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Relationships between genetic change and infectious disease in domestic livestock
Pieter W. Knap1 and Stephen C. Bishop2
1
PIC Group, Roslin Institute (Edinburgh) and 2Roslin Institute (Edinburgh), Roslin, Midlothian EH25 9PS,
United Kingdom
Abstract
The relations between genetic change in domestic livestock and infectious disease (including both its epide-
miology and the animal's reaction to it) are examined. The overall picture is confusing because there are dif-
ferent, and seemingly unrelated, ways of considering the issue. An attempt is made to put these together into
a more general framework. Four processes of particular interest are distinguished and discussed in more de-
tail: (i) the way a population's genetic potential for immunocompetence can be changed by breeding, (ii) the
way an animal's immunocompetence is influenced by that animal's production potential, in combination with
the environmental resources that are available to it at a given time, (iii) the way the disease status of an ani-
mal (and a population of animals) is influenced by its immunocompetence, and (iv) the way the production
level of an animal is influenced by activation of its immune system. Ultimately, all four processes influence
the realised level of production.
This comes down to four questions that need to be addressed: (i) can we use genetic variation in immuno-
competence in animal breeding? (ii) does a higher production potential (today's direction of breeding) have a
negative impact on immunocompetence? (iii) does improved immunocompetence result in improved health?
and (iv) how large is the negative impact of disease on production?
Introduction
The second half of the 20th century has witnessed a strong intensification of domestic livestock production
conditions, and an equally strong increase in animal densities. Perhaps as a direct result of these factors, the
spread of infectious diseases has become the major factor to jeopardise the animal production sector in the
western world. At the same time, livestock breeding programmes have mainly focused on creating genetic
change in production traits. The contributions of McKay et al. (2000), Merks (2000), Preisinger (2000) and
McGuirk (2000) in this volume show that they have been very successful in doing so in all important live-
stock species, and that we must expect a continuation, if not an acceleration, of genetic trends into the next
few decades.
The animal production sector has mainly relied on medication, vaccination and management techniques for
the control of animal health, and as a consequence health-related traits have played a minor role in practical
animal breeding. The classical illustration of this is the case of Marek's disease in chickens. Commercial
poultry breeders spent considerable effort on selection for resistance against this viral disease after the ge-
netic background of such resistance was established in the 1940's (Gavora, 1990), but when vaccines became
available in the 1970's (Spencer et al., 1972), that selection effort was commonly perceived as unjustified,
and it was widely abandoned. Since the advent of molecular genetic technology in the late 1990's, resistance
to Marek's disease is the subject of scientific interest again, this time in search of QTL (Bumstead, 1998;
Vallejo et al., 1998). This coincides with a growing concern in western society that the use of vaccines and
medicines in animal production should be reduced.
The relationships between genetic change (either in production traits or in health-related traits) and infectious
disease (either its epidemiology or the animal's reaction to it) have received little serious attention until very
recently. This paper examines those relationships. The overall picture is confusing because there are at least
four very different, and seemingly unrelated, ways of considering the issue; we attempt to put these together
into a more general framework.

65
Terminology
Throughout this text terms are used that need proper definition to avoid ambiguity. A host organism is sus-
ceptible to a pathogen when the pathogen is able to replicate in the host. For example, humans are not sus-
ceptible to Marek's virus. Resistance to (infection with) a pathogen is then equivalent to absence of suscepti-
bility: "the pathogen cannot establish infection even after exposure by injection" which can be "the result of
the absence of receptors [to the pathogen in the host's tissue] or the presence of specific gene products inter-
fering with [pathogen] replication" (Schat and Davies, 2000). On the other hand, when a host organism is
resistant to disease, it is possible that "infection becomes established and the pathogen replicates, but this
does not result in the development of disease". In that particular context, disease is equivalent to pathology,
the situation characterised by fever and often by dysfunction and/or damage of host tissue. This generally
causes "disruptions in metabolism and deviations in nutrient requirements" (Klasing et al., 1991). That the
resistant host organism does not develop the disease is because it is able to launch an immune response
against the pathogen. The term immunocompetence is used here in a broad sense to indicate the capability of
the host to launch an immune response of sufficient specificity and magnitude, roughly indicating the effec-
tive quality of the host's immune system. This implies that animals tend to vary in their genetic potential for
immunocompetence. The effects of pathology, and the resources required to launch an immune response,
both lead to metabolic costs for the host organism. The term resilience refers to "the host's ability to maintain
a reasonable level of productivity in the face of a [disease] challenge" (Albers et al. 1987; Coop and Kyri-
azakis, 1999), i.e. to maintain the situation where those metabolic costs do not lead to a significant reduction
of production-related metabolic processes, which is of obvious relevance in animal production.
The term environment is used here in its genetical context: it denotes everything that is not under control of
the animal's genes. This includes nutrition and health care.
Relationships between genetic change and infectious disease
We distinguish four processes of particular interest: (i) the way a population's genetic potential for immuno-
competence can be changed by breeding, (ii) the way an animal's immunocompetence is influenced by its
production potential, in combination with the environmental resources that are available to it at a given time,
(iii) the way the disease status of an ani-
mal (and a population of animals) is in-
fluenced by its immunocompetence, and E resources P immunocompetence
(iv) the way the production level of an
animal is influenced by activation of its (ii) (iii)
immune system.
G production G immuno-
These processes are indicated in Figure
1, which shows the main relationships potential competence (i)
among the animal's genetic potential (for potential
immunocompetence and production P production
traits), its environment (in terms of the E epidemiology
available resources and the epidemiology
of the prevalent infectious disease), and
its phenotypic expression of genetic po- immune
tential (in terms of immunocompetence (iv) disease
system
and production traits). status
activation
The factor that connects the four proc-
esses is the influence of environmental
conditions on the relation between the Figure 1 The main genetic (G), environmental (E) and phe-
genetic potential for production traits and notypic (P) entities that play a role in the relation between
the genetic potential for immunocompe- genetic change in domestic livestock and infectious disease.
tence. The most striking effect of this is The processes (i) to (iv) are described in the text.

66
environmental sensitivity of genetic correlations. Ultimately, all four processes influence the realised level of
production. A main task for the future is to fit the four together into a comprehensive framework that is ac-
cessible for animal breeders, nutritionists, epidemiologists and veterinarians.
(i) Genetic change in immunocompetence
Pinard et al. (1992) report on a selection ex- 5
periment in which 37-day old chickens were
immunised with sheep red blood cells, the se- 4
lection criterion being the total antibody titer in
3
the blood plasma five days after immunisation.

selection response (titer)

Divergent (high and low titer) lines and an un- 2
selected control line were maintained for nine
generations. The development of the selection 1
criterion over generations is shown in Figure 2. 0
These results make it clear that high or low im-
munocompetence can be selected for; the real- -1
ised heritabilities of the selection traits in this
-2
experiment tended to increase over generations
up to 0.40 and 0.44 in the high and low lines, -3
respectively. The two lines differed in the fre-
quencies of certain MHC haplotypes, and these -4
were responsible for a significant part of the -5
within-line variation of antibody production 0 5 10 15 20
(Pinard et al., 1993a). The authors stress that cumulative selection differential (titer)
"interactions between MHC genes and back-
ground genes have been extensively demon- Figure 2 Direct phenotypic selection response of
strated" earlier, and conclude that their results antibody titers in chickens after immunisation with
"are in agreement with a polygenic control of sheep red blood cells, in relation to cumulative se-
the antibody response" to sheep red blood cells. lection differentials over nine generations of selec-
tion. Data of the divergent selection lines are ex-
When birds of the ninth generation of these lines pressed as deviations from an unselected control
were infected with Marek's virus at one day of line. Data from Pinard et al. (1992).
age, the low titer line showed 70 % mortality up
to 17 weeks of age compared to 43 % in the
control line and 41 % in the high titer line (Pinard et al., 1993b). Mortality developed significantly faster in
the order low > control > high line (38, 18 and 12 % mortality at 9 weeks, respectively). Although the herita-
bility of resistance against Marek's virus in these lines was found to vary from 0.45 to 0.78 (and somewhat
higher when adjusting for the effect of the MHC genotype), no clear genetic relationship between antibody
production and resistance to Marek's virus could be established within lines.
These findings provide a convenient illustration of the observations made by Nicholas (1996): "genetic varia-
tion in hosts for resistance to pathogens and parasites [… ] is present in most [… ] populations of hosts in rela-
tion to most [… ] parasites and pathogens that have been investigated. The genetic variation exists between
and within breeds, and is usually multifactorial. Among the many documented examples are genetic variation
for resistance to various bacteria, viruses and protozoa in chickens; [… ] to bacteria in turkeys; [… ] to bacte-
ria, viruses and protozoa in fish; [...] to insects, bacteria, nematodes and various viruses in sheep; [… ] to
bacteria in pigs; and [… ] to arthropods, nematodes, trypanosomes and bacteria in cattle [… ] The most obvi-
ous way to exploit this variation is to select for increased resistance. However, there is a major limitation to
this approach, namely that the whole population has to be deliberately exposed to the pathogen or parasite".
Rothschild (1991) evaluated the consequences of selection programmes that "require exposure to the disease"
of interest, and implied that such selection for resistance to specific diseases by sibling challenge routines and

67
comparable systems is expensive, time-consuming, information-demanding and inconvenient. This would
hold especially for intensive production systems (pigs, poultry), extensively farmed ruminants are often con-
tinuously exposed to the macroparasites that are their most important pathogens.
Because of such limitations, much effort has been directed to find other ways to exploit genetic variation for
disease resistance than by direct selection on the phenotype of actual interest. One of these ways is selection
for "general immunocompetence", usually measured as the antibody production triggered by immunisation
with an non-pathogenic substance such as sheep red blood cells, mollusc hemocyanin, chicken eggwhite ly-
sozyme, bacterial lipopolysaccharide, etc. Another factor motivating the quest for improved general immu-
nocompetence is that it is a desirable feature anyway, especially when the sector is not dominated by a small
number of important diseases (so that the "phenotype of actual interest" cannot be clearly defined).
In that respect, the above mentioned absence of a genetic relationship between the antibody production of
Pinard's chickens and their resistance to a specific disease (i.e. Marek's) is at first sight disappointing. Pinard
et al. (1993b) conclude that "indirect selection for resistance to Marek's disease by selecting for a unique
immune parameter, which would not require exposure to the disease, does not seem feasible". This conclu-
sion may be premature, as described below.
Wilkie et al. (1998) discuss a similar selection experiment in pigs, in which the selection criterion was a
BLUP-based selection index of four immunocompetence indicator traits (Mallard et al., 1992). When pigs of
the fifth generation of these lines were infected with Mycoplasma hyorhinis, the high immunocompetence
line developed significantly less severe peritonitis and pleuritis than the low line, but significantly more se-
vere arthritis and similarly severe pericarditis. The authors note that their indicator traits were prone to strong
fluctuations in between-animal variation, and that this "undoubtedly led to substantial variation in relative
weighting on the four traits across generations" (Mallard et al., 1998), which makes it difficult to follow what
has been exactly selected for in this experiment. Wilkie and Mallard (2000) conclude that "it should be pos-
sible to adjust the selection index to minimize negative effects and optimize breeding citeria". From that
rather optimistic point of view, the abovementioned disappointing results of Pinard's attempts to create spe-
cific resistance by selecting for a general immunocompetence indicator trait, may simply suggest that she
started accidentally with the wrong indicator trait for the disease she was ultimately interested in, creating an
improvement in another component of the immune system than would have been relevant for that specific
pathogen. It would be interesting to measure the resistance of Mallard's high and low selection lines to a seri-
ous bacterial or viral disease, and correlate the results to her immunocompetence indicator traits within lines.
Rothschild (1991) suggested an alternative approach, "to identify individual marker genes that are associated
with disease resistance and improved immune response [… ] Once specific MHC alleles and other genes can
be identified, they can be used in marker-assisted selection or transferred to create transgenic animals with
improved disease resistance and immune responsiveness".
A decade later, the transgenic route is still posing problems. Schat and Davies (2000) write: "Although the
development of transgenic chickens with increased resistance to avian leukosis virus certainly demonstrated
the feasibility of this approach, the use of transgenic techniques for improved resistance to disease is a long
way from becoming applicable in commercial lines [… ] The techniques for transgenesis are available, but it
remains a costly and time-consuming approach. Moreover, the results are not always positive when biologi-
cal costs are taken into account".
Likewise, the application of marker-assisted selection to increase the resistance to specific diseases is now
proving to be difficult because the resistance to many diseases is polygenic, and it is not easy to find the right
genes. Hence there seems to be little hope for true "genetic eradication" of many livestock diseases, the obvi-
ous exceptions being resistance mechanisms that rely on a single gene, such as the ones that code for intesti-
nal receptors for F18 or K88 Escherichia coli in pigs (Edfors-Lilja and Wallgren, 2000).
It seems that for the approaches to genetic improvement that target a single disease, the drawback is that
there are so many other diseases (and alternative pathotypes of the same pathogen) waiting to take over the
first position on the animal production industry's priority list. For the more general approaches, the draw-
backs are that the various mechanisms of host immunity may be not, or may even be unfavourably, intercor-

68
related (Rothschild, 1991; Mallard et al., 1998), and that an increase of "general" immunocompetence does
not necessarily lead to an increase in resistance to a specific disease (for more evidence see Biozzi et al.,
1982). Nevertheless, commercial breeding companies have nowadays a keen interest in breeding for disease
resistance, simply because every successful attempt may be very advantageous in terms of competitive ad-
vantage when marketed properly.
Of course, the recently re-developing interest in "breeding for disease resistance stems partly from awareness
of the development of pathogen resistance to the therapeutic agent, which has led to calls for reduction in the
use of antibiotics and other drugs throughout human and animal medicine" (Axford et al., 2000). This devel-
opment of pathogen resistance is the simple result of artificial selection pressure placed on the pathogen by
the exposure to the therapeutic, combined with the generally short generation intervals of pathogenic organ-
isms. Such a reduction of drugs usage may require the development of (i) alternative therapeutic intervention
methods, such as biological pest control, (ii) methods to reduce the need for therapy, such as modified animal
management systems, and/or (iii) genetic resistance. An important question in this respect is if selection for
increased host resistance will be able to elude the pathogens' inevitable co-evolutionary attempts to resist
such increased resistance. See also Bishop and Gettinby (2000).
(ii) Production potential and immunocompetence
The actual expression of immunocompetence will depend in the first place on the animal's genetic potential
for immunocompetence, as discussed in the previous section. But there is growing evidence for environment-
dependent effects of the genetic potential for production traits on the actual expression of immunocompe-
tence. Genotypes with high production potential (suitably dubbed "metabolic athletes" by Elsasser et al.,
1999), when placed in an environment that is inadequate in terms of metabolic resources to support their in-
trinsically high production levels and maintain homeostasis, tend to allocate resources primarily towards pro-
duction-related processes (see Coop and Kyriazakis, 1999). This will leave other metabolic functions with
insufficient resources. When that environment is at the same time challenging in terms of infectiousness, the
immune system may become constrained that way, which will lead to inadequate immune response to infec-
tion (Emmans et al., 2000, in this volume; Luiting, 1999; Knap and Luiting, 1999; Thorp and Luiting, 2000).
Rauw et al. (1998) reviewed "undesirable side effects of selection for high production efficiency" in domestic
livestock, and write: "Selection for high body weight [in broiler chickens and turkeys] has resulted in a cor-
related negative immune performance. Broilers selected for high growth rate showed lower antibody re-
sponses when challenged with sheep erythrocytes than a low BW line (Miller et al., 1992) and a randombred
control line (Qureshi and Havenstein, 1994). Little or no differences were found [… ] in the non-adaptive
components of the immune system. Nestor et al. (1996ab) found a significantly higher mortality in turkeys
selected for high BW compared to a randombred control line in a natural outbreak of erysipelas (11.8 and 1.6
% respectively), and when challenged with either Pasteurella multocida (72.1 and 43.6 %) or Newcastle dis-
ease virus (32.5 and 15.8 %)".
Likewise, Nir (1998) refers to selection studies for high and low antibody response to sheep red blood cells in
poultry (Van der Zijpp, 1983; Siegel and Gross, 1980; Martin et al., 1990; Kreukniet et al., 1994; Praharaj et
al., 1995), which show a negative relationship between antibody production and growth rate.
At present, the formal literature provides very little quantitative information on this issue in other livestock
species, but tendencies towards unfavourable relations between immunocompetence and lean growth capac-
ity in growing pigs have been reported by Stahly et al. (1994), Frank et al. (1997), McComb et al. (1997) and
Schinckel et al. (1998). The results of these authors are difficult to interpret, not only because there is little
information about standard errors in the reports, but also because the described trends are not always consis-
tent between traits. The most striking result is perhaps the mortality of the pigs of Frank et al. (1997). Their
"lean" and "fat" genotypes (with on average 57.1 and 50.7 % carcass lean, respectively) showed 3.6 and 2.8
% mortality, respectively, in a "low immunostimulation" environment (segregated early weaning, disinfected

69
finishing facilities, etc.) and 18.5 and 5.6 % mortality, respectively, in a "high immunostimulation" environ-
ment (conventional weaning, "continuous flow finisher", etc.).
Sinclair et al. (1999) studied the immune response against bovine herpes virus vaccine in dairy cows of high
versus average genetic merit for milk production, and provisionally concluded that the high merit cows, when
given a diet low in concentrates, "redirect resources from the maintenance of an adequate immune system to
milk production in order to maintain advantages in milk yield". The average merit cows did not show any
dependence of immune response on diet.
Environmental sensitivity may have profound
effects on the results of genetic parameter esti- 2.5
mation, dependent on the environment in which
the data are collected or the genotype on which
they are measured. An example, admittedly
making use of data on a non-infectious disease,
2.0
is the study of the genetic relation between

BW (kg)
growth rate and susceptibility to ascites in
broiler chickens by De Greef et al. (2000). The
result from this study that is most relevant to
the present discussion is the genetic correlation 1.5
between growth rate and arterial pressure index
(API, the ratio of the weight of the right heart
ventricle to the weight of both ventricles plus
their septum). API is used in this study as a
direct measurement of ascites, it had a genetic 1.0
correlation with mortality due to ascites of
+0.84. The genetic correlation between API
and growth rate was estimated as rG = –0.26 ± 1.0 1.2 1.4 1.6
log API
0.09 in the entire chicken population; but when
the "non-diseased" subpopulation with API Figure 3 Body weight (BW) at 35 days of age in rela-
values below the population mode (about 40 % tion to log-transformed arterial pressure index (API) in
of the total number) was analysed separately, broiler chickens. The data is divided into subsets below
the estimate changed to rG = +0.29 ± 0.20. The (? ) and above (o) the mode of API. Solid lines: linear
observed phenotypes are in Figure 3. The regressions through the subsets, broken line: through
authors concluded that (i) genetically, the faster the whole data. Data from De Greef et al. (2000).
growing animals have a stronger susceptibility
to ascites; (ii) susceptibility to ascites is only expressed in a challenging environment; and (iii) growth rate
becomes depressed when ascites actually occurs. As a result, their animals with the highest genetic potential
for growth rate showed below-average growth due to ascites; genetic correlation estimates will then depend
on environmental conditions, and breeders will have to take this into account.
Studies of resistance against intestinal nematodes in growing sheep have revealed a considerable variation in
genetic correlation estimates between resistance and growth rate. Published estimates range from strongly
favourable (Bishop et al., 1996), through moderately favourable or neutral (Albers et al., 1987; Bisset et al.,
1992; Douch et al. 1995; Eady, 1998) to moderately unfavourable (McEwan et al., 1992, 1995). A part of
these differences can be explained by differences in nutritional conditions, but a more important factor seems
to be the parasite species: paradoxically, the more tissue-damaging and resource-demanding nematode spe-
cies turn out to evoke less of an immune response in the host.
Environmental sensitivity of high-production genotypes is, of course, a key issue in "The challenge of genetic
change in animal production". At the same time, the current experimental evidence is rudimentary and some-
times anecdotal. Apart from the nematodiasis and ascites studies, all the above sources derived their genetic

70
contrasts from comparisons of different breeds or, at best, selection lines that were developed from the same
base population. For the animal breeding industry to take relevant action on this issue would require infor-
mation on the within-population variance and covariance of these traits (Knap and Luiting, 1999). Without
any doubt, environmental sensitivity will be a major topic for fundamental research and simulation modelling
during the coming decade. Given the current lack of quantitative data, research emphasis should be on the
quantification of genetic variation and covariation within genotypes, rather than on revealing contrasts be-
tween breeds.
(iii) Immunocompetence and disease status
As we discussed in the section on Genetic change in immunocompetence above, breeding for improved
immunocompetence in domestic livestock is a costly exercise. Therefore its implementation should be pre-
ceded by a proper cost-benefit analysis. The benefits of enhancing disease resistance in a breeding population
can be studied by means of genetic-epidemiological models, which are being developed recently. These
models translate (i) the infectiousness of a pathogen and (ii) the level of genetic resistance against it in a host
population, into the disease status of that population. The latter can be described in terms of the minimum
proportion of animals that must be resistant to protect the population from an epidemic, or the decline of the
probability (and severity) of an epidemic as time (and selection) progresses, etc.
The form of the genetic-epidemiological model will differ according to the type of pathogen and method of
disease transmission, as well as the host species. For example, simple compartmental models describing the
status of the host as susceptible, latent, infected or recovered are generally sufficient for bacterial and viral
infections, whereas for more complex macroparasitic (such as nematode) infections, each stage of the para-
sitic lifecycle must be described – possibly for every host animal. Additionally, whether the infection is
transmitted by direct animal contact or from an environmental reservoir of infection must also be modelled.
For environmental sources of infection, scenarios exist where the animals' disease status feeds back to the
environmental contamination causing a direct interaction between host resistance and disease epidemiology,
as in nematode infections, or where the environmental source of infection is essentially infinite, as for try-
panosomiasis. Published examples of genetic-epidemiological models for livestock include models of nema-
tode infections in sheep (Bishop and Stear, 1997), scrapie in sheep (Stringer et al., 1998) and viral infections
in pigs (MacKenzie and Bishop, 1999).
The model of the latter authors summarises the type of
information obtainable from genetic-epidemiological 2.5 1.0
models. For direct contact diseases, a useful parameter R0
summarising the transmission dynamics is R0, the 2.0 no 0.8
basic reproductive ratio, which describes the number epidemic

probability
of secondary infections expected from a primary in- 1.5 0.6
fected individual. If R0 is greater than 1, an epidemic
R0

is expected. If the epidemic gains a foothold in the 1.0 0.4

population and persists longer than a defined period it minor
may be termed major, if it dies out naturally it may be 0.2
0.5
defined minor. Using a stochastic model which mod-
major
els the disease transmission as a series of random
0.0 0.0
events in time, MacKenzie (1999) was able to de-
0 10 20 30
scribe the dynamics of transmissible gastroenteritis
time since start of selection (years)
epidemics in a structured pig farm. Assuming that
selection for resistance to this disease is possible, and Figure 4 Simulated consequences of selection
assuming an arbitrary rate of genetic progress, for resistance on R0 and on the probabilities of a
MacKenzie demonstrated how R0 and the probabilities major, minor or no epidemic.
of major/minor/no epidemics change as selection pro-

71
gresses, should the infectious agent be present. This is shown in Figure 4. Additionally, she also showed how
the duration and severity of the major, but not necessarily the minor, epidemics decreased with selection.
In the case of single genes conferring resistance to a disease, ge-
1.0
netic-epidemiological models can also be used to answer the im-
portant question of what proportion of the population must be re-
sistant to protect the population as a whole against an epidemic. 0.8

resistant proportion
This problem was solved by MacKenzie and Bishop (1999) and is
shown in Figure 5. The key result is that only for the most virulent 0.6
diseases is it necessary for the whole population to be resistant. For
many potential diseases the population can carry sizeable propor- 0.4
tions of susceptible individuals without apparent detriment. This is
analogous to vaccination strategies in human populations. 0.2

The value of these models, in addition to the insight they provide, is

0.0
as a tool to enable breeders to make rational decisions about 1 3 5 7 9
breeding for disease resistance. The fundamental concepts to con- basic reproductive ratio (R0)
sider when making these decisions are the costs incurred in imple-
menting a selection strategy (which may be large) compared to the Figure 5 The proportion of a popu-
beneficial consequences, as evaluated from the model. It must be lation that must be resistant, in the
demonstrated that breeding for resistance will be truly beneficial case of single genes for resistance,
and serve to produce populations that, in a reasonable timescale, to protect the population as a whole
will no longer be susceptible to the disease. against an epidemic.
(iv) Immune system activation and production
The immune system can actively regulate the various components of nutrient metabolism in three ways
(Klasing et al., 1991): (i) by direct neural connections to the central nervous system, which may trigger
behavioural adaptations and/or release of hypothalamic and pituitary hormones; (ii) by release of hormones
such as ACTH and thyrotropin by immune cells; (iii) most importantly, through leucocytic cytokines which
trigger not only anorexia and fever but also processes like the upregulation of gluconeogenesis from
glycogen, fatty acids and amino acids, accompanied by the downregulation of muscle protein deposition
(and/or muscle proteolysis) to support this gluconeogenesis and to support acute-phase glycoprotein synthesis
(Jepson et al., 1986).
As a result, infection and the associated activation of the immune system will lead to a cascade of resource-
reallocating processes in the host, most notably the following: (i) the production of acute-phase glycopro-
teins, immune cells and immunoglobulins, which requires extra protein synthesis; (ii) repair of damaged tis-
sue, which may cause a strong increase in protein turnover rates and hence increase metabolism considerably
(see Carli et al., 1989, for an example in post-surgery humans); (iii) fever, with the same metabolic effect as
subcritical ambient temperature; (iv) depression of voluntary feed intake (anorexia), the process with the
most dramatic effects on energy metabolism.
Apart from fever (see below), the quantitative impact of these processes on nutrient metabolism is poorly
documented. Demas et al. (1997) immunised mice with a non-pathogenic mollusc hemocyanin. Compared to
non-immunised controls, immunised mice showed significantly increased specific antibody serum levels. On
days 10 and 15 after immunisation they had developed a mild fever: their rectal temperatures were increased
by 1.6 and 1.0 °C, and their metabolic rate (O2 consumption) by 30 %. This increase in body temperature
would by itself cause a 7 to 20 % increase in metabolic rate (see below); the remaining 10 to 23 % increase in
metabolic rate would then be due to immune system activation per se (mainly the protein synthesis processes
(i) above).
Fever constitutes an important "metabolic cost": a raise of body temperature by 1 °C causes an increase of
metabolic rate by 5 to 13 % (Baracos et al., 1987; Van Dam et al., 1996ab; Demas et al., 1997). Further-

72
more, fever is usually accompanied by body protein catabolism. "Only after fever begins does the nitrogen
balance become abruptly negative [… ] Daily losses [in humans] may then range from 2 to 23 g per day, de-
pending on the presence of anorexia [… ] and the magnitude of hypermetabolism [… ] Early losses of nitrogen
come chiefly from the so-called labile nitrogen pool, [… ] primarily the protein in skeletal muscle and other
somatic tissues. If an infection enters a subacute or chronic phase, and if the body supplies of labile nitrogen
become exhausted, daily losses of nitrogen begin to lessen, and the body enters a new relatively steady state
[… ] Rapidly growing normal children typically exhibit a strongly positive nitrogen balance. If they become
ill with an infection of mild to moderate severity, they may not revert to a negative nitrogen balance, but
show a less positive balance instead" (Beisel, 1985).
But overall energy partitioning may be only little affected in the absence of fever. Schrama et al. (1997) re-
viewed trials in which the energy metabolism of growing pigs was studied in relation to immunisation with
Pasteurella multocida toxin and various non-pathogenic substances, none of which resulted in fever. The
authors conclude: "In general, the presented data [… ] suggest that mild stress and/or disease first result in the
reallocation of energy between different maintenance processes [i.e. the immunity-related maintenance proc-
esses are increased, and activity is reduced by a similar amount]. More severe stress and/or disease will result
in a decreased feed intake, which often coincides with an increase in the total energy required for mainte-
nance processes [… ] The reallocation induced by exposure to stressors can conflict with the reallocation of
nutrients required for the animal to maintain its health status".
Anorexia during immune system activation seems counterproductive, as the body would need more resources
to deal with its elevated metabolism and with the nutrient requirements of the pathogen. Indeed, studies have
been directed to the required "upgrade" of diet composition to keep production at the economically desired
levels (Klasing et al., 1991; Stahly, 1996; Van Houtert, 1997), and attempts have been made to reduce the
anorexia response by genetic selection (i.e. selection for increased resilience; Albers et al., 1987; Albers and
Gray, 1989; Bisset et al., 1994, 1996). Kyriazakis et al. (1998) attempted to explain the paradox, which is
especially significant from a production point of view, by suggesting that anorexia promotes an effective
immune response in the host by removing possible immunotoxic effects of micronutrient excesses.
All the above was summarised in terms of production traits by Stahly (1996), who discussed trials with
young growing pigs subjected to high and low immune system activation (achieved by conventional weaning
and medicated early weaning, respectively; Williams et al., 1997ab). He concludes that "minimizing the acti-
vation of the pig's immune system" in those trials resulted in higher ad libitum feed intake, growth rate, mus-
cle development, and feed efficiency.
Livestock nutrient metabolism has been modeled extensively (see Baldwin and Sainz, 1995; Black et al.,
1995). Typically these simulation models deal with the resource requirements of the animal, given its genetic
potential, in addition to the resource demands of various environmental "load" factors (most notably, nutri-
tion and climate). Immunological costs have not been included in any of these models yet. Modeling the re-
source demands of an immune system activation in a similar manner would then require a quantitative de-
scription of the ways the immune system interacts with nutrient metabolism, in terms of the four resource-
reallocating processes listed above (protein synthesis, tissue repair, fever, anorexia). This interaction is likely
to depend on environmental factors (type of pathogen, other load factors, pathogen density in the case of
macroparasites) and on animal-intrinsic factors (immunocompetence potential, nutritional status).
Modeling these processes is of interest in an animal breeding context because the genetic evaluation of
breeding animals is based evermore often on performance data that have been created in various environ-
mental settings. The system to be described in such evaluations (e.g. a lactating cow, a growing pig, a laying
hen) is non-linear in terms of its metabolic processes and their genetic background. When health-related fac-
tors are included in the description, the system also becomes strongly environment-variant. This makes the
use of linear additive models to describe such systems questionable, and calls for the development of sto-
chastic, dynamic, mechanistic simulation models. Similar arguments hold for the prediction of performance
of a particular genotype in novel conditions. Ultimately, what needs to be modeled is genotype by health en-
vironment interaction.

73
In modeling, the distinction between clinical disease (with its extreme but usually short-lasting conse-
quences) and subclinical disease (with its less extreme but chronic consequences) is important. Severe fever
is a common aspect of clinical disease, and possibly the most important one in terms of resource demands.
Because fever is usually not severe in subclinical disease conditions, the metabolically most important con-
sequence of subclinical disease is likely to be anorexia.
An interesting question is if there are interactive effects around resource reallocation in case of infection: do
specific production-related processes become suppressed selectively? If so, the environment-variant aspects
of the infectious scenario become even more relevant. Beisel (1985) writes: "… the function of [… ] host de-
fensive mechanisms [… ] requires an ongoing capacity of body cells to synthesize new proteins. For this rea-
son, any nutritional deficit or imbalance that influences protein synthetic functions can lead in turn to [… ] a
weakening of host resistance", and Coop and Kyriazakis (1999) propose that resources are preferentially (not
absolutely) allocated towards (i) maintenance of body protein, including repair, replacement and reaction to
tissue damaged or lost due to infection; (ii) the processes of acquisition of immunity that precede the actual
immune response; and (iii) growth and reproduction, in that order of preference. They conclude that "the
ability to maintain relatively undepressed functions of growth and reproduction" (i.e. resilience) will depend
on the extent of tissue damage due to infection, and also that this implies a strong influence of nutrition on
the expression of immunocompetence. The tendency of modern highly productive genotypes to allocate re-
sources preferentially towards production-related processes (see the section on Production potential and
immunocompetence above) would not accord with Coop and Kyriazakis's (1999) order of preference. There
may be a genotype-dependent trend here, which would make mechanistic modelling all the more attractive.
Modeling can be done empirically or mechanistically: empirical models are much easier to develop, whereas
mechanistic models are more generally applicable and provide more insight in the processes between input
and output. Empirical modeling of the resource demands of an immune system activation would require
measurement of the degree of immune system activation in animals in some infectious setting, and of the
associated nutrient intakes and/or production performance. The latter measurements can then be regressed on
the former ones, and the resulting prediction equation can be used to predict resource requirements in future
conditions. Such analyses have been performed by Leathwick et al. (1992) and Bishop and Stear (1999) for
nematode infections in sheep. The former authors developed a model to simulate the epidemiology of nema-
todiasis that distinguishes between gut tissue damage (in terms of "worm burden", the number of established
parasites in the gut) and immune response (in terms of the number of infective larvae ingested daily) as the
components responsible for the parasite's effect on the host's growth performance. The relevant equation in
this model empirically predicts host weight loss (WL) as a function of cumulative daily worm burden (WB)
and cumulative daily larvae intake (LI) as WL = a × WB + b × LI + c × WB × LI. The constants a, b and c
are derived from regression analysis of field data.
By contrast, the mechanistic approach would attempt to describe the host genotype in terms of (i) its resource
requirements for acquisition of immunity to infection; (ii) its resource requirements for the actual expression
of the immune response, including the effects of fever and anorexia; (iii) its increased protein turnover rates
due to infection, all in relation to infection with a specific pathogen. For a particular host genotype in a par-
ticular environmental setting (nutrition, climate) and infected with a particular pathogen, a mechanistic model
would then predict the extra resource requirements to maintain full expression of its production potential.
Failing the fulfilment of these resource requirements, it would predict the realised sub-optimal production
level. Such an approach would require the description of the infectious environment in terms of a few pa-
rameters that make it possible to quantify its metabolic load. It would also require much more quantitative
information about the resource demands of the various components of immune system activation than is cur-
rently available.

74
Conclusions
We can now return to Figure 1, and look again at the processes summarised there. The previous sections have
shown that (i) there is, in principle, ample opportunity for changing a population's genetic potential for im-
munocompetence by breeding, because many of the related characteristics show substantial genetic variation
between animals. However, direct selection on the target (resistant) phenotype is inconvenient in the inten-
sive production systems because it requires challenge routines, and this makes it difficult to create genetic
change in practice. Indirect selection on more general expressions of immunocompetence may provide an
alternative, but requires detailed knowledge of the specific components to be targeted. Molecular genetic
technology seems promising, especially for resistance mechanisms controlled by a single gene, but needs
much more development for the many diseases that are dealt with by polygenic resistance mechanisms.
Furthermore, (ii) information about the way an animal's immunocompetence is influenced by its production
potential (in combination with the environmental resources that are available to it at a given time) is gradu-
ally emerging, although part of this information is still confusing. Although there are no signs, as yet, for
immediate immunological disaster as the sole result of extreme selection for production traits, it seems clear
that genotype by health environmental interactions should receive more specific attention. The environmental
sensitivity of genetic (co)variances is particularly worrying, since it makes breeding value estimation much
more complicated.
Taken together, points (i) and (ii) suggest that animal breeders should extend their breeding objectives (con-
ventionally emphasising production traits) with immunocompetence characteristics. The challenge here is to
do so in a structured way rather than on an ad hoc basis, and this will require information on within-
population (co)variation.
The way (iii) the disease status of an animal population is influenced by its immunocompetence profile can
be modeled now, which has created a functional link between epidemiology and animal breeding. This is
important because the eventual genetic outcome of points (i) and (ii) will have to be evaluated in its eco-
nomic context, and that context is largely governed by epidemiology. As with most fitness-related traits (see
Knap and Luiting, 1999), a successful incorporation of health-related traits into animal breeding programmes
will demand a multidisciplinary approach. Genetic-epidemiological models provide a convenient vehicle for
this approach. Ultimately, the economic values that will be required to set up the breeding objectives men-
tioned in the previous paragraph will have to be estimated by using such models.
Finally, (iv) activation of an animal's immune system is likely to result in increasingly non-linear and envi-
ronment-variant components of the metabolic processes that govern its production performance. Because
breeding value estimation is increasingly based on production performance data from various environmental
conditions, it becomes more and more important to estimate that production potential using models that can
represent this non-linear and environment-variant system. The challenge here is to develop a model that can
predict the above mentioned environmentally sensitive (co)variances, as opposed to treating them as a statis-
tical nuisance factor. Such models would also make it possible to specify the environmental conditions (nu-
trition, climate, health) that would allow a high-performance genotype to express its full potential. The con-
cerns expressed by Nir (1998) and Tamminga (2000, in this volume) about the possibilities of feeding and
managing modern poultry and future dairy cattle genotypes in order to achieve just that, illustrate that we
may expect a strong demand for such tools, perhaps in the first place to decide which genotypes are suitable
for a given market.
This review has indicated some strong needs for further information, as related to the processes in Figure 1:
(i) quantification of the genetic relationships between immunocompetence and resistance to specific patho-
gens within lines; quantification of the co-evolutionary response of pathogen virulence to selection for host
resistance; (ii) quantification of genetic variation and covariation between immunocompetence and produc-
tion traits within lines; (iii) quantification at the population level of the infectiousness (i.e. R0) and impact on
productivity of various diseases; use of this information to predict the consequences of altering disease resis-
tance in terms of the probability and severity of infection, and how this translates into economic benefits; (iv)
quantification of the resource demands of the various components of immune system activation; description

75
of the infectious environment in terms of a few parameters that make it possible to quantify its metabolic
load.
Acknowledgements
Brad Bosworth and especially Ilias Kyriazakis made valuable contributions to PWK's insight in the matter.
SCB wishes to thank BBSRC CSG for funding. Karel de Greef and Luc Janss provided us with their experi-
mental results prior to publication.
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