are prospects for selective breeding for improved resistance (Gray, 1991). It is only in New

488

G. D. GRAYand H. S. GILL

Zealand that intraspecific or “within-population” genetic variation has been utilised in commercial sheep production (Parker, 199 1; Bisset, Vlassoff, Morris, Southey, Baker & Parker, 1992;). Faecal worm egg counts which occur naturally in lambs of fully pedigreed flocks of Romney sheep are used to estimate the relative value of rams for sale-rams are ranked from best to worst on the basis of their worm egg counts and those of all their relatives after exposure to naturally occurring infections. It is not essential that the ram has his own egg count recorded. Mechanisms of resistance Protective responses of mammals to parasitic infections include non-specific cellular immunity, particularly by macrophages and specific immunity mediated by antibodies and T cells and their products (Templeton et al., 1988). Among parasites there are no known equivalents to the resistance to Escherichia coli in pigs conferred by the absence of the glycoprotein receptor which allows bacteria to attach to the gut epithelium (Edfors-Lilja, 1991). The lack of the Duffy blood group glycoprotein which confers resistance to Plasmodium knowlesi is the nearest equivalent. But cell-bound glycoproteins on the surface of lymphocytes have been shown to be crucial in the control of specific immunity. These proteins are highly polymorphic and are controlled by the major histocompatabihty complex (MHC). This complex is sufficiently polymorphic for each individual in an outbred population to have a unique set of MHC genes. It is not surprising therefore that differences in response to parasitism between populations which are of different MHC haplotype have been described, in some detail in laboratory mice (Wakehn, 1985) but also in domestic livestock (Warner, Meeker & Rothschild, 1987; Gogolin-Ewens, Meeusen, Scott, Adams & Brandon, 1990). The functional basis of T cell control of immune response to parasites has been the subject of intensive recent research and confirms the conviction (Mitchell, 1979; Wakelin, 1988) that T lymphocytes play an important role in genetic control of resistance to parasites. Studies in mice and humans have shown that CD4+ T lymphocytes can be divided into two functionally distinct subsets, Th, and Th, based on their pattern of cytokine production (Mosmann & Coffman, 1989; Romagnani, 1991). The preferential activation of one or other CD4+ T cell subset has been shown to account for differences in susceptibility of mice to parasitic infections (Pond, Wassom & Hayes, 1989; Else, Hultner & Grencis, 1992; Locksley & Scott, 1991). Recent studies by Gill, Watson and Brandon (1993) have shown that CD4+ T cells play a pivotal role in mediating genetic resistance to

Haemonchus contortus in sheep. Whether differential induction of Th cell subsets also account for variation in responsiveness of sheep to gastrointestinal nematodes remains to be determined. It has also been demonstrated that parasites can use elements of the host immune response to stimulate their own development. For example, Amiri, Locksley, Parslow, Sadick, Rector, Ritter & McKerrow (1992) have shown that the T-cell derived cytokine TNFcw triggers both the granulomatous reaction of mouse tissue to eggs of Schistosoma mansoni and increases fecundity of the worms, both in vivo and in vitro, in cultures of explanted worms. The parasite is therefore exploiting one aspect of the immune response of the host (Damian, 1987) and there is the intriguing prospect that selection of mice for elevated TNFa responses to S. mansoni would actually exacerbate the infection. In general there is the possibility that selection of hosts for single facets of the immune response may lead to other aspects of the immune response being suppressed (Warner et al., 1987). In outbred Merino sheep populations, parents selected on the basis of MHC alleles (ovine lymphocyte antigens), identified by a microcytotoxicity test, produced lambs with predictable differences in faecal egg count (Outteridge, Windon & Dineen 1988): lambs with OLA types Sy la and SY 1b were significantly more resistant. A similar effect was found (Douch & Outteridge 1989) in Romneys which were infected with T. colubriformis. Other attempts to demonstrate such associations in nematode infections of sheep have been unsuccessful (Cooper, van Oorschot, Piper & Le Jambre, 1989; Luffau, Nguyen, Cullen, Vu Tien Khang, Bouix & Ricordeau, 1986). Positive results have been obtained by Stear, Hetzel, Brown, Gershwin, McKinnon & Nicholas (1990) in cattle and Lunney & Murrell (1988) report MHC-enhanced resistance to Trichinella spiralis in pigs. Another approach to detecting genetic polymorphisms of the MHC, or other polymorphic systems that influence resistance, is to look directly at the genome. Techniques for detecting polymorphism of digested DNA (Restriction Fragment Length Polymorphism) have been used in sheep with equivocal results (Hulme, Windon, Nicholas & Beh, 1991; Blattman, Hulme, Kinghorn, Gray, Woolaston & Beh, in press), and at present they have no predictive value. EFFECTS OF HOST GENES ON PARASITES Genetic effects on parasites are usually assessed by some aspect of parasite growth or development (number, size, weight), production of reproductive stages (spores, cysts, eggs) or by the direct or indirect effects of the parasite on the host. The importance of making the distinction between these depends on the

Host genes, parasites 100 -

.

90 -

%

Establishment

80 70 60 50 -

and parasitic

n q

Resistant Random-bred

3000

Female

489

Rate

80

70

infections

Weights

1

Worm

Counts

60 2000 50

mg

40

No.

30

20

FIG. 1. Differences in mean establishment rates, faecal egg counts, numbers of worms and weights of 25 female worms in groups of resistant and random-bred lambs from the University of New England Resistance Flock. Establishment rates were measured by the administration of radiolabelled H. contortus larvae to sheep grazing pastures contaminated with nematodes (Gray et al., 1992). The other data were taken from sheep infected artificially with ll,OOO-20,000 infective larvae of H. contortus and faecal sampled or slaughtered at intervals after infection (Weight data from Gill, 1991, other data from Gray,

Presson, Burgess & Adams, unpublished). perspective of the study in question. For animal production perhaps only the latter is important (though not necessarily so)-for the parasite biologist only the first and second. Evolutionary ecologists will, by definition, concern themselves with all three. Resistance (e.g. Albers, Gray, Piper, Barker, LeJambre & Barger, 1987) is usually expressed as a function of the biology of the parasite, such as growth or fecundity. In contrast, tolerance (e.g. Trail ef al., 1991) and resilience (Riffkin & Dobson 1979, Albers et al., 1987) are expressed in terms of the host response to infection. As usual, however, such terms mean little without accompanying definition. There is evidence that all stages of nematode development are under genetic influence of the host (Fig. 1). In Huemonchus infections of sheep Gray et al. (1992) have shown that establishment rates vary between lambs from parents selected for decreased egg counts and lambs from unselected parents. Egg production rises to a lower level and declines more quickly, and female worms weigh less and are less fecund (Presson, Gray & Burgess, 1988; Gill, 1991; Gill, Gray& Watson, 1991). Similar general effects can be seen in other hostparasite systems and in outbred populations. It is clear therefore, that resistance is regulated by a complex interaction of immune processes controlled by many genes. In inbred mouse populations Wassom, Wakelin,

Brooks, Krco & David (1984) describe 3 elements of genetic control of T. spiralis infection described as “anti-fecundity”, “anti-adult” and “rapid expulsion” responses and each of these is under separate genetic control. These studies are only possible using congenic strains of mice which differ only at single MHC loci. Genetic responses by parasites to genetic changes in their hosts are more difficult to measure. It is axiomatic, however, that parasites have evolved in response to the evolution of their hosts although the mechanisms by which they have done so are controversial (Toft & Karter, 1990; Rollinson & Anderson, 1985; Mitchell, 1991). Experimental evidence for that has been difficult to acquire, perhaps because artificially induced changes in host resistance have been relatively short term, not on an “evolutionary” time scale. But in mice it has been possible to infer that changes in infectivity in strains of Nematospiroides dubius after repeated passage through genetically resistant lines of mice (Dobson & Owen, 1977) are genetic changes. The African tick Rhipicephafus uppendiculatus has adapted genetically to multiple passages through rabbits, becoming less infective for its natural cattle host (Chiera, Newson, & Karuhize, 1989). Albers & Burgess (1988) and Adams (1988) were unable to detect changes in H. contortus after multiple passages through immune sheep.

490

G. D. GRAY and H. S. GILL

Experimentally, therefore, it has been difficult to show genetic effects on parasites that live in resistant hosts. But clearly nematodes have the ability to respond genetically in a relatively short number of generations: genetically determined resistance to anthelmintics is sufficient evidence for that (Waller & Prichard, 1986). In a long-term experiment designed to test if H. contortus will respond genetically to increased genetic resistance of sheep Woolaston, Elwin & Barger (1992) established a population of H. contortus with a wide genetic base, and these were maintained in Merino sheep that had been selected (Woolaston, Barger & Piper, 1990) for increased and decreased resistance to H. contortus. After 14 parasite generations (14 passages through resistant or susceptible sheep) the lines of parasites were tested for their infectivity of the selected sheep lines and a randombred population. It is encouraging that there were no differences in infectivity between the base population of parasites and the selected lines and it will be of great interest to know if this is still the case when the experiment is complete, after 30 parasite generations. Lack of field evidence that nematodes will respond genetically to increased host resistance may be related to the nature of the mechanism by which resistant hosts attack parasites. Anthelmintics, though highly effective (> 99% mortality of parasites in many cases) have a relatively simple mode of action (Behm & Bryant, 1985) whereas genetic resistance may be expressed, as indicated above, by many immune processes (Gill et al., 1991; Windon 1991; Gill, Watson & Brandon, 1993). There is certainly no evidence to suggest that the vaccine used to control the cattle lungworm Dictyocaulus viviparus has become any less effective after over 20 years of use in the same populations of host and parasites (Oakley, 1982). INTERACTIONS

BETWEEN

RESISTANCE

GENES

o.oI 1

3

2

4

Age FIG. 2. Heritability estimates from 184 to 190 calves aged, grazing pastures contaminated (drawn from data of

0

14

26

42

56

5

6

(months)

of faecal egg counts collected on average, l-6 months and with several nematode species Gasbarre et al., 1990).

70

Time

64

+

RESISTANT

-*“-@

RANDOM-BRED

96

112126140154

(Days)

FIG. 3. Faecal egg counts of genetically resistant and randombred lambs following primary and secondary infection with 20,000 H. conforms infective larvae. Resistant lambs had significantly higher faecal egg counts than random-bred lambs on days 49, 52 and 56 days after primary infection but significantly lower 35, 38 and 42 days after secondary infection (Gill, 1991).

AND

THE ENVIRONMENT

In the context of evolution and animal breeding, environmental influences are usually seen as external forces-weather, food availability, predators, population density. For parasites (exclusively for some) the environment is their host or hosts. All hosts: vertebrate, invertebrate (Lackie, 1986) and plants (Webster, 1975) respond to the presence of parasites. In mammals the reaction is complex involving multiple components, specific and non-specific, of the immune system. Dineen (1963) made the point clear that: “the immune response of the host should not be regarded simply as a mechanism which may cause elimination of the parasite infection but rather as an environment which has a profound effect on the host/parasite relationship.”

Worm-Free

Pasture-Reared

FIG. 4. Worm burdens of genetically resistant and random-bred lambs raised worm-free or on pasture following challenge infection with 20,000 H. contortuS infective larvae. The pasture-reared lambs were on a low plane of nutrition on pasture contaminated with nematodes and were drenched 5 weeks before challenge. The wormfree lambs had experienced an artificial infection of 20,000 H. contorfus larvae of 11 weeks duration, terminated 5 weeks before challenge by drenching, and had been on a high plane of nutrition (Gill rr ul., 1991).

491

Host genes, parasites and parasitic infections

The immunological environment of ruminants changes with age of the host, with the period of time to which the host has been exposed to parasites, the number of parasites and to their level of nutrition in terms of protein, energy and minerals (Wakelin, 1989). In cattle Gasbarre, Leighton & Davies (1990) showed that the response to Cooperia and Ostertagia, expressed in terms of faecal egg count, was heritable with a range of heritabilities from 0.08 to 0.27, depending on the time of sampling. The pattern of heritability estimates (Fig. 2) is interesting, showing an increase from April to September (spring-summer) in calves that were born from February to April. Three influences in the immune response are changing throughout this period-the calves are becoming immunologically more mature, (a process which is also influenced by nutritional status), the number of parasites to which the calves are being exposed is increasing, as is the length of time to which the calves have been exposed to infection. It is not possible to separate these elements in this experiment. As the infection progresses, more of the variation in egg count can be attributed to the genes of the calves-i.e. they become under greater genetic control. Lack of heritability (0.08, not significantly different from zero) in September could have meant there was a sudden increase in the effect of the environment on resistance or that some stage of immunological tolerance or saturation had been reached. Whatever the explanation, the apparent level of genetic control by these calves of their nematode infections varied with the environment in which it was measured. Lack of heritability (0.04 in young goats, 0.08 in adult goats) of faecal egg count has also been described in goats in Fiji (Woolaston, Singh, Tabunakawai, LeJambre, Banks & Barger, 1992). It may be that goats, in contrast to sheep and cattle, have no genetic control of their nematode infections oy that exposure to the high, continuous levels of parasite challenge in the tropics has modified the expression of resistance genes. Gill (1991) has shown that differences between genetically resistant and random bred lambs are highly dependent on previous exposure to parasites. Pasturereared lambs, of genetically resistant parents, are more resistant than their random-bred counterparts (Fig. 3) but worm-free lambs of the same parents are more susceptible than their random-bred counterparts. The nature of the pre-challenge environment, exposure to parasites, has dramatically modified the expression of the resistance genes. On a more positive note, Woolaston et al. (1991) and Gray et al. (1992) have shown that once exposed to parasites, lambs of genetically resistant parents are relatively resistant from weaning through to adulthood and also at the critical times around parturition.

Nutrition may have a marked effect on the magnitude of genetic differences in resistance. Figure 4 shows differences in the level of resistance between Haemonchw resistant and random bred sheep. Overall the level of resistance in pasture-reared (and poorly fed) sheep was much less than the well-fed sheep maintained indoors. At the time of challenge, both groups of sheep had been exposed to parasites, the indoor sheep by artificial infection. The difference between the groups was markedly greater in the pasture-reared animals. Although the difference in the nature of the first infection to which the sheep were exposed must be considered as a cause of this interaction, the effect of nutritional status cannot be discounted. CONCLUSION

Despite overwhelming evidence that parasites and hosts interact with each other at the genetic level and that much variation in host response to parasites has a genetic basis, our ability to predict the outcome of parasitic infections from oui knowledge of the genetic make-up of the host is disappointingly poor. In practice there are very few examples where genetic variation in parasite resistance has been exploited. Choice of breed for tolerance to trypanosomes or resistance to ticks have been the only, albeit very important, examples of widespread successful implementation of our knowledge of genetic differences between populations. In Australia and New Zealand the sheep industry is starting to select within flocks for resistance to nematode parasites. The potential gains to be achieved from understanding and utilising genetic variation in resistance to parasites have yet to be realised. The problems that may accompany genetic improvement-reduction in genetic diversity, loss of potentially useful alleles and possible increase in susceptibility to other diseasesmay be overshadowed by the advantages to be gained from permanent, non-chemical and sustainable control of parasitic disease. Acknowledgemenr-Financial authors

was provided

support for the work of the

by the Australian

Wool Corporation.

REFERENCES ACKERT J. E. 1942. Natural resistance to helminthic infections. Journal of Parasitology 28: l-24. ADAMS D. B. 1988. Infection with Haemonchus confortus in sheep and the role of adaptive immunity in selection of the parasite. International Journal for Parasitology 18: 1071L 1075.

ALBERS G. A. A., GRAY G. D., PIPER L. R., BARKERJ. S. F., LEJAMBRE, L. F. & BARGER I. A. 1987. The genetics of resistance and resilience to Haemonchus contortus infection in young Merino sheep. International Journal for Parasitology 17: 1355-1363.

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