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Is MHC enough for understanding wildlife immunogenetics?
Opinion
TRENDS in Ecology and Evolution
Vol.21 No.8
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Is MHC enough for understanding wildlife immunogenetics? Karina Acevedo-Whitehouse and Andrew A. Cunningham Institute of Zoology, Regent’s Park, London, NW1 4RY, UK
Along with reproductive success and predation, infectious disease is a major demographic and evolutionary driver of natural populations. To understand the evolutionary impacts of disease, research has focussed on the major histocompatibility complex (MHC), a genetic region involved in antigen presentation. There is a pressing need for the broader research currently conducted on traditional vertebrate models to be transferred to wildlife. Incorporating such knowledge will enable a broader understanding of the levels at which natural selection can act on immunity. We propose two new approaches to wildlife immunogenetics and discuss the challenges of conducting such studies. At a time when novel pathogens are increasingly emerging in natural populations, these new approaches are integral to understanding disease dynamics and assessing epidemic risks. The genetics of host defence against pathogens Under natural conditions, populations and individuals are challenged constantly by pathogens, which act as one of the main selective forces influencing fitness. Thus, it is not surprising that vertebrates have evolved numerous innate and adaptive immune responses to overcome these infectious challenges. For a pathogen, the selective pressures arising from the host immune system are a major influence on the evolution of mechanisms of infectivity and of immune-recognition avoidance [1]. It is in the context of this evolutionary arms-race between host and pathogen that infectious diseases occur and persist [2]. Given the influence that pathogens can exert on both demographic and reproductive parameters of natural populations [3,4], it is of interest to characterize the genetic components of host immunity and to elucidate the way in which they give rise to functional variations in resistance to infectious diseases. Ever since the description of the first molecule of the human major histocompatibility complex (MHC) (termed human leukocyte antigen, HLA-A2) in 1958 [5], there has been rapid growth in our understanding of the structure and function of this genetic region (Box 1). Pioneer studies on tissue-graft rejection led to the identification of the importance of this multigene family in the adaptive immune response [6]. Since then, the MHC has become one of the best studied genetic systems in gnathostomes (jawed vertebrates) that evidences the long-term operation of natural selection (recently reviewed in [7]). Almost five Corresponding author: Acevedo-Whitehouse, K. ([email protected]). Available online 9 June 2006 www.sciencedirect.com
decades of investigating this group of genetically clustered loci has revealed a convoluted system upon which many immune responses depend. In recent years, the developing field of immunogenetics has identified many other genes involved in shaping the immune repertoire, either solely or in conjunction with other loci. This list ranges from genes involved in innate immunity to those implicated in immunomodulation and adaptive responses (see examples in Table 1). A comprehensive review of the literature describing the structure and function of these genes is well beyond the scope of this article, but excellent recent reviews exist that can be consulted for this purpose [8,9]. Mapping and association studies have revealed that approximately half of the genetic variability for resistance to infection is attributable to non-MHC genes [10], suggesting that MHC-independent immune responses also undergo host–pathogen coevolution. Together, these studies are improving our understanding of the mechanisms of genetically regulated protection against pathogens in humans and model vertebrates, and are providing evidence of a complex interplay between innate and adaptive immunity [11]. Immunity as a complex system Predicting the evolutionary potential of natural populations in response to pathogens requires at least a minimal understanding of pathogenesis and immunity. The complexity of the immune system arises from pathogens not being a natural group per se, but rather a phylogenetically and antigenically diverse suite of organisms that interact at various cellular and intracellular levels with the host [12]. Immunity should not be regarded as an unambiguous event that will occur identically against all pathogens every time it is invoked, or as equal during each stage of a host’s life [13,14]. Rather, it will depend upon determinants of cell surfaces (e.g. structure of receptors on cell membranes), opportune recognition of pathogens, intensity of exposure to the pathogen, timely activation of containment and destruction measures, and, finally, the generation of a specific and definitive adaptive immune response [15]. Failing to consider the complexity of the immune system and the polygenic nature of many infectious diseases limits our ability to test hypotheses regarding the possible role of selection in shaping patterns of variation in pathogen resistance. For instance, it has been recognized recently that non-MHC genes are far more important for helminth resistance in small rodents than are MHC genes [16]. Other well known examples that highlight pathogen-driven selection at non-MHC genes
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Box 1. Structure and immune role of the major histocompatibility complex The MHC is a cluster of genes involved in mate choice, kin recognition and immunity of jawed vertebrates. This gene complex is closely grouped on a single chromosome and appears to segregate in simple Mendelian fashion. The MHC (sensu lato) encodes a collection of both immune and non-immune related molecules. The encoded immune molecules, glycoproteins, deliver peptides to the cell surface during antigen presentation, thereby enabling ‘self’ and ‘non-self’ recognition by T cells
[15]. The mammalian MHC is typically divided into regions or subgroups (Figure I) that vary in their properties and functions. These subgroups are identified as class I, class II, and class III, of which class I and II are considered ‘classical’ genes. A fourth subgroup of genes (class IV), many of which have a role in immunity, has been identified more recently [49]. The presence of each subgroup and the number of genes per subgroup varies between species.
Figure I. Map of the human MHC showing the proposed I, II, III and IV regions. There are essentially three functional immune categories encoded by the genes within the MHC: (i) regulation of innate immunity, inflammation and immunomodulation by class III and class IV genes, such as those encoding heat shock protein 70 (HSP70), cytokine receptors, complement components, tumour necrosis factor (TNF), lymphotoxins, leukocyte-specific transcript (LST)-1, and natural cytotoxicity-triggering receptor 3 (NKp30) [50]; (ii) antigen processing and presentation to CD8+ and CD4+ T cells by the class I and class II genes; and (iii) Intercellular communication via MHC receptors and ligands.
Table 1. Selected non-MHC immune genes, and their functions and known associations with infectious diseasesa Gene or gene family Chemokine receptors (CCR) Chemokine ligands (CCL) Interleukin receptors (IL) Immunoglobulin receptors (FcR)
Interferon (IFN) genes
Leukocyte immunoglobulin-like receptor superfamily (KIR; Ly49)
Mannose binding lectin (MBL)
Natural macrophage protein (NRAMP1; SLC11a1)
Toll-like receptor (TLR4; LPS) Tumour necrosis factor (TNF) genes Vitamin D receptor (VRD) a
Immune function of gene product(s) Transduction of signals that stimulate migration of leukocytes Suppression of viral activity Modulation of cytokines; stimulation of NK cells Linkage of antibody-antigen complexes to cellular effector machinery; stimulation of phagocytosis, release of inflammatory mediators and antibody-dependent cytotoxicity Activation of macrophages and up-regulation of cellular immunity; induction of antiviral state in virally-infected cells; regulation of tumour necrosis factor Family of immune receptors expressed predominantly on monocytes and B-cells and, to a lesser extent, on dendritic cells and NK cells; stimulation or inhibition of NK cell activation and function Opsonisation of pathogens and activation of the complement system before production of antibodies occurs Alteration of intravacuolar environment in which intracellular pathogens reside; regulation of chemokines, inducible nitric oxide release, MHC class II molecules and macrophage activation Recognition of conserved molecules unique to pathogens Multifunctional pro-inflammatory cytokine Differentiation of monocytes; downregulation of lymphocyte proliferation and cytokine secretion
Disease or infection HIV-1; AIDSb; hepatitis B; malaria; Helicobacter pylori HIV-1 HIV; TB; Salmonella; schistosomiasis; H. pylori Recurrent bacterial infection; meningococcal septic shock
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[19,24] [17,19] [19]
HIV-1; TB; listeriosis; malaria; haemonchosis; schistosomiasis
[16,17,19]
HIV-1; AIDSc; hepatitis B; hepatitis C
[24]
HIV-1; AIDSb,c; leishmaniasis
[19,22]
HIV-1; TB; leprosy; Salmonella; leishmaniasis; toxoplasmosis; candidiasis
[19,54]
West Nile virus; Salmonella; Klebsiella Leprosy; cerebral malaria; leishmaniasis; chlamydiasis Hepatitis B; TB; atypical mycobacteria
[18,55,56] [19]
Non-(classical) MHC genes known to produce a functional transcript and demonstrate at least one immune characteristic are shown. Survival. c Disease progression. b
Refs [9,19]
[9,19]
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are the associations between genetic polymorphisms and resistance to TB and malaria, where variations at the gene encoding natural resistance-associated macrophage protein 1 (Nramp1) influence susceptibility to mycobacterial infections in mice and humans [17,18], and particular alleles of the gene encoding chemokine receptors (CCR) have an important role in conferring resistance to malaria (reviewed in [19]). In addition to differences in their association with distinct types of pathogen, different immune genes are important during different stages of infection and disease. For example, following challenge from a pathogen, the first host system to be called upon is the innate immune response, which includes mononuclear phagocytes, complement components, antimicrobial peptides, cytokines, and tumour necrosis factor (TNF) [15] and is mostly under control by genes of the MHC class III subgroup [20] and other genes or gene families [21,22]. Once adaptive immunity is activated, the host defences rely principally on humoral and cellular responses, which are regulated by MHC class I and class II genes [23] and by genes belonging to the leukocyte immunoglobulin-like receptor superfamily [24]. Recent studies have shown that the expression pattern of immune genes differs throughout the period of infection, with many genes showing augmented expression at different stages [25,26]. Hence, conducting a study early in the course of an infection while assaying variation at a gene involved in later stages of immunity could produce misleading results. Strengths and limitations of the MHC as an immune gene marker There are surprisingly few published efforts that incorporate current knowledge from model vertebrate studies to help understand immune genetic variation in natural populations. To date, the majority of existing studies have focused on the MHC and, with very few exceptions (e.g. [27,28]), have examined variability at one particular site of this large genetic complex, that of the peptide binding region (PBR) of the class II transmembrane recognition molecules (hereafter c-II PBR). From an evolutionary
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biology perspective, the c-II PBR is undoubtedly important because it shows the greatest signature of the effects of balancing selection and, as such, is a good marker for explaining the mechanism by which pathogen-driven MHC variability is maintained [29]. However, from a strictly functional perspective, no scientific basis exists to assume that this region is crucial to all immune responses against all types of pathogens (Box 2). Nevertheless, irrespective of the different pathways and immune mechanisms elicited by diverse infective agents, the c-II PBR has been used as the choice marker for studying variation in resistance in natural populations to an immense array of pathogens and conditions, including various helminth groups (e.g. [30,31]), bacteria [32,33], viruses [33,34] and even virus-related cancer [35]. We certainly do not wish to imply that such studies have no value and we do not dispute the role that MHC class II genes have in the ability of vertebrates to respond to pathogenic insults. Rather, we question the rationale behind focusing almost exclusively on this particular region of the MHC when other suitable genetic regions are available to expand and complement research on how particular pathogens affect genetic diversity and, inversely, how genetic variation influences susceptibility or resistance to pathogens. There exist several cases where focusing exclusively on the c-II PBR produced controversial or unexpected results. For instance, the Northern elephant seal Mirounga angustirostris population has amazingly low levels of MHC (class II) genetic variation [36]. However, the population is thriving and there have been no obvious indications of increased susceptibility to infectious diseases [37]. A similar situation was observed in a feral herd of Chillingham cattle Bos taurus from northern England, for which there has been no evidence of increased susceptibility to infectious disease despite their genetic uniformity at the MHC [38]. The opposite situation occurs in desert bighorn sheep Ovis aries populations, which show both high polymorphism and extensive nucleotide and amino-acid sequence divergence at the c-II PBR [39], but have been drastically reduced owing mainly to infectious diseases. One plausible explanation for the first two examples is that both populations have
Box 2. Different pathogens interact with different immune effectors A main characteristic of pathogens is their ability to infect hosts, causing tissue damage and consequently disease. The pathways and mechanisms used to infect hosts can vary greatly among different pathogens. To fight infection, diverse host mechanisms are used according to the pathogen and its pathogenesis [15]. Innate immune responses are initiated by the recognition of specific structures of the invading pathogens. Various effectors of innate immunity, such as the antimicrobial peptides, can kill a broad spectrum of pathogens directly, before the adaptive immunity has an opportunity to intervene in the host response [21]. Other components of innate immunity have well-established effects against particular pathogen types; for instance, cytokine receptors, tumour necrosis factor (TNF) and g-interferon (IFN) are intricately involved in the response against viruses [24,51], and the mannose-binding lectin (MBL) pathway confers protection against microorganisms with a surface rich in mannan and beta-glucan (e.g. pathogenic fungi) [22]. Pathogen recognition prompts an intracellular signalling pathway that results in the induction of pro-inflammatory molecules and in the maturation of dendritic cells, leading to the activation of adaptive immunity. Once this occurs, there are different response-pathways that can be activated depending on www.sciencedirect.com
the pathogen type. For instance, T-cell mediated immunity is crucial for defence against intracellular pathogens such as viruses, some protozoa and some bacteria because the intracellular habitat protects against Bcell mediated responses (humoral immunity). Extracellular pathogens (e.g. most bacteria, fungi and metazoan parasites) will face both T- and B-cell mediated responses [15]. Although some overlap occurs (see [52]), these pathways are generally regulated by different immune-related genes or by a combination of them. For instance, the MHC class I molecules present endogenously derived peptides (from the cytosol and endoplasmic reticulum) to CD8+ cytotoxic T-cells, and hence are associated primarily with adaptive responses against intracellular pathogens. MHC class II molecules, by contrast, are intricately involved in pathogen presentation of extracellular pathogens to CD4+ T-helper cells. Furthermore, non-classical MHC molecules and MHC class I-like molecules (MIC) present antigens to unconventional T-cells, which are important players in the response against intracellular pathogens [53]. Currently, the dynamics between different immune genes are slowly being unravelled, including whether they act together or sequentially, or whether they control different types of immune responses [11].
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maintained enough variability at other immune genes to account for their apparently robust immune systems. Analogously, the high disease susceptibility observed in bighorn sheep could be driven by a lack of variation in other genetic regions, as discussed by Gutierrez-Espeleta et al. [39]. Taking these examples together, it seems prudent to state that low variation at the c-II PBR will not always be the most important genetic source of high susceptibility to infectious disease in wildlife, as was suggested initially [40] and as is still generally accepted. A paradigm shift – New approaches for wildlife immunogenetic studies Taking into consideration what we now know from studies in model vertebrates as well as the increasing availability of modern technologies (see [41]), we envisage two approaches that could be used for a broader assessment of genetic variation in pathogen susceptibility of wildlife. The first approach entails a case-tailored selection of the candidate gene(s) relevant to the infectious condition to be studied in the population; the second approach relies on a large-scale cladistic genomic survey of immune genes using any of quantitative trait loci (QTL) analysis, single nucleotide polymorphism (SNP) chips, or array-based analyses [41,42]. Both approaches face practical and conceptual issues that define their practicality, limitations and strengths in different scenarios (Table 2). However, we believe they will prove useful, offering new insights into evolutionary adaptations to pathogens as well as facilitating analysis on the contribution of different immune genes throughout the course of an infection. Can we ever hope to study other immune genes in nonmodel species? Evolutionary biologists might, in all fairness, question the need for more candidate immune target genes. Research on the MHC (sensu lato) is burdened with all sorts of problems that certainly emphasize the difficulty of taking ‘off-theshelf’ genes and using them effectively across a range of non-model systems. Obviously, there is a risk that attempting to investigate another set of genes from a model system will produce exactly the same challenges for studies on wildlife. However, advances in science are accomplished precisely because of these challenges. Cloning and characterising MHC genes in non-model species was perceived initially as an obstacle to the study of MHC variation in natural populations. Nonetheless, although still faced with difficulties, this concern has gradually become unwarranted [7], as can be concluded from the growing number
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of studies on the topic. Characterisation and analysis of other immune regions in non-model species is undoubtedly feasible, although this approach might be perceived currently as being potentially difficult. A few recent studies have already described non-MHC immune genes in nonmodel species (e.g. [25,28]), and databases containing sequences of immune-related genes from various vertebrates (e.g. The Immuno Polymorphism Database; http:// www.ebi.ac.uk/ipd) can provide useful information for designing conserved PCR sequence-specific primers that amplify across diverse vertebrate taxa [42]. The escalating amount of DNA sequence information will no doubt facilitate efforts to identify the effects of selection on other immune genes and gene regions, as well as to estimate the distribution of pathogen-driven selection effects across the genome of non-model vertebrates. From studies on vertebrate models, we know that several genes involved with innate and adaptive immunity exhibit high levels of polymorphism [8,9]. Research on humans has shown that many immune genes are present in virtually all individuals as major haplotypes associated with particular diseases [43], and has raised the possibility of a synergistic relationship between different immune genes [19]. Accounting for genetic events such as meiotic recombination rates and linkage disequilibrium between pairs of loci [44] could help identify which locus is effectively involved in resistance or susceptibility to a pathogen and, as such, is under selective pressure. Moreover, some of the genes regulating innate immunity, such as the those encoding natural killer (NK) receptors and killer immunoglobulin-like receptors (KIR), are closely involved with reproductive success and pregnancy [45] and as such are not only ideal to expand current research on pathogen resistance, but also on mate choice and sexual selection. Conclusions and perspectives In view of advances in molecular techniques and the available information on immune genes of humans and model vertebrates, for the first time we have the opportunity to test complex hypotheses about pathogen-mediated selection that can occur at different times during infection, such as examining the contribution of host genetics on both innate and adaptive immunity to pathogens in natural populations. This could be an important step toward characterising the genetic adaptations that lead to survival and understanding the microevolution of the host immune system. During recent decades, it has become clear that pathogens are emerging and re-emerging as significant disease
Table 2. Practical and conceptual limitations and strengths of case-tailored and cladistic immunogenetic approaches Case-tailored selection of genetic marker A priori knowledge of the pathogenesis and immune response pathways for the particular pathogen is required Gene sequences need to be described for the species of interest or for similar species Genotyping is restricted to single genes Relatively inexpensive Technically simple Can be conducted in all laboratories with basic molecular biology equipment Enables assessment of the contribution of a particular immune gene during the course of the infection www.sciencedirect.com
Large-scale cladistic genome screening A priori case-specific knowledge of immunopathogenesis is not essential because all or most immune genes will be screened Gene sequences need to be described for the species of interest or for similar species Full immuno-genotyping is needed Relatively expensive Technically demanding Specialist laboratory equipment is required Enables assessment of the contribution of different immune genes during the course of the infection
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threats to wildlife and human health at an increasing rate [3,4]. Infectious disease is now recognised as a serious threat to small or endangered populations, often by causing sudden and unexpected demographic declines and there is a growing concern that both novel and resurgent pathogens are having an increasing impact on natural populations [3]. In this light, understanding how resistance to pathogens is regulated in natural populations is not only of academic interest, but is of key importance for conservation plans and management decisions, particularly for populations at high risk of disease outbreaks or pathogen introductions. There is no doubt that the current MHC-based studies have been useful in explaining some of the variation in disease susceptibility in wildlife. However, we emphasize caution in drawing general conclusions from the study of just one part of the immunogenetic complex. To prevent future pathogen-driven population declines, we need to identify and quantify risks before the disease causes a significant problem. If we were to focus on only one of the immune genes (e.g. allelic diversity of the MHC class II genes) as a predictive indicator of ‘immunocompetence’, we would be ignoring the contribution of other genes involved with immune responses. A broader understanding of the immunogenetic status of small or endangered populations would enable informed risk assessments to be made for the likelihood of specific pathogens, or types of pathogen, to pose a serious risk to the species’ survival. Host–pathogen interactions are dynamic [2] in such a way that ‘protective’ genotypes will not necessarily be so over longer time periods; hence, it would not be advisable to attempt selection for particular genotypes (for discussion, see [46–48]). We simply suggest using immunogenetic data to help complement management decisions in the event of a pathogenic threat. Prioritisation of disease detection, prevention, and mitigation strategies (e.g. translocation or quarantine of individuals or subpopulations more likely to be susceptible to the pathogen) could then be included in any risk assessment. We hope that, in the future, studies on wildlife immunogenetics will contribute to understanding the dynamics and predicting the consequences of epizootics. Acknowledgements We thank David Watkins, Jim McCluskey and Frank Christiansen for their stimulating discussions about this topic. Ailsa Hall, Frances Gulland and Horacio de la Cueva read through previous versions of the article and provided helpful suggestions. We also thank three anonymous reviewers who provided valuable comments that helped improve the article.
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Is MHC enough for understanding wildlife immunogenetics? Karina Acevedo-Whitehouse and Andrew A. Cunningham Institute of Zoology, Regent’s Park, London, NW1 4RY, UK
Along with reproductive success and predation, infectious disease is a major demographic and evolutionary driver of natural populations. To understand the evolutionary impacts of disease, research has focussed on the major histocompatibility complex (MHC), a genetic region involved in antigen presentation. There is a pressing need for the broader research currently conducted on traditional vertebrate models to be transferred to wildlife. Incorporating such knowledge will enable a broader understanding of the levels at which natural selection can act on immunity. We propose two new approaches to wildlife immunogenetics and discuss the challenges of conducting such studies. At a time when novel pathogens are increasingly emerging in natural populations, these new approaches are integral to understanding disease dynamics and assessing epidemic risks. The genetics of host defence against pathogens Under natural conditions, populations and individuals are challenged constantly by pathogens, which act as one of the main selective forces influencing fitness. Thus, it is not surprising that vertebrates have evolved numerous innate and adaptive immune responses to overcome these infectious challenges. For a pathogen, the selective pressures arising from the host immune system are a major influence on the evolution of mechanisms of infectivity and of immune-recognition avoidance [1]. It is in the context of this evolutionary arms-race between host and pathogen that infectious diseases occur and persist [2]. Given the influence that pathogens can exert on both demographic and reproductive parameters of natural populations [3,4], it is of interest to characterize the genetic components of host immunity and to elucidate the way in which they give rise to functional variations in resistance to infectious diseases. Ever since the description of the first molecule of the human major histocompatibility complex (MHC) (termed human leukocyte antigen, HLA-A2) in 1958 [5], there has been rapid growth in our understanding of the structure and function of this genetic region (Box 1). Pioneer studies on tissue-graft rejection led to the identification of the importance of this multigene family in the adaptive immune response [6]. Since then, the MHC has become one of the best studied genetic systems in gnathostomes (jawed vertebrates) that evidences the long-term operation of natural selection (recently reviewed in [7]). Almost five Corresponding author: Acevedo-Whitehouse, K. ([email protected]). Available online 9 June 2006 www.sciencedirect.com
decades of investigating this group of genetically clustered loci has revealed a convoluted system upon which many immune responses depend. In recent years, the developing field of immunogenetics has identified many other genes involved in shaping the immune repertoire, either solely or in conjunction with other loci. This list ranges from genes involved in innate immunity to those implicated in immunomodulation and adaptive responses (see examples in Table 1). A comprehensive review of the literature describing the structure and function of these genes is well beyond the scope of this article, but excellent recent reviews exist that can be consulted for this purpose [8,9]. Mapping and association studies have revealed that approximately half of the genetic variability for resistance to infection is attributable to non-MHC genes [10], suggesting that MHC-independent immune responses also undergo host–pathogen coevolution. Together, these studies are improving our understanding of the mechanisms of genetically regulated protection against pathogens in humans and model vertebrates, and are providing evidence of a complex interplay between innate and adaptive immunity [11]. Immunity as a complex system Predicting the evolutionary potential of natural populations in response to pathogens requires at least a minimal understanding of pathogenesis and immunity. The complexity of the immune system arises from pathogens not being a natural group per se, but rather a phylogenetically and antigenically diverse suite of organisms that interact at various cellular and intracellular levels with the host [12]. Immunity should not be regarded as an unambiguous event that will occur identically against all pathogens every time it is invoked, or as equal during each stage of a host’s life [13,14]. Rather, it will depend upon determinants of cell surfaces (e.g. structure of receptors on cell membranes), opportune recognition of pathogens, intensity of exposure to the pathogen, timely activation of containment and destruction measures, and, finally, the generation of a specific and definitive adaptive immune response [15]. Failing to consider the complexity of the immune system and the polygenic nature of many infectious diseases limits our ability to test hypotheses regarding the possible role of selection in shaping patterns of variation in pathogen resistance. For instance, it has been recognized recently that non-MHC genes are far more important for helminth resistance in small rodents than are MHC genes [16]. Other well known examples that highlight pathogen-driven selection at non-MHC genes
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Box 1. Structure and immune role of the major histocompatibility complex The MHC is a cluster of genes involved in mate choice, kin recognition and immunity of jawed vertebrates. This gene complex is closely grouped on a single chromosome and appears to segregate in simple Mendelian fashion. The MHC (sensu lato) encodes a collection of both immune and non-immune related molecules. The encoded immune molecules, glycoproteins, deliver peptides to the cell surface during antigen presentation, thereby enabling ‘self’ and ‘non-self’ recognition by T cells
[15]. The mammalian MHC is typically divided into regions or subgroups (Figure I) that vary in their properties and functions. These subgroups are identified as class I, class II, and class III, of which class I and II are considered ‘classical’ genes. A fourth subgroup of genes (class IV), many of which have a role in immunity, has been identified more recently [49]. The presence of each subgroup and the number of genes per subgroup varies between species.
Figure I. Map of the human MHC showing the proposed I, II, III and IV regions. There are essentially three functional immune categories encoded by the genes within the MHC: (i) regulation of innate immunity, inflammation and immunomodulation by class III and class IV genes, such as those encoding heat shock protein 70 (HSP70), cytokine receptors, complement components, tumour necrosis factor (TNF), lymphotoxins, leukocyte-specific transcript (LST)-1, and natural cytotoxicity-triggering receptor 3 (NKp30) [50]; (ii) antigen processing and presentation to CD8+ and CD4+ T cells by the class I and class II genes; and (iii) Intercellular communication via MHC receptors and ligands.
Table 1. Selected non-MHC immune genes, and their functions and known associations with infectious diseasesa Gene or gene family Chemokine receptors (CCR) Chemokine ligands (CCL) Interleukin receptors (IL) Immunoglobulin receptors (FcR)
Interferon (IFN) genes
Leukocyte immunoglobulin-like receptor superfamily (KIR; Ly49)
Mannose binding lectin (MBL)
Natural macrophage protein (NRAMP1; SLC11a1)
Toll-like receptor (TLR4; LPS) Tumour necrosis factor (TNF) genes Vitamin D receptor (VRD) a
Immune function of gene product(s) Transduction of signals that stimulate migration of leukocytes Suppression of viral activity Modulation of cytokines; stimulation of NK cells Linkage of antibody-antigen complexes to cellular effector machinery; stimulation of phagocytosis, release of inflammatory mediators and antibody-dependent cytotoxicity Activation of macrophages and up-regulation of cellular immunity; induction of antiviral state in virally-infected cells; regulation of tumour necrosis factor Family of immune receptors expressed predominantly on monocytes and B-cells and, to a lesser extent, on dendritic cells and NK cells; stimulation or inhibition of NK cell activation and function Opsonisation of pathogens and activation of the complement system before production of antibodies occurs Alteration of intravacuolar environment in which intracellular pathogens reside; regulation of chemokines, inducible nitric oxide release, MHC class II molecules and macrophage activation Recognition of conserved molecules unique to pathogens Multifunctional pro-inflammatory cytokine Differentiation of monocytes; downregulation of lymphocyte proliferation and cytokine secretion
Disease or infection HIV-1; AIDSb; hepatitis B; malaria; Helicobacter pylori HIV-1 HIV; TB; Salmonella; schistosomiasis; H. pylori Recurrent bacterial infection; meningococcal septic shock
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[19,24] [17,19] [19]
HIV-1; TB; listeriosis; malaria; haemonchosis; schistosomiasis
[16,17,19]
HIV-1; AIDSc; hepatitis B; hepatitis C
[24]
HIV-1; AIDSb,c; leishmaniasis
[19,22]
HIV-1; TB; leprosy; Salmonella; leishmaniasis; toxoplasmosis; candidiasis
[19,54]
West Nile virus; Salmonella; Klebsiella Leprosy; cerebral malaria; leishmaniasis; chlamydiasis Hepatitis B; TB; atypical mycobacteria
[18,55,56] [19]
Non-(classical) MHC genes known to produce a functional transcript and demonstrate at least one immune characteristic are shown. Survival. c Disease progression. b
Refs [9,19]
[9,19]
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are the associations between genetic polymorphisms and resistance to TB and malaria, where variations at the gene encoding natural resistance-associated macrophage protein 1 (Nramp1) influence susceptibility to mycobacterial infections in mice and humans [17,18], and particular alleles of the gene encoding chemokine receptors (CCR) have an important role in conferring resistance to malaria (reviewed in [19]). In addition to differences in their association with distinct types of pathogen, different immune genes are important during different stages of infection and disease. For example, following challenge from a pathogen, the first host system to be called upon is the innate immune response, which includes mononuclear phagocytes, complement components, antimicrobial peptides, cytokines, and tumour necrosis factor (TNF) [15] and is mostly under control by genes of the MHC class III subgroup [20] and other genes or gene families [21,22]. Once adaptive immunity is activated, the host defences rely principally on humoral and cellular responses, which are regulated by MHC class I and class II genes [23] and by genes belonging to the leukocyte immunoglobulin-like receptor superfamily [24]. Recent studies have shown that the expression pattern of immune genes differs throughout the period of infection, with many genes showing augmented expression at different stages [25,26]. Hence, conducting a study early in the course of an infection while assaying variation at a gene involved in later stages of immunity could produce misleading results. Strengths and limitations of the MHC as an immune gene marker There are surprisingly few published efforts that incorporate current knowledge from model vertebrate studies to help understand immune genetic variation in natural populations. To date, the majority of existing studies have focused on the MHC and, with very few exceptions (e.g. [27,28]), have examined variability at one particular site of this large genetic complex, that of the peptide binding region (PBR) of the class II transmembrane recognition molecules (hereafter c-II PBR). From an evolutionary
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biology perspective, the c-II PBR is undoubtedly important because it shows the greatest signature of the effects of balancing selection and, as such, is a good marker for explaining the mechanism by which pathogen-driven MHC variability is maintained [29]. However, from a strictly functional perspective, no scientific basis exists to assume that this region is crucial to all immune responses against all types of pathogens (Box 2). Nevertheless, irrespective of the different pathways and immune mechanisms elicited by diverse infective agents, the c-II PBR has been used as the choice marker for studying variation in resistance in natural populations to an immense array of pathogens and conditions, including various helminth groups (e.g. [30,31]), bacteria [32,33], viruses [33,34] and even virus-related cancer [35]. We certainly do not wish to imply that such studies have no value and we do not dispute the role that MHC class II genes have in the ability of vertebrates to respond to pathogenic insults. Rather, we question the rationale behind focusing almost exclusively on this particular region of the MHC when other suitable genetic regions are available to expand and complement research on how particular pathogens affect genetic diversity and, inversely, how genetic variation influences susceptibility or resistance to pathogens. There exist several cases where focusing exclusively on the c-II PBR produced controversial or unexpected results. For instance, the Northern elephant seal Mirounga angustirostris population has amazingly low levels of MHC (class II) genetic variation [36]. However, the population is thriving and there have been no obvious indications of increased susceptibility to infectious diseases [37]. A similar situation was observed in a feral herd of Chillingham cattle Bos taurus from northern England, for which there has been no evidence of increased susceptibility to infectious disease despite their genetic uniformity at the MHC [38]. The opposite situation occurs in desert bighorn sheep Ovis aries populations, which show both high polymorphism and extensive nucleotide and amino-acid sequence divergence at the c-II PBR [39], but have been drastically reduced owing mainly to infectious diseases. One plausible explanation for the first two examples is that both populations have
Box 2. Different pathogens interact with different immune effectors A main characteristic of pathogens is their ability to infect hosts, causing tissue damage and consequently disease. The pathways and mechanisms used to infect hosts can vary greatly among different pathogens. To fight infection, diverse host mechanisms are used according to the pathogen and its pathogenesis [15]. Innate immune responses are initiated by the recognition of specific structures of the invading pathogens. Various effectors of innate immunity, such as the antimicrobial peptides, can kill a broad spectrum of pathogens directly, before the adaptive immunity has an opportunity to intervene in the host response [21]. Other components of innate immunity have well-established effects against particular pathogen types; for instance, cytokine receptors, tumour necrosis factor (TNF) and g-interferon (IFN) are intricately involved in the response against viruses [24,51], and the mannose-binding lectin (MBL) pathway confers protection against microorganisms with a surface rich in mannan and beta-glucan (e.g. pathogenic fungi) [22]. Pathogen recognition prompts an intracellular signalling pathway that results in the induction of pro-inflammatory molecules and in the maturation of dendritic cells, leading to the activation of adaptive immunity. Once this occurs, there are different response-pathways that can be activated depending on www.sciencedirect.com
the pathogen type. For instance, T-cell mediated immunity is crucial for defence against intracellular pathogens such as viruses, some protozoa and some bacteria because the intracellular habitat protects against Bcell mediated responses (humoral immunity). Extracellular pathogens (e.g. most bacteria, fungi and metazoan parasites) will face both T- and B-cell mediated responses [15]. Although some overlap occurs (see [52]), these pathways are generally regulated by different immune-related genes or by a combination of them. For instance, the MHC class I molecules present endogenously derived peptides (from the cytosol and endoplasmic reticulum) to CD8+ cytotoxic T-cells, and hence are associated primarily with adaptive responses against intracellular pathogens. MHC class II molecules, by contrast, are intricately involved in pathogen presentation of extracellular pathogens to CD4+ T-helper cells. Furthermore, non-classical MHC molecules and MHC class I-like molecules (MIC) present antigens to unconventional T-cells, which are important players in the response against intracellular pathogens [53]. Currently, the dynamics between different immune genes are slowly being unravelled, including whether they act together or sequentially, or whether they control different types of immune responses [11].
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maintained enough variability at other immune genes to account for their apparently robust immune systems. Analogously, the high disease susceptibility observed in bighorn sheep could be driven by a lack of variation in other genetic regions, as discussed by Gutierrez-Espeleta et al. [39]. Taking these examples together, it seems prudent to state that low variation at the c-II PBR will not always be the most important genetic source of high susceptibility to infectious disease in wildlife, as was suggested initially [40] and as is still generally accepted. A paradigm shift – New approaches for wildlife immunogenetic studies Taking into consideration what we now know from studies in model vertebrates as well as the increasing availability of modern technologies (see [41]), we envisage two approaches that could be used for a broader assessment of genetic variation in pathogen susceptibility of wildlife. The first approach entails a case-tailored selection of the candidate gene(s) relevant to the infectious condition to be studied in the population; the second approach relies on a large-scale cladistic genomic survey of immune genes using any of quantitative trait loci (QTL) analysis, single nucleotide polymorphism (SNP) chips, or array-based analyses [41,42]. Both approaches face practical and conceptual issues that define their practicality, limitations and strengths in different scenarios (Table 2). However, we believe they will prove useful, offering new insights into evolutionary adaptations to pathogens as well as facilitating analysis on the contribution of different immune genes throughout the course of an infection. Can we ever hope to study other immune genes in nonmodel species? Evolutionary biologists might, in all fairness, question the need for more candidate immune target genes. Research on the MHC (sensu lato) is burdened with all sorts of problems that certainly emphasize the difficulty of taking ‘off-theshelf’ genes and using them effectively across a range of non-model systems. Obviously, there is a risk that attempting to investigate another set of genes from a model system will produce exactly the same challenges for studies on wildlife. However, advances in science are accomplished precisely because of these challenges. Cloning and characterising MHC genes in non-model species was perceived initially as an obstacle to the study of MHC variation in natural populations. Nonetheless, although still faced with difficulties, this concern has gradually become unwarranted [7], as can be concluded from the growing number
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of studies on the topic. Characterisation and analysis of other immune regions in non-model species is undoubtedly feasible, although this approach might be perceived currently as being potentially difficult. A few recent studies have already described non-MHC immune genes in nonmodel species (e.g. [25,28]), and databases containing sequences of immune-related genes from various vertebrates (e.g. The Immuno Polymorphism Database; http:// www.ebi.ac.uk/ipd) can provide useful information for designing conserved PCR sequence-specific primers that amplify across diverse vertebrate taxa [42]. The escalating amount of DNA sequence information will no doubt facilitate efforts to identify the effects of selection on other immune genes and gene regions, as well as to estimate the distribution of pathogen-driven selection effects across the genome of non-model vertebrates. From studies on vertebrate models, we know that several genes involved with innate and adaptive immunity exhibit high levels of polymorphism [8,9]. Research on humans has shown that many immune genes are present in virtually all individuals as major haplotypes associated with particular diseases [43], and has raised the possibility of a synergistic relationship between different immune genes [19]. Accounting for genetic events such as meiotic recombination rates and linkage disequilibrium between pairs of loci [44] could help identify which locus is effectively involved in resistance or susceptibility to a pathogen and, as such, is under selective pressure. Moreover, some of the genes regulating innate immunity, such as the those encoding natural killer (NK) receptors and killer immunoglobulin-like receptors (KIR), are closely involved with reproductive success and pregnancy [45] and as such are not only ideal to expand current research on pathogen resistance, but also on mate choice and sexual selection. Conclusions and perspectives In view of advances in molecular techniques and the available information on immune genes of humans and model vertebrates, for the first time we have the opportunity to test complex hypotheses about pathogen-mediated selection that can occur at different times during infection, such as examining the contribution of host genetics on both innate and adaptive immunity to pathogens in natural populations. This could be an important step toward characterising the genetic adaptations that lead to survival and understanding the microevolution of the host immune system. During recent decades, it has become clear that pathogens are emerging and re-emerging as significant disease
Table 2. Practical and conceptual limitations and strengths of case-tailored and cladistic immunogenetic approaches Case-tailored selection of genetic marker A priori knowledge of the pathogenesis and immune response pathways for the particular pathogen is required Gene sequences need to be described for the species of interest or for similar species Genotyping is restricted to single genes Relatively inexpensive Technically simple Can be conducted in all laboratories with basic molecular biology equipment Enables assessment of the contribution of a particular immune gene during the course of the infection www.sciencedirect.com
Large-scale cladistic genome screening A priori case-specific knowledge of immunopathogenesis is not essential because all or most immune genes will be screened Gene sequences need to be described for the species of interest or for similar species Full immuno-genotyping is needed Relatively expensive Technically demanding Specialist laboratory equipment is required Enables assessment of the contribution of different immune genes during the course of the infection
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threats to wildlife and human health at an increasing rate [3,4]. Infectious disease is now recognised as a serious threat to small or endangered populations, often by causing sudden and unexpected demographic declines and there is a growing concern that both novel and resurgent pathogens are having an increasing impact on natural populations [3]. In this light, understanding how resistance to pathogens is regulated in natural populations is not only of academic interest, but is of key importance for conservation plans and management decisions, particularly for populations at high risk of disease outbreaks or pathogen introductions. There is no doubt that the current MHC-based studies have been useful in explaining some of the variation in disease susceptibility in wildlife. However, we emphasize caution in drawing general conclusions from the study of just one part of the immunogenetic complex. To prevent future pathogen-driven population declines, we need to identify and quantify risks before the disease causes a significant problem. If we were to focus on only one of the immune genes (e.g. allelic diversity of the MHC class II genes) as a predictive indicator of ‘immunocompetence’, we would be ignoring the contribution of other genes involved with immune responses. A broader understanding of the immunogenetic status of small or endangered populations would enable informed risk assessments to be made for the likelihood of specific pathogens, or types of pathogen, to pose a serious risk to the species’ survival. Host–pathogen interactions are dynamic [2] in such a way that ‘protective’ genotypes will not necessarily be so over longer time periods; hence, it would not be advisable to attempt selection for particular genotypes (for discussion, see [46–48]). We simply suggest using immunogenetic data to help complement management decisions in the event of a pathogenic threat. Prioritisation of disease detection, prevention, and mitigation strategies (e.g. translocation or quarantine of individuals or subpopulations more likely to be susceptible to the pathogen) could then be included in any risk assessment. We hope that, in the future, studies on wildlife immunogenetics will contribute to understanding the dynamics and predicting the consequences of epizootics. Acknowledgements We thank David Watkins, Jim McCluskey and Frank Christiansen for their stimulating discussions about this topic. Ailsa Hall, Frances Gulland and Horacio de la Cueva read through previous versions of the article and provided helpful suggestions. We also thank three anonymous reviewers who provided valuable comments that helped improve the article.
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