Increased selection pressure applied to commercially important traits in production environments is often accompanied by increases in disease problems. Cost estimates for swine diseases in the U.S. exceed 1.5 billion dollars yearly. At the same time, selection for immune responsiveness and disease resistance has often been ignored by animal geneticists because of the difficulty of measuring these traits. Actual disease resistance to individual diseases would have to be measured under an environment that included disease challenge. Such testing would be prohibitively expensive. New opportunities to improve our understanding of the genetic nature of disease resistance now exist through the recent advances in molecular biology, gene mapping, and immunology and make selection for disease resistance possible in the future. However, genetic considerations involved with testing and selection for disease resistance and improved immune responsiveness will require knowledge of the genetic correlations between disease resistance and immune responsiveness and production traits. Limited research suggests that antagonistic relationships between immune response, disease resistance, and production traits might make simultaneous improvement of these traits difficult by conventional breeding and selection methods. Use of marker-assisted selection or gene-transfer methods with the genes of the MHC or other major genes may offer an alternative approach for simultaneous improvements in all of these traits.

Introduction

Efficient pork production is often disrupted by disease, which costs livestock producers and consumers billions of dollars each year. These considerable monetary losses result from mortality, subclinical losses due to poorer production efficiency, increased veterinary costs and product loss. Selection pressure on commercially important traits under stressful production settings also may increase the incidence of disease. Disease also impairs genetic improvement in production traits because efficiency of selection is reduced. Current methods to control disease include vaccination, medication, sanitation, and isolation of animals from pathogens and eradication of certain diseases. These approaches, however, are not always effective. Lack of effectiveness of some vaccines and increased attempts by consumers to change drug-use regulations because of fears of contamination of human food sources underscore the need for more effective methods to combat disease.

A clear understanding of disease and the animal's defense systems is required for alternative approaches to disease control. The onset of disease is often the result of the interaction between an individual animal's genotype and the environment to which the animal is exposed. If an animal has a genetic predisposition for acquiring a disease, then environmental conditions, including standard disease-prevention methods may be only partly effective in preventing disease. An often-overlooked alternative approach to standard disease control methods would be selective breeding to increase disease resistance in livestock. Genetic resistance to disease involves many facets of the body's defense system and their interactions and is extremely complex.

In this report the current status of knowledge of methods to select for disease resistance and immune responsiveness in pigs and other livestock is reviewed. Opportunities to improve disease resistance and immune responsiveness in pigs through marker-assisted selection and gene-transfer techniques are discussed.

Current Status

The presence of some diseases may result from strictly genetic control, whereas others may be caused by a combination of genetic predisposition and exposure to pathogens. Disease resistance research has included measurement of genetic control of disease losses, estimation of heritabilities, and characterization of breed or strain differences. Numerous examples of this research exist for leukosis and Marek's disease in poultry (Hutt, 1958; Freeman and Bumstead, 1987), mastitis and ketosis in cattle (Philipsson et al., 1980; Solbu, 1982), and parasite infestation and foot rot in sheep (Albers et al., 1987; Bulgin et al., 1988). In pigs, breed differences have been reported for atrophic rhinitis and respiratory diseases (Lundeheim, 1979; Kennedy and Moxley, 1980). More recently, breed differences for infection to PRRS has also been reported (Halbur et al., 1998).

Genetic control of certain diseases may be the result of the presence or absence of receptors that are inherited simply. Resistance to specific subgroups of leukosis virus in chickens seems to be inherited simply (Crittenden, 1975) and may be the result of not having the receptor for the virus. In swine, some individuals lack the receptor for K88, a cell-surface antigen on some Escherichia coli, and the E. coli cannot attach to the gut in these pigs (Gibbons et al., 1977). Resistance to infection from the K88 strain of E. coli is recessive, but susceptible animals remain in the population because maternal antibodies allow some protection. In some breeds, this resistance is not simply recessive (Michaels et al., 1994) and may result from other loci.

Depending on the species, breeders routinely select animals on the basis of from one to perhaps as many as 20 traits. This selection is practiced under environments that challenge livestock greatly and may increase the incidence of disease if management is poor. Many researchers have examined approaches to selection for disease resistance (Gavora and Spencer, 1983; Rothschild, 1985, 1989; Warner et al., 1987; Straw and Rothschild, 1992). These direct approaches, with some modifications, are found in Table 1. The simplest method would be to observe and select breeding stock for disease resistance under normal production conditions. This would have no negative effects on production of breeding stock but probably would not be very informative, because, without disease (under good hygiene and management), expression of disease resistance would be questionable. Challenging breeding stock, progeny, or sibs would be costly, depending on the severity of the disease challenge, and production could be adversely affected. This method would be of limited value unless sufficient numbers of progeny or sibs are tested. Thanks to the new opportunities animal cloning offers, one alternative possibility to testing progeny or sibs would be to obtain a large number of clones of embryos from planned matings of breeding stock. Once raised, one set of these animals (clones) could be challenged with a specific disease or diseases. Selection of their clones (other animals) could then occur on the basis of results from the cloned animals. Because the animals tested were clones, accuracy would be equal to testing the individuals themselves.

Numerous other problems involved with disease challenge or selection under challenging environments exist. These include standardization of the level of challenge exposure to a particular disease and maintenance of isolation facilities for this type of selection. Consider selection under a challenging environment or a disease environment compared with a normal production setting. Although previous research suggests that animals selected under "bad" environments perform as well in "good" environments as those selected directly in "good" environments (Falconer, 1960), if performance rankings of individuals or families seem to be different under the two environments, then genotype by environment interaction probably exists. Estimates of the genetic correlations between disease resistance, immune responsiveness, and production traits under "good" and "bad" environments would be needed to assess the possibility of genetic improvement by this approach. Selection difficulties would arise if there are antagonistic correlations between the disease resistance and production traits. These problems become multiplicative if the number of diseases for which selection is practiced is large. An index approach would be useful, but would require accurate estimates of all the genetic correlations between the disease resistance and performance traits. Such estimates are presently unavailable. Direct selection for disease resistance may also cause a reduction of genetic progress in other traits because of the increased total number of traits.

Given the difficulties in selecting for disease resistance under challenging environments, alternatives to those methods have been proposed (Table 2). Immune responsiveness has been suggested as an indirect indicator of disease resistance (Biozzi et al., 1980; Gavora and Spencer, 1983; Buschmann et al., 1985; Rothschild, 1989; Warner et al., 1987). Early studies with mice (Biozzi et al., 1980) have revealed that genetic control of antibody response to sheep red blood cells was moderately heritable and that selection for humoral immune response for one antigen may improve humoral immune response for other antigens. They also investigated genetic control of cell-mediated responses. Selection for increased humoral response to sheep red blood cells did not improve cell-mediated response, suggesting independence of these traits.

In livestock, the most extensive research with genetic control of immune response has been in poultry (van der Zijpp, 1983a; Lamont and Dietert, 1990). Genetic control of immune responsiveness to sheep red blood cells has been thoroughly investigated (Siegal and Gross, 1980; van der Zijpp and Leenstra, 1980). Heritability estimates have ranged from 0.28 to 0.38, suggesting that this trait is under moderate genetic control. Results suggested that immunization procedures, dosage and site of immunization all affect measurement and extent of genetic control (van der Zijpp, 1983b). Such details may make the use of immune response as an indicator of disease resistance more difficult. Other experiments have demonstrated that response to vaccination with Newcastle disease, Salmonella pullorum, and E. coli are under moderate genetic control and that selection for high and low antibody response following vaccination is effective (Lamont and Dietert, 1990).

Immune response experiments in swine using sheep red blood cells and DNP-hapten as antigens have revealed significant between-breed and within-breed differences (Buschmann et al., 1974; Buschmann, 1980). In a separate series of experiments, the heritability of secondary immune response and peak response to bovine serum albumen were estimated to be 0.51 and 0.42, respectively (Huang, 1977). Using commercial vaccines for Bordetella bronchiseptica and pseudorabies virus, researchers demonstrated significant within-breed and between-breed differences, low to moderate heritabilities (0.05 to 0.52) but little or no non-additive (heterosis) genetic control of immune response (Rothschild et al., 1984a,b; Meeker et al., 1987a,b). Immune responses to vaccines that contained two E. coli antigens also were shown to be under moderate genetic control, with heritability estimates ranging from 0.29 to 0.45 (Edfors-Lilja et al., 1985).

In cattle and sheep, experiments (Lie, 1979; Nguyen, 1984; Muggli et al., 1987) have revealed genetic variation for immune response to a variety of antigens, including chicken red blood cells, human serum albumen, and infectious bovine rhinotracheitis virus (IBRV). These results suggest that genetic control of immune response exists for all livestock species.

A second indirect approach would be to consider in vitro methods as indicators of disease resistance. These methods include, for instance, phagocytic and bactericidal actions of peripheral blood monocytes against disease agents such as Salmonella typhimurium and Staphylococcus aureus (Lacey et al., 1990). Other such methods include neutrophil metabolic and phagocytic activity and lymphocyte blastogenesis in response to antigens. Use of mitogens as an indicator of cell-mediated response has revealed that genetic differences exist in poultry for the T cell mitogens phytohaemagglutinin and concanavalin (Lassila et al., 1979). As with poultry, response to mitogen stimulation has also been demonstrated in swine for reactivity to phytohaemagglutinin and poke-week mitogen. Efforts to create an immunocompetence index in swine have been only moderately successful (Buschmann et al., 1985). In vitro procedures and their relationship to actual disease resistance are unknown in general.

A third method would be to locate genetic markers associated with disease resistance or the actual genes themselves. This approach was generalized first by those suggesting use of RFLP analyses in genetic improvement programs (Soller and Beckmann, 1983). Given the complexity of immune response and its relationship with disease resistance, the search for marker genes associated with these traits was enormous, especially in the 1980s when it began. Modern immunology, however, has revealed that a group of genes, called the major histocompatibility complex (MHC) genes, seem to be intimately associated with both disease resistance and immune responsiveness. All higher life forms are known to possess a MHC that codes for the predominant cell-surface proteins on cells and tissues of each individual species. These antigens are markers of "self" and are unique for animals other than identical twins or clones. Three classes of protein molecules, class I, class II and class III, are encoded for by the MHC. The class I molecules are extremely polymorphic, whereas the class II antigens are less polymorphic. Class III molecules show only limited polymorphism. The function of the MHC genes is now generally known. The class I antigens act as restricting elements in T cell recognition of virally infected target cells and, thus, are necessary to generate an immune response. The class II genes (Ir genes) control the interaction of T cells, B cells, and macrophages in the generation of the humoral immune response and participate, as well, in aspects of cellular immunity. The class III genes are intimately involved with the complement cascade, which ends with the lysis of the cell or virus particle to which antibody has bound. The structure and function of the MHC in pigs seems to be similar to that of humans and mice (Warner et al., 1988; Warner and Rothschild, 1991).

The B complex, the MHC in chickens, has been extensively studied and shown to be involved with both immune response and disease resistance. More specifically, the B complex has been shown to be associated with immune response to synthetic antigens, bovine serum albumen, Salmonella pullorum bacterium, total IgG levels, and cell-mediated responses (Nordskog, 1984; Lamont and Dietert, 1990). Resistance to Marek's disease, Rous Sarcoma virus, fowl cholera, and lymphoid leukosis viruses has also been demonstrated to be associated with the chicken MHC (Lamont and Dietert, 1983; van der Zijpp, 1983a; Lamont, 1989). In retrospect, it seems that poultry-breeding companies have, in fact, indirectly selected for certain MHC genotypes by eliminating lines or strains that were susceptible to certain diseases.

In swine, perhaps the best-studied domestic species, several experiments have shown that the swine MHC (SLA complex) is associated with immune response following vaccination. Researchers, working with miniature inbred pigs and commercial strains, have demonstrated that the SLA complex is associated with immune response to hen egg-white lysoyzme and B. bronchiseptica vaccine (Vaiman et al., 1978b; Rothschild et al., 1984a). The synthetic polypeptide antigen (T,G)-A-L has been shown to be under the control of the class II SLA genes in miniature pigs (Lunney et al., 1986). Differences in quantitative levels of class III molecules have also been shown to be related to the SLA complex (Vaiman et al., 1978a). Evidence of SLA association with parasite infection has been reported (Lunney and Murrell, 1988). A more complete list of disease associations and the structure and function of the SLA complex has been reviewed by Warner and Rothschild (1991) and more recently updated by Lunney and Butler (1998) and Vaiman et al. (1998).

In other livestock species, reports of MHC involvement with immune response and disease resistance also exist. In cattle, the BoLA (bovine MHC) complex has been associated with intestinal parasites, tick susceptibility, and mastitis (Spooner et al., 1988). Bovine leukemia virus has also been demonstrated to be associated wit the BoLA complex (Lewin et al., 1988). In the horse, the ELA (equine MHC) complex seems to be associated with equine sarcoid tumors (Meredith et al., 1986). Resistance to scrapie (Millot et al., 1988) was shown to be associated with the sheep MHC (OLA complex), as was response to vaccination against Trichostrongylus colubriformis (Outeridge et al., 1985). Opportunities exist for discovering additional relationships between the MHC and immune response and disease resistance in livestock. The MHC genes, therefore, may serve as gene candidates for selection.

More recent molecular genetic approaches have included using gene maps and quantitative trait loci (QTL) scans to find genes associated with disease resistance and immune response. To date in pigs, these QTL scans for disease resistance or immune response QTL have been very limited. An exception is work underway by Andersson and colleagues (Edfors-Lilja and Andersson, personal communication) to study some immune response parameters. Some immune capacity QTL have been identified including those regions known to control Ig level and to be associated with immune response to certain vaccines. Also, a QTL for base cortisol level which may be related to stress and perhaps immune response, has been mapped to the end of chromosome 7 (Milan et al., 1998).

Analyses of associations of candidate genes have been more substantial. The general location of the K88 E. coli receptor has been known for some time, and fine mapping and candidate gene analysis of the region is underway in many labs. It is hoped that the actual gene controlling this trait will be found soon. Two alpha (1,2) fucosyltransferase genes (FUT1, FUT2) on porcine chromosome 6q11 have been identified and are closely linked to the blood group inhibitor (S) and Escherichia coli F18 receptor (ECF18R) loci. Vögeli and colleagues (Meijerink et al., 1997) found a polymorphism which is closely linked to ECF18R in Large White, Landrace, Hampshire, Duroc, and Pietrain pigs, and it now is clear that FUT1 and FUT2 loci are associated with E. coli F18 adhesion resistant animals in these breeds. Further research to confirm that the FUT1 or FUT2 gene products are involved in the synthesis of carbohydrate structures responsible for bacterial adhesion remains to be determined. The gene for Natural Resistance Associated Macrophage Protein 1 (NRAMP1), associated with resistance to Salmonella challenge in mice, has been recently mapped to pig chromosome 15 (Sun et al., 1998). Additional studies of the role of NRAMP1 are presently underway. Several other candidate genes are being investigated, including those controlling immunoglobulin and interleukin production. Genes associated with human disorders, which have been identified and mapped in the pig, include clotting factor IX (Signer et al., 1996) and the familial hypercholesterolaemia gene (Hasler-Rapacz et al., 1996).

When one considers the problems of selection under challenging environments, the possibilities to make improvements in disease resistance and immune responsiveness seem limited. First, direct selection for disease resistance may be too costly. Second, results in a number of species suggest that humoral immune response to one antigen is not necessarily a good indicator of humoral response to other antigens or to other aspects of the immune response. Third, MHC genotypes known to be associated with susceptibility to one disease differ from those known to be associated with susceptibility to different diseases. The heterozygosity of genes that influence immune response, especially those of the MHC, is an obvious advantage, and polymorphism for MHC loci would allow species the opportunities to survive a variety of disease challenges. The interrelationships among disease resistance and immune responsiveness must also take into account their association with production traits. It might seem reasonable to believe that selection for improved production efficiency might also have indirectly selected for improved disease resistance and immune responsiveness. Given the use of medication and the frequent vaccination programs that exist in livestock production, it seems that these husbandry practices may have masked genetic resistance to disease.

Experimental evidence of the relationships of disease resistance, immune response and production traits is scarce. In poultry, results are contradictory (van der Zijpp, 1983b; Lamont, 1989). In one experiment, selection for rapid growth rate was associated with increased susceptibility to Marek's disease. In another set of experiments, associations with Marek's disease and egg laying performance were contradictory. Immune response to sheep red blood cell seems to be antagonistically associated with growth rate in broilers. Immune response to Newcastle disease vaccine seems to be negatively correlated with hatchability in Japanese quail and with egg production in chickens.

In other livestock species the results are similar. Meeker et al. (1987a) found that growth rate was negatively correlated with immune response following vaccination with either a commercially prepared B. bronchispetica or pseudorabies virus vaccine but that backfat at market weight was not correlated with either immune response. Pigs that have the intestinal receptor for K88 E. coli (and are therefore susceptible) grew faster and had better feed conversion (Edfors-Lilja et al., 1986). Results with cattle suggest that immune response to IBRV vaccination was not associated with performance.

A final point to consider is that the MHC has been linked to a number of production traits in the pig (as reviewed in numerous articles in Warner et al., 1988; Warner and Rothschild, 1991; Lunney and Butler, 1998). These reports include associations of growth, backfat, and reproduction traits with the pig MHC. It seems reasonable to assume that, inasmuch as immune responsiveness and production traits both seem to be associated with the MHC, these genes should then be the ones to exploit in future selection programs. In addition, the interluekin genes may play a similar role.

Future Directions and Opportunities

A number of limitations seem to exist that may impede progress towards breeding livestock, by conventional methods, that are more disease resistant and have improved immune responsiveness. The first of these is that limited funds are now committed to disease testing of different germplasm. This lack of funds has limited the development of our understanding of the extent of genetic resistance to disease. In addition, the general lack of associations among immune-response parameters and the negative correlations of some diseases and immune response with production traits make conventional selection methods extremely difficult.

The alternative approach would be to identify individual marker loci or the actual genes that are associated with disease resistance and improved immune response. The MHC genes seem to be likely candidates because they are already known to be associated with these traits. Once specific MHC alleles and other genes such as NRAMP1 can be identified, they can be used in marker-assisted selection or transferred to create transgenic animals with improved disease resistance and immune responsiveness. The payoff for such research is likely to be extremely large. For livestock producers, the benefits of genetically engineered animals would most likely include increased protection from disease and improved production performance under challenging environments. In the end, the consumer also would benefit from these developments, which could greatly alter livestock production.

This article is Journal Paper No. J-18175 of the Iowa Agriculture and Home Economics Experiment Station, Ames, Project 3215.

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