Parasite Immunology, 2015, 37, 217–219
DOI: 10.1111/pim.12190
Editorial
Wild Immunology J. E. BRADLEY School of Life Sciences, University of Nottingham, University Park, Nottingham, Nottingham, UK
Keywords Wildlife, Ecoimmunology
INTRODUCTION Good health and successful reproduction in the wild is dependent on an animal’s ability to survive the wide array of infections to which it is continuously subjected. Infectious disease is ubiquitous in natural populations and a major cause of morbidity and mortality. The outcome of infection is highly variable, ranging from susceptibility and death at one end of the spectrum to resistance and pathogen elimination at the other. Whether an animal overcomes infection or not is dependent on the strength and type of immune response generated, and both intrinsic (genetics) and extrinsic factors (environmental influences) affect this. Hence, predicting the outcome of infection in wild populations depends on understanding the immunological consequences of natural genetic and environmental variability. Most of our knowledge of immunological responses to infectious disease, however, has been gained from studies on the laboratory mouse or humans. Studies on laboratory mice are generally designed to minimize both genetic and environmental influences, and most human studies are undertaken on individuals from the developed world who are no longer exposed to the organisms, either infectious or commensal, that would have been present when the immune system evolved. Increasing our understanding of how extrinsic and intrinsic variables impact on immune responses in animals which have been naturally exposed to infections is especially important in the current context. In particular, it is hypothesized that the observed acceleration in the prevalence of immune-mediated diseases such as allergy and autoimmune Correspondence: Prof Janette Bradley, School of Life Sciences, University of Nottingham, University Park Nottingham NG7 2QZ, Nottingham, UK (e-mail: [email protected]). Received: 31 March 2015 Accepted for publication: 31 March 2015 © 2015 John Wiley & Sons Ltd
diseases is due to changes in environmental exposures as a result of urbanization. Progress in evaluating this hypothesis rests on our ability to understand the interaction between genes and environment in natural populations. Studies of laboratory animals and humans have provided us with great detail on the genes and mechanisms involved in controlling infectious disease and the pathogenesis of immune disorders, but applying this information in wild natural infection situations is complex, and until very recently has been inhibited by the ability to effectively measure detailed immune response variables. Brock et al. (1) appraise the history of ecoimmunology in an article to complement a symposium about methods and mechanisms. The term ecoimmunology was first used in the 1990s (2), but the development of the field has been impeded by a lack of suitable reagents for the analysis of immune responses in natural populations. With the advent of technologies that allow the sequencing of full genomes both cheaply and quickly, it is now possible to measure the RNA expression of immunological parameters and the field is rapidly expanding. Inferences from measurements of RNA can be problematic, because RNA concentrations do not necessarily relate linearly to the quantities downstream of the associated protein effector molecules. With careful consideration, however, quantification of RNA does provide major insights into the immunological status of an individual, and generates many testable hypotheses, as has already been demonstrated by microarray and transcriptomic approaches.
ECOLOGY AND IMMUNOLOGY, TWO DIFFERENT CULTURES? Ecologists and immunologists tend to have quite different approaches to addressing questions in their field. Immunologists aim to define in great detail the immunological mechanisms determining the outcome of infection, and to evaluate the importance of particular genes or molecules in these mechanisms. In order to achieve this, studies are designed to minimize intrinsic and extrinsic variation, and
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immunologists rarely have to use complex analytical tools to determine an effect. Ecoimmunologists embrace variation and thus far have aimed to understand the causes of immune function variability, its consequences in the outcome of infection, and how this impacts on survival and reproductive success (3, 4). The economics of resource allocation is also a primary interest: what are the costs and benefits of diverting resources to mounting an immune response on host survival and reproduction (5). In order to address these questions, complex statistical tools are required to disentangle the effects of variation in genetic and environmental influences. Increased interaction between immunologists and ecologists is important in advancing this emerging field. Communication between the two disciplines is, however, not always easy, due to the very different approaches, and to the existence of subject-specific terminology. There is little doubt that the terminology used in immunology can be difficult, particularly as the nomenclature is ever changing as the functions of molecules become clear. Ecologists may use a more accessible language, but some words often have very specific ecological meanings. For example, to the nonecologist, fitness may be interpreted as a general measure of physical health or vitality, whereas to the ecologist it has a much more specific meaning: that is, Darwinian fitness, or the relative ability of an individual to contribute to the next generation’s gene pool via survival and reproduction. These two interpretations of the term fitness do of course overlap, because being physically fit and healthy is positively related to survival and reproduction, but variation in the precision with which the term is used has considerable potential to muddy the waters in discussions of wild immunology. Another word commonly used in both disciplines, tolerance, has similar potential to generate confusion. Here, ecologists have a looser interpretation of the word: an organism which is neither susceptible nor resistant to a pathogen may be said to tolerate it if it displays minimal pathology. In immunology, however, tolerance has a much more specific meaning. Immunological tolerance means a failure to mount an immune response to an antigen. Thus, it is possible for an animal to be tolerant to a pathogen in ecological terms yet be intolerant immunologically. Thus far, much of the published work in this emerging field has been primarily driven by ecologists, who have historically been restricted by the lack of reagents to using fairly primitive tests (from an immunologist’s perspective). As the ability to measure more immunological parameters increases, and it becomes possible to define the immunological phenotype of an animal (6), communication between the two disciplines is particularly important. A
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central issue which remains is what are the most relevant parameters to measure.
THIS SPECIAL EDITION This creation of this ecologically flavoured special edition is motivated by the shortage of ecoimmunological work that has been driven by purely immunological questions. I do hope it may pique the interest of the readers of Parasite Immunology, encourage them to explore this field further and realize the importance of addressing questions about how the immune system functions under the conditions in which it evolved. The organisms represented in this special edition range from invertebrates to wild ungulates. We start with an article on wild nonmodel rodents by Jackson (7), primarily because the first half of the article provides an excellent introduction to this edition. It answers the questions: Why study the immune responses of wild animals? What should we study? and How should we measure it? It then goes on to describe two case studies, the first of which looks at complex interactions between macroparasites and innate immune responses in the wood mouse Apodemus sylvaticus. The second study was performed on field voles, Microtus agrestis from Kielder Forest. Here, an age-related difference in immunological strategy in response to macroparasite exposure was demonstrated. Young male animals adopted a resistance strategy, whereas older males were tolerant. Unexpectedly, both resistance and tolerance were associated with high expression of the transcription factor Gata 3. Longitudinal studies indicated that it was the presence of the parasites which triggered the expression of Gata 3, and counterintuitively, animals with high parasite burdens were found to have better measures of fitness. We move then to a paper describing the relationship between body condition and immune function in the locust Chortoicetes terminifera (8). The insect immune system does not have an adaptive component in that there is no memory. However, some components are induced or upregulated on infection. This paper describes a study that evaluates how the body condition of wild locusts impacts on their immune function. There was considerable variation in both body condition and the parameters of immune function between the populations studied, which suggests variation in the ability to respond to infection. Both haemocyte density and lysozyme-like antimicrobial activity were positively correlated with protein levels in the haemolymph, suggesting that these functions may be constrained by protein reserves. The third paper describes the immune responses of birds to emerging infectious diseases (EIDs) (9). EIDs in wild © 2015 John Wiley & Sons Ltd, Parasite Immunology, 37, 217–219
Volume 37, Number 5, May 2015
Editorial
birds have attracted considerable attention due both to their zoonotic potential and spillover into domestic species, and to the dramatic deaths that can be observed in wild bird populations. This article reviews the types of immune responses associated with variation in disease development in these infections. They also use the case of the epizootic outbreak of Mycoplasma gallisepticum in North American house finches (Haemorhous mexicanus) to show how pathogens can drive immune selection. Studies on wild ungulates have provided important advances in our understanding of patterns of immunity and infection. Their large size and long generation time have some disadvantages, in assessing reproductive fitness for example. However, there are also considerable advantages; wild populations are frequently well managed, individuals can be easily identified and tracked, large samples of blood can be obtained, and commercial immunological reagents are available. A study by Jolles et al. (10) provides a comprehensive review of the current portfolio of ecoimmunological studies published in this area and also provides strong arguments as to their importance in attempts to understand patterns of parasite infection and
immunity in wild populations and how these may be affected by climate change. The final article describes work on the wild mice and rats (11). Surprisingly, considering the wealth of knowledge gained from their laboratory comparators, there have been very few immunological studies carried out these species in the wild. This is perhaps because they are generally commensal with humans, and as a pest species it is difficult to perform longitudinal studies. This article explains the origins of the laboratory mice and reviews the published literature. In comparison with laboratory kept animals, it is apparent that wild animals are immunologically more responsive, probably due to the greater exposure to infections that these animals experience. This review makes an excellent case that it is now timely for the laboratory mouse to get back to the field – a good note on which to finish!
ACKNOWLEDGEMENT Professor Jan Bradley is currently a Leverhulme Research fellow and is grateful to Tom Reader for constructive comments on this editorial.
REFERENCES 1 Brock PM, Murdock CC & Martin LB. The history of Ecoimmunology and its integration with disease ecology. Integr Comp Biol 2014; 54: 353–362. 2 Sheldon BC & Verhulst S. Ecological immunology: costly parasite defences and tradeoffs in evolutionary ecology. Trends Ecol Evol 1996; 11: 317–321. 3 Schmid-Hempel P. Variation in immune defence as a question of evolutionary ecology. Proc R. Soc. Lond ser B-Biol Sci 2003; 270: 357–366. 4 Pedersen AB & Babayan SA. Wild Immunology. Mol Ecol 2011; 20: 872–889.
5 Van Boven M & Weissing FJ. The evolutionary economics of immunity. Am Nat 2004; 163: 277–294. 6 Bradley JE & Jackson JA. Measuring immune system variation to help understand host pathogen community dynamics. Parasitology 2008; 135: 807–823. 7 Jackson JA. Immunology in wild non-model rodents: an ecological context for studies of health and disease. Parasite Immunol 2015; 37: 219–231. 8 Graham R, Deacutis J, Simpson S & Wilson K. Body condition constrains immune function in field populations of a female Austra-
© 2015 John Wiley & Sons Ltd, Parasite Immunology, 37, 217–219
lian plague locust Chortoicetes terminifera. Parasite Immunol 2015; 37: 232–240. 9 Staley M & Bonneaud C. Immune responses of wild birds to emerging infectious disease. Parasite Immunol 2015; 37: 241–259. 10 Jolles A, Beechler B & Dolan B. Beyond mice and men: environmental change, immunity and infections in wild ungulates. Parasite Immunol 2015; 37: 260–271. 11 Viney M, Lazarou L & Abolins S. The laboratory mouse and wild immunology. Parasite Immunol 2015; 37: 272–278.
219
Copyright of Parasite Immunology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
DOI: 10.1111/pim.12190
Editorial
Wild Immunology J. E. BRADLEY School of Life Sciences, University of Nottingham, University Park, Nottingham, Nottingham, UK
Keywords Wildlife, Ecoimmunology
INTRODUCTION Good health and successful reproduction in the wild is dependent on an animal’s ability to survive the wide array of infections to which it is continuously subjected. Infectious disease is ubiquitous in natural populations and a major cause of morbidity and mortality. The outcome of infection is highly variable, ranging from susceptibility and death at one end of the spectrum to resistance and pathogen elimination at the other. Whether an animal overcomes infection or not is dependent on the strength and type of immune response generated, and both intrinsic (genetics) and extrinsic factors (environmental influences) affect this. Hence, predicting the outcome of infection in wild populations depends on understanding the immunological consequences of natural genetic and environmental variability. Most of our knowledge of immunological responses to infectious disease, however, has been gained from studies on the laboratory mouse or humans. Studies on laboratory mice are generally designed to minimize both genetic and environmental influences, and most human studies are undertaken on individuals from the developed world who are no longer exposed to the organisms, either infectious or commensal, that would have been present when the immune system evolved. Increasing our understanding of how extrinsic and intrinsic variables impact on immune responses in animals which have been naturally exposed to infections is especially important in the current context. In particular, it is hypothesized that the observed acceleration in the prevalence of immune-mediated diseases such as allergy and autoimmune Correspondence: Prof Janette Bradley, School of Life Sciences, University of Nottingham, University Park Nottingham NG7 2QZ, Nottingham, UK (e-mail: [email protected]). Received: 31 March 2015 Accepted for publication: 31 March 2015 © 2015 John Wiley & Sons Ltd
diseases is due to changes in environmental exposures as a result of urbanization. Progress in evaluating this hypothesis rests on our ability to understand the interaction between genes and environment in natural populations. Studies of laboratory animals and humans have provided us with great detail on the genes and mechanisms involved in controlling infectious disease and the pathogenesis of immune disorders, but applying this information in wild natural infection situations is complex, and until very recently has been inhibited by the ability to effectively measure detailed immune response variables. Brock et al. (1) appraise the history of ecoimmunology in an article to complement a symposium about methods and mechanisms. The term ecoimmunology was first used in the 1990s (2), but the development of the field has been impeded by a lack of suitable reagents for the analysis of immune responses in natural populations. With the advent of technologies that allow the sequencing of full genomes both cheaply and quickly, it is now possible to measure the RNA expression of immunological parameters and the field is rapidly expanding. Inferences from measurements of RNA can be problematic, because RNA concentrations do not necessarily relate linearly to the quantities downstream of the associated protein effector molecules. With careful consideration, however, quantification of RNA does provide major insights into the immunological status of an individual, and generates many testable hypotheses, as has already been demonstrated by microarray and transcriptomic approaches.
ECOLOGY AND IMMUNOLOGY, TWO DIFFERENT CULTURES? Ecologists and immunologists tend to have quite different approaches to addressing questions in their field. Immunologists aim to define in great detail the immunological mechanisms determining the outcome of infection, and to evaluate the importance of particular genes or molecules in these mechanisms. In order to achieve this, studies are designed to minimize intrinsic and extrinsic variation, and
217
J. Bradley
immunologists rarely have to use complex analytical tools to determine an effect. Ecoimmunologists embrace variation and thus far have aimed to understand the causes of immune function variability, its consequences in the outcome of infection, and how this impacts on survival and reproductive success (3, 4). The economics of resource allocation is also a primary interest: what are the costs and benefits of diverting resources to mounting an immune response on host survival and reproduction (5). In order to address these questions, complex statistical tools are required to disentangle the effects of variation in genetic and environmental influences. Increased interaction between immunologists and ecologists is important in advancing this emerging field. Communication between the two disciplines is, however, not always easy, due to the very different approaches, and to the existence of subject-specific terminology. There is little doubt that the terminology used in immunology can be difficult, particularly as the nomenclature is ever changing as the functions of molecules become clear. Ecologists may use a more accessible language, but some words often have very specific ecological meanings. For example, to the nonecologist, fitness may be interpreted as a general measure of physical health or vitality, whereas to the ecologist it has a much more specific meaning: that is, Darwinian fitness, or the relative ability of an individual to contribute to the next generation’s gene pool via survival and reproduction. These two interpretations of the term fitness do of course overlap, because being physically fit and healthy is positively related to survival and reproduction, but variation in the precision with which the term is used has considerable potential to muddy the waters in discussions of wild immunology. Another word commonly used in both disciplines, tolerance, has similar potential to generate confusion. Here, ecologists have a looser interpretation of the word: an organism which is neither susceptible nor resistant to a pathogen may be said to tolerate it if it displays minimal pathology. In immunology, however, tolerance has a much more specific meaning. Immunological tolerance means a failure to mount an immune response to an antigen. Thus, it is possible for an animal to be tolerant to a pathogen in ecological terms yet be intolerant immunologically. Thus far, much of the published work in this emerging field has been primarily driven by ecologists, who have historically been restricted by the lack of reagents to using fairly primitive tests (from an immunologist’s perspective). As the ability to measure more immunological parameters increases, and it becomes possible to define the immunological phenotype of an animal (6), communication between the two disciplines is particularly important. A
218
Parasite Immunology
central issue which remains is what are the most relevant parameters to measure.
THIS SPECIAL EDITION This creation of this ecologically flavoured special edition is motivated by the shortage of ecoimmunological work that has been driven by purely immunological questions. I do hope it may pique the interest of the readers of Parasite Immunology, encourage them to explore this field further and realize the importance of addressing questions about how the immune system functions under the conditions in which it evolved. The organisms represented in this special edition range from invertebrates to wild ungulates. We start with an article on wild nonmodel rodents by Jackson (7), primarily because the first half of the article provides an excellent introduction to this edition. It answers the questions: Why study the immune responses of wild animals? What should we study? and How should we measure it? It then goes on to describe two case studies, the first of which looks at complex interactions between macroparasites and innate immune responses in the wood mouse Apodemus sylvaticus. The second study was performed on field voles, Microtus agrestis from Kielder Forest. Here, an age-related difference in immunological strategy in response to macroparasite exposure was demonstrated. Young male animals adopted a resistance strategy, whereas older males were tolerant. Unexpectedly, both resistance and tolerance were associated with high expression of the transcription factor Gata 3. Longitudinal studies indicated that it was the presence of the parasites which triggered the expression of Gata 3, and counterintuitively, animals with high parasite burdens were found to have better measures of fitness. We move then to a paper describing the relationship between body condition and immune function in the locust Chortoicetes terminifera (8). The insect immune system does not have an adaptive component in that there is no memory. However, some components are induced or upregulated on infection. This paper describes a study that evaluates how the body condition of wild locusts impacts on their immune function. There was considerable variation in both body condition and the parameters of immune function between the populations studied, which suggests variation in the ability to respond to infection. Both haemocyte density and lysozyme-like antimicrobial activity were positively correlated with protein levels in the haemolymph, suggesting that these functions may be constrained by protein reserves. The third paper describes the immune responses of birds to emerging infectious diseases (EIDs) (9). EIDs in wild © 2015 John Wiley & Sons Ltd, Parasite Immunology, 37, 217–219
Volume 37, Number 5, May 2015
Editorial
birds have attracted considerable attention due both to their zoonotic potential and spillover into domestic species, and to the dramatic deaths that can be observed in wild bird populations. This article reviews the types of immune responses associated with variation in disease development in these infections. They also use the case of the epizootic outbreak of Mycoplasma gallisepticum in North American house finches (Haemorhous mexicanus) to show how pathogens can drive immune selection. Studies on wild ungulates have provided important advances in our understanding of patterns of immunity and infection. Their large size and long generation time have some disadvantages, in assessing reproductive fitness for example. However, there are also considerable advantages; wild populations are frequently well managed, individuals can be easily identified and tracked, large samples of blood can be obtained, and commercial immunological reagents are available. A study by Jolles et al. (10) provides a comprehensive review of the current portfolio of ecoimmunological studies published in this area and also provides strong arguments as to their importance in attempts to understand patterns of parasite infection and
immunity in wild populations and how these may be affected by climate change. The final article describes work on the wild mice and rats (11). Surprisingly, considering the wealth of knowledge gained from their laboratory comparators, there have been very few immunological studies carried out these species in the wild. This is perhaps because they are generally commensal with humans, and as a pest species it is difficult to perform longitudinal studies. This article explains the origins of the laboratory mice and reviews the published literature. In comparison with laboratory kept animals, it is apparent that wild animals are immunologically more responsive, probably due to the greater exposure to infections that these animals experience. This review makes an excellent case that it is now timely for the laboratory mouse to get back to the field – a good note on which to finish!
ACKNOWLEDGEMENT Professor Jan Bradley is currently a Leverhulme Research fellow and is grateful to Tom Reader for constructive comments on this editorial.
REFERENCES 1 Brock PM, Murdock CC & Martin LB. The history of Ecoimmunology and its integration with disease ecology. Integr Comp Biol 2014; 54: 353–362. 2 Sheldon BC & Verhulst S. Ecological immunology: costly parasite defences and tradeoffs in evolutionary ecology. Trends Ecol Evol 1996; 11: 317–321. 3 Schmid-Hempel P. Variation in immune defence as a question of evolutionary ecology. Proc R. Soc. Lond ser B-Biol Sci 2003; 270: 357–366. 4 Pedersen AB & Babayan SA. Wild Immunology. Mol Ecol 2011; 20: 872–889.
5 Van Boven M & Weissing FJ. The evolutionary economics of immunity. Am Nat 2004; 163: 277–294. 6 Bradley JE & Jackson JA. Measuring immune system variation to help understand host pathogen community dynamics. Parasitology 2008; 135: 807–823. 7 Jackson JA. Immunology in wild non-model rodents: an ecological context for studies of health and disease. Parasite Immunol 2015; 37: 219–231. 8 Graham R, Deacutis J, Simpson S & Wilson K. Body condition constrains immune function in field populations of a female Austra-
© 2015 John Wiley & Sons Ltd, Parasite Immunology, 37, 217–219
lian plague locust Chortoicetes terminifera. Parasite Immunol 2015; 37: 232–240. 9 Staley M & Bonneaud C. Immune responses of wild birds to emerging infectious disease. Parasite Immunol 2015; 37: 241–259. 10 Jolles A, Beechler B & Dolan B. Beyond mice and men: environmental change, immunity and infections in wild ungulates. Parasite Immunol 2015; 37: 260–271. 11 Viney M, Lazarou L & Abolins S. The laboratory mouse and wild immunology. Parasite Immunol 2015; 37: 272–278.
219
Copyright of Parasite Immunology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
