In order for an individual to control or avoid infection and ultimately contribute offspring to the next generation, they must have a well-functioning immune system (Møller and Saino, 2004). An individual’s immune function is in part determined by their genotype (e.g., Paterson et al., 1998; Wanelik et al., 2018; Turner et al., 2011). Individuals within a population differ from each other in the genotypes they carry, with the potential for these different genotypes to affect the activity of different immune components, and thereby influence susceptibility to infection and reproduction and survivorship. Indeed, variability in immune responses to infection is well-characterized. The phenotypic expression of a genotype is dependent on the environment, including the sex of an individual (intrinsic environment) and exposure to infection (extrinsic environment). Since capturing genotypic and environmental variability in controlled laboratory studies is problematic, natural wildlife populations have been proposed as models in which to understand the phenotypic expression of genetic variation and its consequences for susceptibility to infection and reproduction.

Studies of natural populations have explored the effects of genotype on immune phenotype and have observed consequences for susceptibility to infection. Most notably, variability in the genes of the major histocompatibility complex (MHC) has been associated with resistance to intestinal nematodes in domestic sheep (Paterson et al., 1998) and with resistance to malaria, hepatitis, and AIDS in humans (Hill et al., 1991; Carrington et al., 1999; Thursz et al., 1997). The role of variability elsewhere in the genome, for shaping immune phenotype, has also been studied (Wanelik et al., 2018; Turner et al., 2011). However, it remains challenging to follow the consequences of a genotypic effect for immunity, infection, and reproduction and to account for any sex-dependent expression of a genotype. This is because of the difficulty in obtaining phenotypic data across immune, infection, and reproductive traits, especially for large enough sample sizes to test for data-hungry genotype by sex interactions (Ober et al., 2008). In many cases, sex and other environmental factors are considered as a confounding variable to be controlled for in order not to hide any subtle genetic associations (Paterson et al., 1998). Other studies focus on a single sex for the sake of simplicity (Jackson et al., 2014). More recently, however, there has been a growing body of large-scale field studies of natural populations able to apply genetic and immunological methods to follow large numbers of individuals, exposed to a challenging environment and with varying genetic backgrounds, throughout their lives. This allows us to make a more complete assessment of the impacts of genotype throughout the life of an individual, whether male or female. For example, Graham et al., 2010 found evidence for heritable variation in immunity associated with sex-dependent effects on Soay sheep reproduction. However, we know of no documented example of a polymorphism affecting immunity, susceptibility to infection, and reproduction in a natural population investigated in males and females. Here, we use a wild rodent, the field vole (Microtus agrestis), as a model in which to do this. Wild rodents, in particular, offer an opportunity to quickly follow large numbers of individuals throughout their lives, given their short lifespans. They also offer the opportunity to draw on the immunological and genetics resources developed for laboratory rodents, while providing a much more realistic ecological model of human populations (Turner et al., 2014; Turner and Paterson, 2013).

Immunoglobulin E (IgE)-mediated responses are associated with defense against helminths (Gounni et al., 1994) and with allergy (Tomassini et al., 1991). They are controlled by the high-affinity IgE receptor, FCER1, which is found on the surface of various immune effector cells, for example, mast cells, basophils, and eosinophils (Daeron and Nimmerjahn, 2014). In humans, naturally occurring polymorphisms in FCER1 are known to affect an individual’s serum IgE levels, with consequences for their susceptibility to infection (Weidinger et al., 2008; Granada et al., 2012) and their risk of developing inflammatory disease (Hasegawa et al., 2003; Potaczek et al., 2006; Zhou et al., 2012; Niwa et al., 2010). Furthermore, sex differences in serum IgE levels (Weiss et al., 2006) and the incidence of IgE-mediated inflammatory disease (Chen et al., 2008) have been documented in humans, suggesting that any polymorphism in this pathway is likely to experience different contexts in males and females. Indeed, one study found evidence for a polymorphism in the Fcer1a gene (the alpha chain of FCER1) whose association with susceptibility to systemic lupus erythematosus (a chronic inflammatory disease) differed between males and females (Yang et al., 2013).

In a previous study of a natural population of M. agrestis, we found that males carrying the GC haplotype of the Fcer1a gene expressed the transcription factor GATA3 at a lower level than males carrying non-GC haplotypes (Wanelik et al., 2018). GATA3 is a biomarker of tolerance to macroparasites in mature males in our population (macroparasite infection gives rise to increased expression of GATA3, which gives rise to improved body condition and survival; Jackson et al., 2014). Here, we explore the effects of this GC haplotype further in both males and females to analyze the effect of genotype acting across immune gene expression, infection susceptibility and reproductive success.

We sampled a natural population of M. agrestis in Kielder Forest, Northumberland, UK, over 3 years (2015–2017) and across seven different sites. Our study involved a cross-sectional component (n = 317 destructively sampled voles) and a longitudinal component (n = 850 marked individuals monitored through time, with n = 2387 sampling points). We tested the consequences of the GC haplotype of the Fcer1a gene using both cross-sectional and longitudinal components of our study. As well as the GC haplotype (present at a frequency of 0.08), three other haplotypes were present in our study population: AC haplotype, AT haplotype, and GT haplotype, present at frequencies of 0.81, 0.10, and 0.01, respectively. The two single-nucleotide polymorphisms (SNPs) composing the haplotype were found to be tightly linked (r² = 0.50; D’ = 0.70).

The GC haplotype has effects on inflammation that differ between sexes

In humans, naturally occurring polymorphisms in the Fcer1a gene have previously been linked to inflammatory disease (Hasegawa et al., 2003; Potaczek et al., 2006; Zhou et al., 2012; Niwa et al., 2010). Therefore, we used the cross-sectional component of our study to test the effects of the GC haplotype on inflammation in males and females. Differential gene expression (DGE) analysis was performed on unstimulated splenocytes taken from 53 males and 31 females assayed by RNASeq, with the aim of identifying individual genes that were differentially expressed between those individuals with and without a copy of the GC haplotype. This DGE analysis showed that the identity of top differentially expressed genes differed between the sexes. In males, the top differentially expressed immune gene was the cytokine, Il33 (log fold change [logFC] = 2.76, p<0.001, q < 0.001; Appendix 1—table 2) while in females it was the suppressor of cytokine signaling Socs3 (logFC = 1.07, p<0.001, q = 0.05; Appendix 1—table 3). Looking at the ranking of each top differentially expressed immune gene in the opposite sex strengthens the case for differing effects in males and females, with Il33 ranked markedly lower in females (rank = 8224/12904, logFC = 0.29, p=0.70, q = 1.00) and Socs3 markedly lower in males (rank = 10886/12904, logFC = –0.05, p=0.84, q = 1.00). Il33 is commonly associated with the anti-helminthic response (Liew et al., 2010) and Socs3 with regulation of the immune response more broadly (Carow and Rottenberg, 2014). Given the link between Il33 and the antihelminthic response (and more generally, IgE-mediated responses and the antihelminthic response), we repeated the DGE analysis while controlling for cestode burden, but this had little effect on our results (same top differentially expressed immune genes; see Appendix 1—table 4 and Appendix 1—table 5), suggesting that these effects were not driven by differences in cestode infection.

Both Il33 and Socs3 also share an association with the inflammatory response (Carow and Rottenberg, 2014; Cayrol and Girard, 2014). While Il33 positively regulates this response (appearing in the gene set GO:0050729), Socs3 negatively regulates it (GO:0050728). To test whether these effects on the inflammatory response were limited to these genes or were more widespread, we performed a gene set enrichment analysis (GSEA) that looked at the rankings of all genes present in each of these gene sets (GO:0050729 and GO:0050728). This analysis showed that both gene sets were more highly relatively expressed in individuals with the GC haplotype than individuals without the haplotype, and that this was true for both males and females. However, males with the GC haplotype showed a stronger signal for genes that positively regulate the inflammatory response (GO:0050729: p=0.007; GO:0050728: p=0.04; Figure 1A, upper panel) while females with the GC haplotype showed a stronger signal for genes that negatively regulate the inflammatory response (GO:0050728: p=0.001; GO:0050728: p=0.04; Figure 1A, lower panel).

Figure 1

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To further explore these effects on the inflammatory response, we used an independent dataset for males and females whose spleens were stimulated with two immune agonists and assayed by Q-PCR (for a panel of 18 immune genes with limited redundancy; see 'Materials and methods' for how these genes were selected). From this ex vivo assay, one can gain insight into the types of immune response that could be made to a pathogen in vivo (see 'Materials and methods' for details). Although our panel of genes did not include Il33 or Socs3, it did include other genes associated with the inflammatory response, including Il17a, Ifng, Il1b, Il6, and Tnfa. We found that the effect of the GC haplotype on the stimulated expression levels of Il17a, a pro-inflammatory cytokine involved in the antibacterial response, displayed a significant interaction with sex (genotype by sex interaction in follow-up linear mixed effects model [LMM], likelihood ratio test [LRT] p=0.001). While females with the GC haplotype expressed lower levels of Il17a (estimate = –0.12, 95% CI = −0.19 to −0.04), males with the GC haplotype did not differ in their expressed levels of Il17a (estimate = 0.03, 95% CI includes zero = –0.02 to 0.08; Appendix 1—table 6 and Appendix 1—table 7).

In this study, we describe a polymorphism in the high-affinity receptor for IgE with effects that act across immune gene expression, oxidative stress, susceptibility to infection, and ultimately reproductive success in a natural population. This begins to reveal how genotypic effects can have multiple effects on different phenotypic or life history traits for organisms living in the natural environment. Interestingly, effects often differed between sexes, with evidence for opposing effects in the sexes (unstimulated immune gene expression) and an effect present in one sex but not the other (stimulated immune gene expression, susceptibility to infection, and reproductive success). However, we cannot rule out that, in the case of susceptibility to infection and reproductive success, there was a smaller effect present in the opposite sex (in the same or opposite direction), which our analysis did not have sufficient power to detect.

In humans, naturally occurring polymorphisms in the high-affinity IgE receptor have previously been linked to inflammatory disease (Hasegawa et al., 2003; Potaczek et al., 2006; Zhou et al., 2012; Niwa et al., 2010). Our work is consistent with this and suggests differing effects of this polymorphism on the inflammatory phenotype of males and females. While males with the GC haplotype showed a pro-inflammatory bias, females with the haplotype showed an anti-inflammatory bias. A previous study on another polymorphism in the human ortholog of Fcer1a also found evidence for sex-dependent effects on inflammatory disease (Yang et al., 2013). In order to fully understand this genotype by sex interaction, it is important to consider background differences in the inflammatory phenotypes of males and females. Females in this study were pregnant for a large proportion of their lives (57% of post-juvenile females were pregnant or lactating at the time of capture in the longitudinal component of our study). In mammals, including humans, pregnancy has been shown to be a largely anti-inflammatory state, with pregnant females suppressing inflammation. This is to protect the fetus from attack by the mother’s immune system (Wegmann et al., 1993). While testosterone in males has an anti-inflammatory effect (Bianchi, 2019), it also drives males to use more space (Davis et al., 2015) and to be more aggressive (Martínez-Sanchis et al., 2003). These behaviors might increase their rates of contact with other individuals, and with their environment, and hence their likelihood of infection and subsequent immune stimulation. We suggest that the polymorphism may be exaggerating background sex differences in inflammatory activity. Sex hormones have been implicated in the differential expression of some autosomal genes in males and females (Mayne et al., 2016), and could be driving these opposing effects. Some of the differences in immune phenotype that we observed may also be driven by difference in parasite infection (although we accounted for cestode burden in a follow-up analysis, we cannot rule this out).

The effect of Fcer1a polymorphism on inflammatory responses may also, in turn, affect individual susceptibility to infection. This is consistent with a previous association found between IgE-mediated responses and defense against helminths (Gounni et al., 1994). Although we did not find an association between macroparasite burden (including cestode burden) and the GC haplotype in this study, in our previous study, we showed that males with the GC haplotype had a lower level of an immunological marker of tolerance to ticks, fleas, and adult cestodes (i.e., they were less tolerant) (Wanelik et al., 2018). Here, we use data on infection incidence to show that, in a different context, the same haplotype is also associated with resistance to a microparasite, B. microti, in females. Although observational studies of this kind are not able to identify causal relationships, a realistic scenario is that females with the GC haplotype are more likely to be infected with B. microti (i.e., they are less resistant) as a result of a lower pro-inflammatory to anti-inflammatory cytokine ratio. Pro-inflammatory cytokines (e.g., IL-6, IFN-γ, and TNF-α) may help to resist B. microti infection (Djokic et al., 2018). A lack or imbalance of these cytokines may hamper this resistance. The panel of parasites that we have measured is not exhaustive, and previous studies have highlighted the important role of species interactions in the parasite community in driving infection risk in this study population (Telfer et al., 2010). B. microti may therefore represent a community of parasites, to which this haplotype affects resistance in females.

A fitness consequence of the GC haplotype was observed in reduced male reproductive success. A realistic scenario is that the larger cost incurred by males with the GC haplotype due to inflammation reduced their reproductive value, as reproducing and mounting a pro-inflammatory response are both costly activities (Sheldon and Verhulst, 1996). Another realistic scenario is that the positive effect of the GC haplotype on levels of oxidative stress (as indicated by a tendency for higher SOD1 activity) may have had a more detrimental effect in males, damaging sperm and reducing fertilizing success. Sperm competition can be an important feature in the reproduction of microtines, for example, meadow vole (M. pennsylvanicus) (Delbarco-Trillo and Ferkin, 2004), with males having to produce many sperm of high quality in order to successfully outcompete other males. Sperm are also highly susceptible to damage by reactive oxygen species (ROS) (Losdat et al., 2011). In addition, the heightened level of oxidative stress may have impaired olfactory sexual signals, for example, excretion of major urinary proteins (MUPs) making males less attractive to females and negatively impacting on mating success (Garratt et al., 2014).

Despite the immune system playing an important role in determining the health and reproductive fitness of an individual, natural selection has not converged on a single immune optimum. Instead, individuals in natural populations vary widely in their response to infection. Understanding why immunoheterogeneity is maintained is a key question in eco-immunology. Antagonistic selection, where a mutation is beneficial in some environmental contexts and harmful in others, is thought to be one mechanism by which balancing selection is generated, and genetic variation in immunity can be maintained within natural populations (Graham et al., 2010). In samples collected between 2008 and 2010, we previously identified four haplotypes at this locus, GC, AC, AT, and GT, at frequencies of 0.12, 0.76, 0.07, and 0.05, respectively (Wanelik et al., 2018). Seven years on, these frequencies have remained relatively unchanged (0.08, 0.81, 0.10, and 0.01). The fact that the GC haplotype remains in the population, despite its detrimental effects on male reproductive success and female infection susceptibility, suggests that it may be under balancing selection.

In order to be under balancing selection though, the GC haplotype would need to confer some advantage. We were not able to find evidence for any such advantage in this study, but we can speculate on one. Microtines show cyclical population dynamics, alternating between a 'peak' phase (associated with good conditions and high vole densities) and a 'crash' phase (poor conditions and low vole densities). Selection pressures acting during these two phases will be very different. We found that the GC haplotype was associated with a pro-inflammatory bias in males, indicating higher investment in promoting inflammation. Thus, one possible scenario is that higher investment in promoting inflammation is disadvantageous in the 'peak' phase when the risk of parasitism is low due to dilution effects, and it pays not to waste energy mounting a stronger immune response that is unnecessary. However, it might be advantageous in the 'crash' phase when conditions are poor, and the risk of parasitism is high due to the time-lagged transmission of parasite infectious stages that have accumulated during the peak phase. Vole numbers were extremely low in our study area between 2012 and 2013 (indicating a 'crash phase'). In 2014, vole numbers began to increase and by the beginning of 2015 (the start of our study) had reached a peak. Although vole numbers declined throughout our study period, they never reached the extremely low numbers recorded in 2012–2013 (X. Lambin, personal communication, 2016). This suggests that we sampled in the region of a 'peak' phase, when this investment was disadvantageous, and that if we sampled during a true 'crash' phase we might detect an advantage to the GC haplotype in males.

There is a growing interest in human genomic (or precision) medicine, with the potential to use a patient’s genotypic information to personalize their treatment. What we have shown here demonstrates that considering genotype in isolation can be misleading as the same polymorphism can have different outcomes not only for the immune gene expression, but the susceptibility to infection and ultimate reproductive success of males and females.

We studied M. agrestis in Kielder Forest, Northumberland, UK, using live-trapping of individual animals from natural populations. Trapping was performed from 2015 to 2017 across seven different sites, each a forest clear-cut. Access to the sites was provided by the Forestry Commission. At each site, 150–197 Ugglan small mammal traps (Grahnab, Gnosjo, Sweden) were laid out in a grid, spaced approximately 3–5 m apart. Our study was divided into longitudinal and cross-sectional components.

RNASeq data have been deposited in the European Nucleotide Archive (study accession number PRJEB51626). Longitudinal phenotypic data are available from the NERC EDS Environmental Information Data Centre (https://doi.org/10.5285/e5854431-6fa4-4ff0-aa02-3de68763c952). Cross-sectional phenotypic data are available from the University of Liverpool's Research Data Catalogue (https://doi.org/10.17638/datacat.liverpool.ac.uk/1850). Genotype data are also available from the University of Liverpool's Research Data Catalogue (https://doi.org/10.17638/datacat.liverpool.ac.uk/1849).

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Author details

1. Klara M Wanelik

   Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom

   Contribution

   Formal analysis, Writing – original draft, Writing – review and editing

   For correspondence

   klara.wanelik@biology.ox.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1485-0340

2. Mike Begon

   Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom

   Contribution

   Conceptualization, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1715-5327

3. Janette E Bradley

   School of Life Sciences, University of Nottingham, Nottingham, United Kingdom

   Contribution

   Conceptualization, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3973-7977

4. Ida M Friberg

   School of Environment and Life Sciences, University of Salford, Salford, United Kingdom

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Joseph A Jackson

   School of Environment and Life Sciences, University of Salford, Salford, United Kingdom

   Contribution

   Conceptualization, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0330-5478

6. Christopher H Taylor

   School of Life Sciences, University of Nottingham, Nottingham, United Kingdom

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4299-7104

7. Steve Paterson

   Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom

   Contribution

   Conceptualization, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1307-2981

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