Introduction. Ecological immunology
Hinrich Schulenburg1,*, Joachim Kurtz2, Yannick Moret3
and Michael T. Siva-Jothy4
1Zoological Institute, University of Kiel, Am Botanischen Garten, 24098 Kiel, Germany
2Institute for Evolution and Biodiversity, University of Mu ¨nster, Hu ¨fferstrasse 1, 48149 Mu ¨nster, Germany
3Universite ´ de Bourgogne, UMR5561 Bioge ´osciences, E´quipe E´cologie E´volutive, 6 Boulevard Gabriel,
21000 Dijon, France
4Department of Animal and Plant Science, University of Sheffield, Sheffield S10 2TN, UK
An organism’s fitness is critically reliant on its immune system to provide protection against parasites
and pathogens. The structure of even simple immune systems is surprisingly complex and clearly will
have been moulded by the organism’s ecology. The aim of this review and the theme issue is to
examine the role of different ecological factors on the evolution of immunity. Here, we will provide a
general framework of the field by contextualizing the main ecological factors, including interactions
with parasites, other types of biotic as well as abiotic interactions, intraspecific selective constraints
(life-history trade-offs, sexual selection) and population genetic processes. We then elaborate the
resulting immunological consequences such as the diversity of defence mechanisms (e.g. avoidance
behaviour, resistance, tolerance), redundancy and protection against immunopathology, life-history
integration of the immune response and shared immunity within a community (e.g. social immunity
and microbiota-mediated protection). Our review summarizes the concepts of current importance
and directs the reader to promising future research avenues that will deepen our understanding of the
defence against parasites and pathogens.
Keywords: ecological immunology; coevolution; adaptive immune system; innate immune system;
1. TIMELINESS OF A MERGER BETWEEN
ECOLOGY AND IMMUNOLOGY
Ecology is the study of the distribution and abundance
of organisms and their interactions with their environ-
ment, including parasites and pathogens. Immunology
is the study of the physiological functioning of the
immune system in states of health and disease. The
former discipline implicitly acknowledges the import-
ance of the latter but treats it as a black box. Likewise,
the latter discipline implicitly acknowledges the
importance of variation between individuals, but relies
on a logistic foundation that necessarily removes
individual variation from its empirical approach and
so avoids the complex interactions which determine an
organism’s life history in its natural environment.
Over the past decade, new molecular information
and techniques have become available, which have
facilitated a combination of the two fields and thus
placed mechanistic understanding into an ecological
context and vice versa. Examples include the inference
of natural selection on the immune system by
quantitative trait loci mapping of defence genes in
natural insect populations such as fruitflies (e.g.
Bangham et al. 2007, 2008; Dubuffet et al. 2007),
mosquitoes (e.g. Menge et al. 2006; Riehle et al. 2006)
or bumblebees (e.g. Wilfert et al. 2007; Wilfert &
Schmid-Hempel 2008); the analysis of naturally
occurring polymorphism in insect immunity genes
(Lazzaro et al. 2004, 2006; Jiggins & Kim 2006,
2007; Obbard et al. 2006) or the comparison of
whole genomes of different Drosophila species for
reconstruction of immune system evolution (Sackton
et al. 2007). Perhaps most important is the realization
that although substantial basic information has accu-
mulated independently in both disciplines, full under-
standing of the complexity encountered demands a
perspective that can only be provided by a joint cross-
Our review provides an overview of the recently
expanding research field of ecological immunology.
This research field is concerned with the ecological
factors (biotic as well as abiotic) which determine the
evolution of the immune system and which may
therefore provide the key to understanding its structure
and enormous complexity. Here, we will contextualize
the main categories of ecological factors and the
resulting immunological consequences, and will sup-
port our perspective with selected case examples: we
make no excuse for cherry-picking key examples
rather than attempting a full coverage of the field.
Based on this information, we will highlight promis-
ing topics for future research that we believe
will further our understanding of both ecological and
immunological mechanisms. More specific aspects
will be addressed in the different reviews of this
Phil. Trans. R. Soc. B
One contribution of 11 to a Theme Issue ‘Ecological immunology’.
*Author for correspondence (email@example.com).
This journal is q 2008 The Royal Society
2. ECOLOGICAL INPUTS
There are four main categories of ecological factors
that influence the diversity and complexity of the
immune system: interactions with parasites; other
types of biotic as well as abiotic interactions; intraspe-
cific selective constraints; and population genetic
processes that influence the evolution of immune
components (figure 1).
(a) Interactions with parasites
Interactions with parasites (here used in its wide sense,
thereby including viruses, bacteria, protists and eukary-
otes) will affect the evolution of immune systems,
which directly serve to protect the host from parasitic
infections and the associated damage. Certain types of
interactions are believed to have particular impact on
immune systems. The first of these is coevolution with
parasites, where parasites in close and long-term
association with a particular host species may continu-
ously adapt to the current as well as newly evolving host
defences. Parasite adaptation is usually faster than host
counter-adaptation due to the parasite’s comparatively
shorter generation time, its usually larger population
size and its often haploid genome (cf. Hamilton et al.
1990). The speed and perseverance of parasite
adaptations produce one of the strongest selective
pressures known in evolution—with direct relevance
for host immunity. Examples for rapidly evolving
parasites are found among human viruses such as
influenza and HIV (reviewed in Arien et al. 2007;
Nelson & Holmes 2007), the well-documented
interactions between snail hosts and their trematode
parasites in New Zealand lakes (reviewed by Jokela
et al. 2003), or rabbit hosts and the myxoma virus
(reviewed in Fenner & Fantini 1999).
The second factor impacting on the evolution of
immune systems is the necessity to deal with an
unpredictable set of many parasites, either different
parasite species or different strains of the same species.
In both cases, the different parasite ‘types’ are likely to
attempt infection with distinct ‘attack’ mechanisms,
thus requiring diversity and flexibility in host recog-
nition, processing and effector mechanisms. One of the
few systematic studies of parasite diversity and its
immunogenetic consequences was performed in lake
and river ecotypes of the three-spined sticklebacks
Gasterosteus aculeatus in northern Germany, which
contain approximately 15 different eukaryotic parasite
species (Kalbe et al. 2002; Scharsack et al. 2007).
Parasite species richness within a population affects
relevant components of both the innate and adaptive
immune systems (Scharsack et al. 2007), such as the
diversity of major histocompatibility complex (MHC)
genes (Wegner et al. 2003a,b). The general importance
of interactions with multiple parasite species or strains
on host evolution has been emphasized in several
theoretical articles. Heterogeneous infections may lead
to higher virulence (here defined as reduction in host
fitness, resulting from the combination of parasite
pathogenicity and host immunity, thus representing a
joint character of both host and parasite) if there is
competition among parasites (e.g. Antia et al. 1994;
Bonhoeffer & Nowak1994; Nowak & May 1994; Frank
1996; De Roode et al. 2005). Lower virulence may
result if parasites are closely related (thus being subject
to kin selection), if they cooperate in host exploitation,
and/or if they get the same share irrespective of their
actions (e.g. Frank 1996; Brown 1999; Brown et al.
2002; Schjorring & Koella 2003; Rauch et al. 2008). In
turn, the former scenario should increase, whereas the
latter decreases selection on host immunity.
Finally, manipulation by parasites is another poten-
tially relevant factor in many host–parasite associations.
In general, the immune system aims at preventing
interaction with parasites
multiple parasite species + strains
manipulation by parasites
predators, competitors, prey, microbiota
diverse abiotic factors
diversity of defences
diverse immune responses
immunity and reproductive rate
immunity and ageing
redundancy + immunopathology
defence against manipulations
defence against immunopathology
pop size, migration, mutation
different selective processes
Figure 1. Ecological inputs and immunological outcomes.
2H. Schulenburg et al.Introduction
Phil. Trans. R. Soc. B
invasion and damage through the recognition and
elimination of parasites. In a simple world, parasites
adapt to host defences by escaping detection or
elimination, e.g. by changing surface molecules. In
this case, the most direct evolutionary response of a
host consists of changing the efficiency of recognition
and immune effector mechanisms. However, if
parasites attack by manipulating host defence
reactions, the selective pressure on the host becomes
more complex. Such interference strategy is wide-
spread among parasites and may affect different levels
of the host immune response, as summarized by
Schmid-Hempel (in press; see also Schmid-Hempel
2008). In this case, selection no longer acts exclusively
on host recognition and elimination mechanisms,
but also on protection against manipulations—either
by directly targeting such parasite manipulator
molecules or by indirectly enhancing robustness of
defence responses, e.g. through redundancy in
(b) Additional interactions
Abiotic and biotic ecological factors are major driving
forces for the evolution of host–parasite interaction and
immune defence. For example, the availability of food
organisms biases anti-parasite defence in the nematode
host Caenorhabditis elegans (Schulenburg & Mu ¨ller
2004; Sicard et al. 2007). Similarly, nutrient availability
altered parasite resistance of mosquitoes (Ferguson &
Read 2002; Bedhomme et al. 2004; Lambrechts et al.
2006). The presence of symbiotic micro-organisms in
aphids strongly influences immunity against parasitoid
wasps, as well as fungal parasites (Oliver et al. 2003;
Scarborough et al. 2005; von Burg et al. 2008), and the
composition and diversity of the mammalian gut
microbiota affects resistance against pathogens and
activity of different components of the immune system
(reviewed in O’Hara & Shanahan 2006; Sansonetti &
Di Santo 2007). Abiotic factors such as temperature
have a severe effect on parasite resistance in the nema-
tode C. elegans (Schulenburg & Mu ¨ller 2004), the water
flea Daphnia magna (Mitchell et al. 2005) and the
fruitfly Drosophila melanogaster (Lazzaro et al. 2008).
However,as discussed by Lazzaro & Little (in press),
environmental factors will influence immune system
evolution only if their impact varies with host
genotype, i.e. some host genotypes are more immuno-
competent in one environment, whereas others per-
form better in another environment (genotype!
environment interaction; Lazzaro & Little in press).
In this case, the environmental factor may act as a
potent selective force that directly determines the
distribution of host genotypes and thus the evolution
of defence in host populations. Among the above
examples, such genotype!environment effects were
found for food quality and temperature (Ferguson &
Read 2002; Schulenburg & Mu ¨ller 2004; Mitchell et al.
2005; Lambrechts et al. 2006; Lazzaro et al. 2008).
(c) Intraspecific constraints
Immunity comes at a cost. Since resources are usually
limited, these costs should have an important influence
on immune system evolution. This section is concerned
with such immunity costs that become manifest in the
form of trade-offs between immunity and other fitness-
related traits. There are three non-exclusive forms
in which costs of immunity arise: genetic costs (i.e.
genetically fixed higher investment in immunity); usage
costs (i.e. energetic costs that only apply upon
activation of the immune system); and immunopathol-
ogy (i.e. tissue damage caused by the immune system).
The importance of the resulting life-history trade-
offs has been indicated in numerous studies and a
large diversity of organisms (reviewed by Sheldon &
Verhulst 1996; Schmid-Hempel 2003; Siva-Jothy et al.
2005), and it is also discussed in this issue’s review by
Lazzaro & Little (in press). The most important trade-
off should be between immunity, which ensures
survival, and reproductive rate, which directly correl-
ates with fitness. Reduced reproductive rates were
indeed observed for immunocompetent individuals/
strains (high genetic immunity costs), e.g. in mosqui-
toes or fruitflies (e.g. Ferdig et al. 1993; Yan et al. 1997;
McKean et al. 2008). Similar reductions were found
after experimental activation of the immune system
(high usage costs; reviewed in Schmid-Hempel 2003),
e.g. in mosquitoes, fruitflies or birds (e.g. Bonneaud
et al. 2003; Ahmed & Hurd 2006; McKean et al. 2008).
One study in insects has provided unequivocal
experimental evidence for a cost of immunopathology,
namely on tissue integrity in the mealworm beetle
(Sadd & Siva-Jothy 2006). Interestingly, immunity
costs can often only be demonstrated when organisms
are examined in stressful environments, further high-
lighting the potentially strong influence of the environ-
ment (discussed in Lazzaro & Little in press). For
example, fruitflies selected for increased parasitoid
resistance showed reduced larval competitiveness only
under food limitation (Kraaijeveld & Godfray 1997).
Another constraint ultimately originates from Bate-
man’s principle, i.e. one sex (typically females) invests
more in individual offspring than the other (typically
males). As a consequence, the two sexes differ in their
evolutionary interests, leading to various sex-related
selective processes usually summarized under the
header ‘sexual selection’. The consequences on
the immune system are manifold. As highlighted in
this issue’s study by Nunn et al. (in press), intra-sexual
selection among the limited sex (usually females)
favours female individuals with a high investment in
immunity if this investment increases not only lifetime
per se but also particularly lifetime reproductive success
(see also Rolff 2002). By contrast, intra-sexual selection
among the less limited sex (usually males) may provide
an advantage to male individuals that mainly invest into
competition with other males, resulting in the reduced
availability of resources for immune functions. More-
over, selection that acts on the interaction between the
two sexes (inter-sexual selection) may result in mate
choice, usually female choice, where an important
criterion for choice is immunocompetence (i.e. the
ability to prevent or limit parasitic infections). In this
context, choice may be more direct, such that females
choose uninfected males or those that indicate high
resistance with the expression of other costly traits (e.g.
immunocompetence handicap hypothesis; Hamilton &
Zuk 1982; Folstad & Karter 1992). A non-exclusive
alternative is that choice is more indirect, favouring
H. Schulenburg et al.
Phil. Trans. R. Soc. B
advantageous immunity allele combinations among
the offspring (reviewed in Milinski 2006). The latter
has been investigated in much detail in sticklebacks,
where an intermediate level of allele diversity was found
to be optimal (Reusch et al. 2001; Wegner et al. 2003a;
Kurtz et al. 2004), as further elaborated by Woelfing
et al. (in press).
(d) Population genetic processes
Evolutionary dynamics in populations are not only
affected by particular selective pressures, but also
depend on population genetic characteristics, including
population size, migration, mutation frequency, num-
ber of genes involved in trait expression and meta-
population structure. These population genetic
characteristics are of major importance for host–
parasite coevolutionary dynamics (e.g. Ebert et al.
2002; Forde et al. 2004; Cooper et al. 2005; Morgan
et al. 2005; Brockhurst et al. 2006; Vogwill et al. 2008),
which in turn implies that they also affect evolution of
the immune system. In fact, Boots et al. (in press)
review a number of theoretical articles which use
population genetic models in order to evaluate
evolution of different aspects of immune defence (e.g.
avoidance, resistance or tolerance). These models are
either based on a few defence loci (gene-for-gene and
matching allele models) or many loci (quantitative
genetic models and game theoretical approaches).
They emphasize the importance of life-history trade-
offs for the evolution of resistance versus either
tolerance or immune memory (reviewed in Boots
et al. in press).
The particular combination of selective constraints
and population genetic characteristics determines the
dynamics of evolutionary change (Woolhouse et al.
2002). Five different non-exclusive forms of such
selective dynamics are expected in the context of
the evolution of host–parasite interactions and thus
(i) Directional selection if the host is confronted
with a predictable set of parasites or parasite
attack mechanisms (i.e. no large changes in the
encountered pathogenicity mechanisms over
time); the relevant resistant genes should then
spread through the population to fixation.
(ii) Negative frequency-dependent dynamics may
be observed when host and parasite coevolve; in
this case, parasites are likely to adapt to the
most common host resistance allele, thus
favouring rare alleles, which then spread
through the population to high frequency,
which in turn leads to a selective advantage of
a then rare allele and so on; ultimately this leads
to repeated cycles of increase and decrease in
particular allele frequencies (e.g. Dybdahl &
Lively 1998; Decaestecker et al. 2007; Gandon
et al. in press).
(iii) Host–parasite coevolution may also be asso-
ciated with repeated selective sweeps (e.g.
Buckling & Rainey 2002; Bangham et al. 2007;
Gandon et al. in press); this selective process is
related to the last point, in that selection favours
rare resistance alleles because parasites are likely
to evolve to the most common alleles; in this
case, however, the rare allele is produced by
mutation, recombination or migration, followed
by its spread through the population to fixation
(similar to directional selection, point (i)); a new
sweep is then initiated by a new mutation,
recombination event or migrant and so on;
this selective process could additionally be
initiated if a new variant allele at a particular
locus is duplicated at a new locus, where it is
present in homozygous condition, facilitating
its fast spread through the population, as is
possibly true for the numerous plant R resist-
ance genes (Bergelson et al. 2001; Bakker et al.
2006; reviewed in Mitchell-Olds et al. 2007;
Salvaudon et al. 2008).
(iv) The presence of coevolving or large numbers of
different parasites may favour hosts with high
diversity at particular immunity genes (e.g.
recognition receptors), because these are better
able to fend off the diverse set of parasites;
such heterozygote advantage or overdominant
selection maydirectly select for high population-
wide diversity in immunity genes, as inferred
for human innate immunity genes (Ferrer-
Admetlla et al. 2008), a mouse virus resistance
gene (Ferguson et al. 2008) or possibly mam-
malian MHC genes (e.g. Apanius et al. 1997;
Penn & Potts 1999; but see De Boer et al. 2004).
(v) Neutral processes such as genetic drift may also
affect immune system evolution, particularly in
small populations and in the absence of
selection and migration.
It should be noted that these evolutionary dynamics
either operate on standing genetic variation or require
new mutations or a combination thereof (e.g. through
the recombination of short sequence motifs of variable
alleles; see Reusch & Langefors 2005). Therefore, they
may entail different time scales of evolutionary change
and thus become manifested in gene sequence
evolution at either population or species level, as
discussed for RNA interference genes by Obbard
et al. (in press).
3. IMMUNOLOGICAL OUTCOMES
High diversity in ecological processes should favour
high diversity in immunological mechanisms, since
these are more likely to mediate an effective response
against different parasites under different environmental
conditions. In the following, we discuss the impact on
four aspects of immune defence (figure 1): diversity of
alternative mechanisms; protection against compli-
cations such as parasite manipulations or immuno-
pathology; life-history integration of the immune
response; and shared immunity within a community.
(a) Diversity of defences
The availability of a diversity of immune defence
options should increase an organism’s survival in a
variable world. It is likely to be enhanced in the
presence of immunity costs: the alternatives are then
not only more effective under certain environmental
4H. Schulenburg et al.Introduction
Phil. Trans. R. Soc. B
conditions but—as a direct consequence—also allow a
more economic usage of resources. Alternative
defences may occur at several different levels as follows.
(i) behavioural avoidance of parasites, which limits
exposure to parasites and thus minimizes
(ii) physical barriers that minimize invasion rates of
(iii) other boundary defence mechanisms that
reduce the likelihood of infection, e.g. alteration
of certain cell surface molecules, which are
exploited by parasites for invasion, or constitu-
tively expressed antimicrobial genes on the skin
as part of the immediate innate immune system,
(iv) control of parasite invasion and replication with
the help of the immediate inducible immune
response (inducible innate immune system)
and/or the delayed adaptive immune response
based on, e.g. antibodies, Tand B cells,
(v) a learned immune response based on immuno-
logical memory mediated by the adaptive
immune system, and
(vi) tolerance, i.e. the compensation/attenuation of
parasite damage without restriction of parasite
invasion and growth.
We would like to draw particular attention to some
of these defence strategies, which we think deserve
further research effort. If a first encounter with a
parasite comes with a high likelihood of a second
encounter with the same parasite, then selection should
favour both high immune specificity and immuno-
logical memory in order to increase protection of
the host upon secondary exposures, irrespective of
the host’s phylogenetic affiliation (Moret & Siva-Jothy
2003; Kurtz 2004; Schulenburg et al. 2007). This
verbal argument is supported by theoretical models,
which additionallyemphasize the importance of disease
characteristics for the evolution of immunological
memory (discussed in this issue’s review of Boots
et al. in press). Specific memory is very well charac-
terized for the adaptive immune system, which not only
provides higher protection during an individual’s
lifespan but also enhances offspring immunity through
the maternal transfer of antibodies, as detailed in this
issue’s review by Hasselquist & Nilsson (in press).
Importantly, a similar priming of the immune system
has now been repeatedly observed in invertebrates that
lack the ‘adaptive’ system, e.g. the crustacean copepod
Macrocyclops albicans (Kurtz & Franz 2003), the
crustacean water flea D. magna (Little et al. 2003),
the bumblebee Bombus terrestris (Sadd et al. 2005;
Sadd & Schmid-Hempel 2006), the beetles Tenebrio
molitor (Moret 2006) and Tribolium castaneum (Roth
et al. in press) and the fruitfly D. melanogaster (Pham
et al. 2007). The underlying molecular mechanisms are
currently unknown. They appear to require phagocytes
and the Toll pathway (Pham et al. 2007). They
may also involve highly diverse recognition receptors,
e.g. those generated through alternative splicing of
the Dscam immunoglobulin in arthropods (Watson
et al. 2005; Dong et al. 2006; Brites et al. 2008),
or the synergistic interaction of different immune
components (reviewed in Schmid-Hempel 2005; Du
Pasquier 2006; Kurtz & Armitage 2006; Schulenburg
et al. 2007).
Tolerance is defined as the ability to limit the
damage caused by a given parasite burden. As
elaborated in detail in this issue by Ra ˚berg et al.
(in press), the concept of tolerance towards parasites is
widely applied in the plant literature, but currently
ignored in animal studies. To date, there is only one
conclusive demonstration of animal tolerance, namely
in mice infected with rodent malaria (Ra ˚berg et al.
2007). Tolerance may represent a highly economic
strategy, since it may be energetically cheaper to limit
the damage rather than invest in parasite elimination
mechanisms. Moreover, tolerance should be evolution-
arily advantageous since it may also favour less
pathogenic parasites. In fact, theoretical models
suggest that immunity costs as well as high parasite
virulence favour the evolution of tolerance (reviewed in
this issue by Boots et al. in press).
Parasite avoidance behaviours are widespread
among animals (reviewed in Moore 2002) and are
particularly common among social organisms (this
issue’s review by Cremer & Sixt in press; see also
Cremer et al. 2007). They most likely provide a highly
economic defence, since they minimize both the
exposure to parasites (thus potential damage) and
possibly the energetic costs required for activation
of the physiological immune system (discussed in
Schulenburg & Ewbank 2007). To date, the underlying
genetics are not well understood. The most compre-
hensive data have been generated for the nematode
C. elegans. Avoidance behaviours appear to be central
in the nematode’s defence against parasites. Genetic
analysis implicated the involvement of three main
mechanisms: physical pathogen avoidance based on
G-protein signalling in chemosensory neurons (Pradel
et al. 2007); learning of pathogen avoidance behaviour
through serotonin signalling in the nervous system
(Zhang et al. 2005); and physical avoidance as well as
reduced oral uptake of pathogens as part of a general
stress response mediated by insulin-like signalling
(Hasshoff et al. 2007). These mechanisms may provide
several links to other life-history functions including
the physiological immune system, longevity and
reproduction (reviewed in Schulenburg & Ewbank
2007). Physical avoidance behaviours may also show
a high level of specificity, since nematodes responded
differently to distinct Serrawettin surfactant molecules
from the pathogen Serratia marcescens (Pradel
et al. 2007). This specificity may be mediated by the
highly numerous (more than 1000 genes) G-protein-
coupled chemoreceptors (review by Schulenburg &
Diversity in defence options may be fixed genetic-
ally or it may be generated phenotypically during an
individual’s lifespan. The latter may be favoured by
selection if it enables a more specific (and thus
potentially more economic) response to the parasite
repertoire encountered by the individual. This
strategy is manifested in the adaptive immune system
of the higher vertebrates: somatic recombination
results in highly diversified antibodies and B/T cell
receptors which can then be activated specifically
H. Schulenburg et al.
Phil. Trans. R. Soc. B
upon exposure to non-self-peptides, leading to
specific immune memory (e.g. Janeway et al. 2001).
Importantly, this particular system highlights that
diversity per se is not necessarily advantageous. Even
though it enhances efficiency of parasite detection,
high receptor diversity also increases the risk of a
misinterpretation of self-molecules as being foreign,
potentially causing autoimmune responses. There-
fore, specific selective processes act within the
immune system to ensure that self-reacting receptors
are eliminated. The exact dynamics of these selective
processes as well as their consequences on other
components of the immune system are as yet not fully
understood. They are believed to be responsible for
various phenomena, such as an intermediate optimal
level of MHC receptor diversity, as discussed in this
issue by Woelfing et al. (in press).
(b) Redundancy and immunopathology
We would like to point to two complications that
represent a particular challenge for host organisms.
One of them results from the widespread strategy of
parasites to interfere with host defence signalling (see
this issue’s reviews by Obbard et al. (in press) and
Schmid-Hempel (in press)). Such parasite manipu-
lation could be particularly problematic for the host:
even if it shows 100 per cent efficiency in parasite
recognition, this will not help if the recognition signal
cannot be transferred to the immune effectors. One
possible solution is the availability of several redundant
immune signalling pathways. These pathways could act
independently, thus making it difficult for the parasite,
which would have to target all of them. However, in this
case, the host response may not be entirely efficient,
since it may overreact if there is no parasite manipu-
lation or it could even be very weak if parasites
successfully interfere with one of the pathways. There-
fore, an interacting network of separate immunity
pathways could be advantageous. Such a network
would have two important effects. It would minimize
the consequences of parasite manipulations, and it
would also allow for compensatory actions if it
enables the host to detect parasite-mediated disruption
of host signalling. To date, the importance of
redundancy as well as interconnections among immun-
ity signalling pathways as a defence against parasite
manipulations is unexplored.
Another important complication is the risk of
immunopathology (this issue’s review by Sorci & Faivre
in press; see also Graham et al. 2005). Parasite
elimination often relies on cytotoxic compounds, e.g.
reactive oxygen and nitrogen species (ROS and RNS),
which may be activated in the immediate inflammatory
response in vertebrates. These compounds are very
efficient at destroying parasites. However, they are
generic cytotoxins. Therefore, their activation auto-
matically leads to the damage of host tissue. In turn,
selection should favour a very strict regulation of these
substances, including their deactivation upon usage. In
fact, activation of cytotoxic compounds is usually
followed by secretion of anti-inflammatory molecules
such as interleukin-10 or transforming growth factor-b
(review by Sorci & Faivre in press). Furthermore, we
also expect evolution of specific protective mechanisms
within the host, such as expression of antioxidant
enzymes such as superoxide dismutase or catalase (e.g.
Sorci & Faivre in press). The amount of oxidative
damage, mainly resulting from respiratory burst during
innate immune defence, may also depend on the
effectiveness of other immune functions, such as
MHC-mediated adaptive immunity (Kurtz et al.
2006), even though the exact underlying mechanism
is as yet unknown. Immunopathology also represents
an important complication in invertebrate innate
immune systems: activation of cytotoxic compounds
leads to measurable damage of self-tissue in the
mealworm beetle T. molitor (Sadd & Siva-Jothy 2006).
Similarly, in many organisms, such as the nematode
C. elegans, ROS are produced as a defence against
pathogens, but may also cause oxidative stress leading
to protein damage in the host (Chavez et al. 2007;
Mohri-Shiomi & Garsin 2008). In this case, pathogen
exposure not only leads to activation of ROS but also
antioxidant enzymes such as superoxide dismutase,
which significantly minimizes oxidative damage
thereby increasing nematode survival (Chavez et al.
2007). Consequently, such a protective mechanism
may represent a universal component of animal
(c) Life-history integration
The immune system has evolved, and still is evolving,
in the context of other life-history requirements
and environmental conditions (i.e. not in isolation).
Two processes are likely to be of major importance.
(i) The most relevant environmental information
(e.g. parasite abundance and diversity, food
availability) should be filtered and integrated in
order to determine the most efficient response.
(ii) Activation of the immune system must take into
account developmental stage and nutritional
state of the organism in order to minimize
negative effects on other life-history functions,
which may result from autoimmune damage
or resource competition. In this context, we
particularly expect a trade-off between immunity
It is as yet unclear how life-history integration of
immune defence is mediated at the molecular level.
Within the innate immune system, an interesting
candidate is the insulin-like signalling cascade. This
pathway shows a high degree of conservation across
animals. To date, its functions are best understood in
the nematode C. elegans. Pathway activation depends
on external cues such as food availability or environ-
mental stress (heat, oxidative stress, crowding). Its
normal activity in the wild-type associates with high
reproductive rates (e.g. Gems et al. 1998; Houthoofd
et al. 2005). By contrast, its downregulation in mutant
strains leads to activation of many stress resistance
genes, including components of the immune system
such as antimicrobial peptides and ROS-protective
antioxidant enzymes (Murphy et al. 2003; McElwee
et al. 2004), ultimately leading to high pathogen
resistance (Garsin et al. 2003; Chavez et al. 2007;
Hasshoff et al. 2007).
6H. Schulenburg et al.Introduction
Phil. Trans. R. Soc. B
Aspects of mating are expected to be of special
importance, since they have a direct effect on fitness
(i.e. reproductive success). We would like to point to
the following three aspects:
(i) Based on Bateman’s principle, the two sexes
have different evolutionary interests, and there-
fore they appear to vary in their investment in
immune defence (reviewed in Rolff 2002; Nunn
et al. in press). The underlying mechanisms are
(ii) Mate choice may serve to optimize offspring
immunity, either by choice of immunocompe-
tent males displaying costly ornaments or by
choice of males with complementary immune
genes, e.g. for MHC receptor loci. In verte-
brates, the relationship between immunocom-
petence and male ornaments could possibly be
mediated by testosterone (see discussion in
Nunn et al. in press). In insects, this relationship
could be influenced by the prophenoloxidase
cascade, which contributes to both immunity
(e.g. the melanization response, production of
cytotoxic compounds; Cerenius et al. 2008) and
epigamic traits (Siva-Jothy 2000). Choice of
mate partners with complementary immunity
alleles was shown in sticklebacks to be mediated
by chemosensory perception of the diversity of
peptides bound to MHC receptors (Milinski
et al. 2005).
(iii) Since finding a mate as well as all the following
steps finally leading to the fertilization of eggs is
energetically costly, we also expect a direct
trade-off for resources between mating and
immunity. Such a trade-off may be mediated
by testosterone in the vertebrates (Folstad &
Karter 1992) and juvenile hormone in insects
(Rolff & Siva-Jothy 2002).
(d) Community immunity
Organisms do not live in isolation, but are usually part
of a community. If composition of the community is
comparatively stable over time, selection should favour
comprehensive co-adaptations among its members,
which may also extend to immune defence. Such
stability is most convincing for social organisms.
Indeed, animal societies
mechanisms to protect the community from parasite
attack, ranging from specific behaviours against
parasite-rich material or infected members of the
society, structure and organization of the nest, as well
as a systemic society-wide activation of physiological
immunity, as discussed in this issue’s review by
have evolved several
Box 1. The role of associated microbes for evolution of immunity
How does the immune system distinguish between ‘friend’ and ‘foe’? Although this is one of the oldest questions
for immunologists, there is now fresh impetus from ecological studies, which have directed attention to hosts
that are commonly disregarded by immunological research. A prime example is the highly specialized system of
the squid light organ and its symbiont Vibrio fischeri (McFall-Ngai & Ruby 1991; Nyholm & McFall-Ngai
2004). Based on recent technological innovations, it is now possible to characterize the genetic underpinnings of
such host–microbe interactions, including full genome sequencing (Ruby et al. 2005). In this mutualistic
symbiosis, Vibrio releases molecular patterns that have long been known as immune response-inducing
pathogen-associated molecular patterns (PAMPs), e.g. peptidoglycan and lipopolysaccharide. In this case,
however, these molecules trigger the establishment of a mutually beneficial symbiosis (Koropatnick et al. 2004).
These findings have modified our viewof the patterns and receptors regulating host–symbiont relationships, and
led to the distinction of PAMPs and context-dependent microbe-associated molecular patterns.
More generally, most animal bodies seem inhabited by a hitherto underestimated diversity of microbes,
especially in the gut (e.g. O’Hara & Shanahan 2006; Dethlefsen et al. 2007; Ley et al. 2008). How the immune
system manages to learn which of those are harmful and which are not is still a puzzle. It may well be that the
necessity to evaluate, and then appropriately respond to, this microbial diversity contributed to the evolution of
the adaptive immune system or the repertoire of antimicrobial peptides (e.g. McFall-Ngai 2007; Anselme et al.
in press; see also Reynolds & Rolff in press). At the same time, these associated microbes appear to play an
important direct role in pathogen defence (e.g. Oliver et al. 2003; Scarborough et al. 2005; O’Hara & Shanahan
2006; Sansonetti & Di Santo 2007), including, among others, the development of the B-cell repertoire
(reviewed in Lanning et al. 2005). The underlying molecular genetics of microbe-mediated immunity are just
being addressed in research. One recent example demonstrates that a single molecule, polysaccharide A, from
the intestinal symbiont Bacteroides fragilis, acts as an anti-inflammatory factor, thereby preventing the
development of Helicobacter pylori-induced disease (Mazmanian et al. 2008).
Dealing with communities of organisms and explaining their relationships is the core competence of
ecologists. Moreover, evolutionary biologists may give further insights by explaining the evolution of such
associations. Here, the community of a host and all its symbionts’ genomes may be viewed as a ‘hologenome’,
such that selection shapes the genomes of the symbionts faster than the genome of the longer lived host, an
ecological view originally brought up for corals and their symbionts, facing the risk of coral bleaching
(Rosenberg et al. 2007). Since it is more widely applicable, this view might revolutionize our current
understanding of evolution and immunity. Molecular immunologists may then help us understand how this
community of organisms interacts and coordinates important life-history functions such as defence.
H. Schulenburg et al.
Phil. Trans. R. Soc. B
Cremer & Sixt (in press; see also Cremer et al. 2007).
The underlying molecular mechanisms for such
social immunity are as yet unexplored. Considering
that humans also evolved to live within social groups,
detailed understanding of these processes will be of
considerable medical interest.
We further expect the relationship between multi-
cellular organisms and their associated microbes to be
of particular importance for immune defence as well as
a particular challenge for future research (box 1). In
humans, the adult body comprises 10 times more
microbial cells than human cells, mainly due to the
large number of microbes in the gastrointestinal tract
(more than 1010cells mlK1intestinal lumen; see
O’Hara & Shanahan 2006). If the associations are
long lasting, then evolution of mutualistic interactions
should be advantageous. In fact, the human microbial
ecosystem contributes to numerous body functions,
e.g. nutrient processing, regulation of fat storage and
also defence against pathogens (reviewed in Backhed
et al. 2005; O’Hara & Shanahan 2006; Sansonetti &
Di Santo 2007). Similar relationships appear to be
widespread among other animal hosts (Oliver et al.
2003; Scarborough et al. 2005; Fraune & Bosch 2007;
Grozdanov & Hentschel 2007; Ikeda-Ohtsubo et al.
2007; Ley et al. 2008). Since the community of a host
and its symbionts can essentially be viewed as an
ecosystem, ecological immunologists should be in the
‘pole position’ to study such interactions (box 1).
An organism’s immune defence is an extraordinarily
complex, continuously evolving system. It is charac-
terized by high levels of diversity, redundancy and
mechanisms for life-history integration. Consequently,
a full functional and mechanistic understanding will
require consideration of the processes that determine
its evolution, i.e. its ecological context. Similarly, the
dynamics of ecological processes in natural popu-
lations, including those related to host–parasite
interactions, depend on molecular genetic mechanisms
such as those related to host immunity. Consequently,
the merger of these disciplines is likely to be very
instructive for practitioners in both parental fields.
Ecological immunology is a young field producing
exciting empirical and conceptual insights into the way
physiology and ecology interact in the context of
disease evolution and host population responses. It
clearly has a raft of applied implications, but is also
exciting because it is one of the few fields that allows
evolutionary ecologists to open up a well-studied
black box and begin to understand the evolutionary
context of a hugely important functional system. At a
more proximate level, ecological immunology will
help us put a meaning to the ever-expanding banks of
comprehensive—omics data from both laboratory and
field environments. Our intention with this review and
the themed issue is to provide a framework of the
ecological processes and immunological consequences
thereof which are of importance in this context.
We are very grateful to all contributors to this issue for
stimulating discussions and advice, two referees for valuable
comments on the manuscript and Claire Rawlinson and
James Joseph for editorial support. H.S. acknowledges
support from the German Science Foundation (grant
SCHU 1415/5-1) and the Wissenschaftskolleg zu Berlin,
J.K. from the Swiss National Foundation (3100A0-112992)
and the Wissenschaftskolleg zu Berlin and Y.M. from the
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