An introduction to ecological immunology

Authors


Correspondence author. E-mail: lmartin@cas.usf.edu

There has been a recent call for an Extended Synthesis in evolutionary biology (Pigliucci 2007). The Modern Synthesis, which united Mendelian and Darwinian ideas about genes and natural selection, has been the cornerstone of evolutionary biology for the last 60 years (Pigliucci 2007). However, many important elements were left out of that synthesis, particularly the mechanisms whereby genetic variation is transduced into phenotypic variation. Such ‘black boxes’ still pervade biology, and for biological fields such as immunology, these black boxes are the explicit subject of interest. Many of these black boxes are so dizzyingly complex, though, that generalizations about their components, much less their architecture, are rare. This lack of generality has made it difficult to link genetic changes to immunological phenotypic variation in an eco-evolutionary context. Indeed, a few exceptions aside (Matzinger 1998), each host–parasite interaction is often considered as a case study.

Enter ecological immunology or, more commonly, ecoimmunology. The focus of ecoimmunology has been to describe and explain natural variation in immune functions (Sheldon & Verhulst 1996), specifically why and how biotic and abiotic factors contribute to variation in immunity in free-living organisms. This approach is in striking contrast to most immunological research, which has typically controlled variation experimentally, sometimes at great lengths (via modifications of gene expression or the use of ultra-clean housing facilities), to ascertain the molecular and cellular details of parasite coping mechanisms. Comparative immunology has taken yet a different tack by investigating major changes in immune system organization among taxa (e.g. alternative B and T cell receptor diversity generating mechanisms) (Litman et al. 2007). These data, as well as those generated by classic immunology, have yielded great insight into how hosts control parasites (and vice versa). However, neither comparative nor mainstream immunology can explain the persistence of parasitism as the most common mode of life on Earth (Price et al. 1986) nor why some hosts remain susceptible to infection (Levin & Antia 2001). All extant and extinct organisms, no matter how elegant their immune systems, are affected by parasites (Hedrick 2004).

It is in this area, understanding variation in susceptibility, that ecoimmunology has made the greatest contributions. Ecoimmunology proposes that susceptibility persists because immune defence is but one element of a context-dependent, integrated, whole-organism response to parasitism (Ardia, Parmentier & Vogel 2011; Baucom & de Roode 2011; Demas, Adamo & French 2011; Graham et al. 2011). Immune defences exist to prevent the spread of cancerous cells or impede infections, but food quantity and quality, weather, threat of predation of conflict with conspecifics, and a host of other factors can matter too (Schulenburg et al. 2009). If ecological demands are great, or if fitness can be maximized via growth or reproduction instead survival of infection, immune defences may be lowered, altered, or outright compromised.

This contribution of ecology to our understanding of immunology has come in just the last 20 years (Fig. 1). Before this period, papers including the terms ecol* and immunol* together were rare in ISI Web of Science (search 10/20/2010). Since about 1990, though, the field has grown rapidly (658 papers since 1991; Fig. 1), almost twice as fast as another ‘hot’ field, oxidative stress ecology (McGraw et al. 2010). The first paper in which the above search terms were used in a manner consistent with modern ecoimmunology concerned schistosomiasis in humans. This paper (Warren 1973), which reviewed whether age-intensity curves for schistosome infections represented evidence of memory of infections or something else, was a centrepiece of classic epidemiological theory (Anderson & May 1985; May & Anderson 1979). Not until the mid-1990s, however, did ecoimmunology mature into a recognized discipline. In 1996, one of the foundational papers for the field was published (Sheldon & Verhulst 1996), which has up until now been cited over 700 times. Sheldon & Verhulst (1996) invoked trade-offs, the allocation of limited resources among competing, costly physiological functions, as a prime cause of variation in immune defences. Trade-offs remain a prime focus in ecoimmunology, although the idea has been developed and extended quite a bit (Graham, Allen & Read 2005; Adelman & Martin 2009). Another pair of papers was also critical to the establishment of the field: one proposing a handicap hypothesis for sexually selected traits (Hamilton & Zuk 1982) and the other a physiological extension, the immunocompetence handicap hypothesis (Folstad & Karter 1992). These two papers have been cited over 1000 times each and continue to be the focus of much ecoimmunological research.

Figure 1.

 Citation history in ecoimmunology. Total citations from 1900 to 2010 (inset) and citations annually since 1990 using the search terms ecol* and immunol* in the ISI Web of Science database. Numbers above bars in inset figure denote the number of citations for the most highly cited paper published in that interval.

Today, though, the breadth of ecoimmunological research has expanded. Trade-offs continue to take a central position, but their roles in species and individual variation (Ardia, Schat & Winkler 2003; Lee 2006; Martin, Weil & Nelson 2007) as well as sex, social and mating system differences in immune functions, are now being explored (Westneat & Birkhead 1998; Rolff 2002; Fedorka & Zuk 2005; Hawley et al. 2007; Nunn et al. 2009). As is common in a maturing field, a large amount of effort is dedicated to the development of methodology, and progress is being made in this area (Martin et al. 2006; Bradley & Jackson 2008). Still, immune functions remain challenging to characterize meaningfully in natural populations because (i) one rarely knows individual parasite exposure history; (ii) repeat capture of wild animals for time-series sampling is difficult; (iii) and the redundancy and complexity of immune systems calls into question extrapolating from simple assays (Keil, Luebke & Pruett 2001; Adamo 2004).

Nevertheless, ecoimmunology has diversified extensively since the inception of the field. This diversification is well-reflected in a special issue of Philosophical Transactions of the Royal Society of London B in 2009 (Schulenburg et al. 2009). Papers in that issue covered many topics including: (i) the various ways hosts can deal with parasites (avoidance, resistance, clearance, tolerance and acquired immunity; (Boots et al. 2009); (ii) why diversity of major histocompatibility genes (MHC; a cell-surface receptor that displays parasite fragments to immune cells) at the individual level is typically less than diversity at the population level (Woelfing et al. 2009); (iii) the ecological ramifications of inter-generational transfer of immunity (Hasselquist & Nilsson 2009); (iv) and the role of parasite evasiveness for the evolution of virulence (Schmid-Hempel 2009) among others.

Our goal for the present special issue was to provide novel perspectives to the burgeoning field of ecoimmunology and identify generalities about immune systems among vertebrates, invertebrates and even plants. The first paper of the issue, by Graham et al. (2011), proposes that three factors (host fitness, parasite density and relevant immune responses) are all important to understanding the ecology and evolution of any host–parasite relationship, regardless of the species in question. As the authors indicate, ‘neither the strongest immune response nor the lowest parasite densities necessarily maximize host fitness.’Baucom & De Roode (2011) emphasizes such non-intuitive outcomes of host–parasite interactions, comparing and contrasting parasite tolerance (Schneider & Ayres 2008; Raberg, Graham & Read 2009) among plants and animals. Tolerance, whereby hosts minimize consequences of damage caused by parasites instead of minimizing the burden of parasites, has been a centrepiece of work in plant–herbivore ecology, but studies in animals remain in their infancy. So far whether animals and plants share similar defence strategies is unknown, but a framework now exists for discovering such patterns. Demas, Adamo & French (2011) highlight how the immune system of both invertebrates and vertebrates is but one element of a tripartite parasite defence mechanism including the nervous and endocrine systems (Ader & Cohen 1975). A whole organism focus has been lacking from most mainstream immunology, but is the prime focus of another emerging field, psychoneuroimmunology.

The fourth and fifth papers attempt to provide applied value to ecoimmunology by illustrating insights provided by ecoimmunology to other research areas, namely Darwinian medicine (Nesse & Stearns 2008) and disease ecology (Raffel, Martin & Rohr 2008). Trotter et al. (2011) use a case study approach to integrate ecoimmunology and Darwinian medicine, reviewing how human diseases associated with allelic variation at the apolipoprotein E locus might be a consequence of mismatched plastic phenotypic responses to modern environments. Hawley & Altizer (2011) suggest that unification of ecoimmunology and disease ecology will inform how within host processes translate to between host dynamics in terms of parasite transmission and persistence. Together, these two papers highlight the broader utility of an ecoimmunological approach for fields of direct public health relevance.

The final three papers in the issue focus on two historic themes – trade-offs and methodology – but each in a unique way. Ardia, Parmentier & Vogel (2011) discuss how genetic, epigenetic and physiological factors can impinge on the ability of organisms to cope immunologically with parasites. They conclude that constraints should always be considered as an alternative explanation for individual variation and reduced immune activity. Van der Most et al. (2011) perform a meta-analysis of selection studies in domesticated birds, finding that selection for growth generally leads to the reductions in immune functions. Finally, Boughton, Joop & Armitage (2011) attempt a challenging yet important task: producing conceptual framework for collecting ecoimmunological data. They emphasize how explicit consideration of parasite and host characteristics when choosing immune techniques will provide maximal insight to study systems.

The papers in this special issue highlight the importance of investigating immune defence from an integrative perspective. This perspective promises to make novel contributions because it spans fields and hence is apt to identify patterns that are not obvious from a within-discipline approach. It is through such integrative study that paradigms most often emerge or shift. One such contribution entails a refinement of concepts in disease biology generally. A full discussion of this contribution is beyond the scope of this short editorial but consider just two examples. First, one often reads about disease transmission. However, rarely can diseases themselves be transmitted; most often, it is parasites that are transmitted, which then can cause disease. Some individuals or species become diseased when infected, in the sense that they change behaviourally or physiologically, but others do not. This distinction is important because organisms that do not experience disease (i.e. tolerators) may be more competent for parasite replication or persistence and hence serve as a super-spreaders (or super-sponges) of parasites (Raffel, Martin & Rohr 2008). A second conceptual refinement involves virulence. Often virulence is studied as a parasite-specific trait (Schmid-Hempel 2009), and research into virulence factor discovery is still well-funded. However, virulence is more realistically understood as an outcome of a particular host–parasite interaction (Raffel, Martin & Rohr 2008), not a trait inherent to a parasite. The same parasite can be benign to one host and virulent to another, or can range from virulent or benign in the same host depending on context. The outcome of an infection is impacted as much by environment and host condition and past experience as by parasite traits themselves.

In the future, ecoimmunology will also contribute to other emerging areas. One is holobiont theory, the idea that hosts are diverse communities of microbial and metazoan genomes all with a shared goal of reproduction (Ley, Peterson & Gordon 2006). We are just beginning to appreciate how profoundly important to the organization of immune systems are the micro-organisms that live on and in hosts (Wen et al. 2008). Studies of wild taxa will give perspective to when and why to expect these relationships to impact host health and disease cycles. A related area entails priority effects of parasites in subsequent infections (De Roode et al. 2005). If one type of parasite infects successfully, the immune system can become polarized to inhibit or promote infections with other parasites. By understanding the molecular components of parasite–parasite–host interactions, we might break or manage parasite cycles in natural systems and protect host populations from certain maladies (Pedersen & Fenton 2007).

A final major future contribution concerns immunology in the wild. There is a growing interest by classic immunologists to learn about the immune systems of non-domesticated animals living in natural environments (Beldomenico et al. 2008; Jackson et al. 2009). The reliance on modern, model organisms (i.e. domesticated animals with short generation times and amenable to genetic manipulation and simple husbandry) has been useful, but a return to more traditional model organisms (i.e. a species that exhibits some natural character amenable to novel biological insight) is also necessary. It will likely be in such ‘dirty’ systems that the causes and consequences of co-infections, infection history, variation in microbiome constituency, and abiotic and biotic factor changes will be revealed.

In closing, we believe that ecoimmunology has a bright future. Multiple institutes for ecoimmunological research now exist (such as the Center for Immunity, Infection and Evolution at the University of Edinburgh, and the Max Planck Institute for Immunoecology and Migration), and the US National Science Foundation has just funded a Research Coordination Network (http://www.ecoimmunology.org) to bring methodological and conceptual unity to the field. We strongly encourage students and interested professionals to incorporate immunological elements into their work, and we hope that mainstream and comparative immunologists will join ecologists to make immunology into a truly multi-disciplinary field.

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