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Sexual Reproduction and Advanced article Article Contents Immunity • Introduction ⋆ • Reproductive Immunity Seth M Barribeau , Institute of Integrative Biology, University of Liverpool, • Three Selection Pressures Linking Reproduction Liverpool, UK and Immunity ⋆ • A Potential Regulation of the Link between Oliver Otti , University of Bayreuth, Bayreuth, Germany Reproduction and Immunity • Conclusion ⋆These authors contributed equally to this work. • Acknowledgements

Online posting date: 20th July 2020

Sexual reproduction is a highly complicated pro- between males and females over the optimal reproductive invest- cess shaped in part by the need to optimise ment (Andersson, 1994). Antagonistic interests of the sexes led reproductive investment, which can differ and to fast-evolving and highly diverse reproductive traits in both evolve antagonistically between the sexes. Sex- sexes, of which male mating strategies and female pre-copulatory mate choice have been intensively studied (Andersson, 1994; ual reproduction is also intimately linked with Eberhard, 1996; Hosken and Stockley, 2004; Jennions and Petrie, immunity through a variety of means. Combining 1997). However, sexual reproduction can also increase the risk these seemingly disparate biological functions has of infection due to wounding and/or encounter probability of led to the emergence of the new field of repro- microbes. Protection against these infections demands resource ductive immunity. One striking parallel between investment in immunity, which, in turn, is a function of the host’s reproduction and immunity is the detection of physiological state (Adamo, 2008a,2008b; Westra et al., 2015) ‘other’. Failure to detect pathogens results in dis- and behaviour. ease. Failure to ignore self causes autoimmunity. There are three broad and likely co-occurring ways that immu- k Similarly, individuals, as well as gametes, must nity and reproduction might be connected. First, resources for any k choose appropriate partners avoiding interspecific individual are finite and thus must be allocated among all func- mating on one extreme or reproducing with kin tions, including immune defences and reproduction (reviewed in Schwenke et al., 2016). The rationale for this trade-off is to avoid inbreeding, on the other. The relation- intuitive; if immune defences increase, fewer resources are avail- ship between reproduction and immunity is likely able for reproduction. Second, mate choice can reduce disease affected by the mating system and the degree of twofold, both to the actor, by choosing healthy noninfectious sexual conflict. Reproduction and immunity seem mates, and by reducing risk to the offspring by acquiring protec- connected in three ways by resource trade-offs tive genes for the next generation (reviewed in Lawniczak et al., among life-history traits, by disease reduction due 2007). Finally, mating can directly affect immune responses, to mate choice of healthy mates and protective which then determines disease susceptibility. The nature of this genes for the offspring and by mating-induced relationship is likely tightly connected to the mating system (see immunity to reduce infection risk. also: Polyandry and Mating System Evolution) and hence the degree of Sexual Conflict. Here, we focus on the latter connection between mating and immunity as the others have been reviewed thoroughly elsewhere (Lawniczak et al., 2007; Siva-Jothy, 2009; Introduction Morrow and Innocenti, 2012; Schwenke et al., 2016). There is a striking parallel between immunity and reproduction The origin and maintenance of sexual reproduction have endured at their shared fundament: the detection of ‘other’. During infec- as a central question in evolutionary biology. Sexual reproduction, this is obvious, if not simple. The task of a host is to identify tion can involve complicated behaviours and physiological pro- the nonself and destroy it to prevent harm. The reality is far more cesses that reflect both evolution to optimise sexual reproduction complicated, as it can result in failures to detect pathogens, result- overall but also as a consequence of an evolutionary arms race ing in greater pathology, or failure to ignore self, resulting in autoimmune responses. In sexual reproduction, processes of iden- eLS subject area: Evolution & Diversity of Life tification are no less important. Individuals, as well as gametes, How to cite: must be able to identify appropriate partners while also, prefer- Barribeau, Seth M and Otti, Oliver (July 2020) Sexual ably, not reproducing with kin to avoid potential costs of inbreed- Reproduction and Immunity. In: eLS. John Wiley & Sons, Ltd: ing (Lihoreau et al., 2008; Ylönen and Haapakoski, 2016). When Chichester. looking at the origin of the link between reproduction and immu- DOI: 10.1002/9780470015902.a0028146 nity, this connection becomes apparent (Box 1). The first sexually

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Box 1 Ancient link between reproduction and immunity The molecular choice mechanisms in Sexual Selection may have been the evolutionary precursor of the recognition system in the vertebrate immune system (Boehm, 2006b). This, perhaps surprising, hypothesis is based on some similarities in how unicellular eukaryotes, such as fungi, and plants determine whether to sexually reproduce with another individual based on self/nonself (SNS) recognition (see also: Innate Immune Mechanisms: Nonself Recognition), which avoids inbreeding and an analogous process by which multicellular organisms use SNS discrimination in immune defence (Boehm, 2006a,2006b; Sanabria et al., 2008); hinting at a very early link of sexual reproduction and immunity. While an intriguing, and in some ways appealing hypothesis, data are limited to support the proposition. In plants, a similar speculation has been suggested about the clear parallels between self-incompatibility alleles and disease recognition alleles (Sanabria et al., 2008) (Box 2). In sexually reproducing animals, the mechanisms which result in the differential success or differential utilisation of sperm depend on the recognition of gametes are in many cases likely to be immunological as well (Birkhead and Møller, 1998). Vertebrates also appear to use immunological mechanisms in mate choice. The Major Histocompatibility Complex (MHC) is primarily used in the presentation of antigens in the immune response, but in a number of studies across vertebrates, it has been implicated in mate choice (Milinski et al., 2005; Milinski, 2006; Ziegler et al., 2005). Because the major histocompatibility complex (MHC) is highly polymorphic, it serves as a reliable signal of genetic similarity to oneself, and odours produced by ligands can be detected by the opposite sex (Milinski et al., 2005; Milinski, 2006; Ziegler et al., 2005). In mammals, the complex chemical signals are sensed by the vomeronasal organ and provide conspecifics with information on an individual’s sex, social and reproductive status (He et al., 2008). Vertebrate females might even perform cryptic female choice (see also: Post-copulatory Reproductive Strategies) and select sperm or ejaculates with a favourable MHC haplotype for the fertilisation of their eggs to optimise MHC alleles in their offspring (Firman et al., 2017; Milinski, 2006). In red junglefowl, females favour sperm from males that are dissimilar in their MHC (Løvlie et al., 2013) and female sticklebacks bias fertilisation towards optimal combinations of MHC haplotypes that maximise offspring fitness (Lenz et al., 2018). Self-incompatibility and more generally genetic incompatibility between mating partners caused by nonoptimal combinations of alleles from the MHC (Kalbe et al., 2009) or other immune genes as shown in humans (Hart et al., 2018) and plants (Chae et al., 2014) might align selection pressure on reproduction and immunity, therefore, maintaining the link. We hypothesise k that the ancient link between reproduction and immunity has set the scene or was the precursor of the derived links between k reproduction and immunity, such as self-incompatibility induced via immune gene incompatibilities in plants (Chae et al., 2014) and mate choice based on the MHC alleles (Firman et al., 2017; Milinski, 2006; Kalbe et al., 2009).

Box 2 The case for plants Fertilisation and immunity in plants. Similar selection pressures seem to have shaped the link between fertilisation and immunity in plants. Especially, in flowering plants, the apparent similarity between self-incompatibility alleles and disease recognition alleles was identified a decade ago (Sanabria et al., 2008) although it is not clear whether this parallel is an example of homologous or analogous adaptations. Even though this is perhaps not directly relevant to the induction of post-fertilisation immunity; nectar and nectaries appear to contain many disease resistance-associated proteins (Zhou et al., 2016; Sasu et al., 2010). Another important selection pressure that has potentially led to a link between fertilisation and immunity in plants is the large body of evidence on pollinator transmitted diseases (Antonovics, 2005). While the process of fertilisation does induce the expression of immune genes (e.g. Mondragón-Palomino et al., 2017; Zhang et al., 2017), we do not know of any study that has examined post-fertilisation induction of immunity, for example upregulation of antimicrobials in nectar, in nectaries or in vegetative tissues and the role of this immune response on functional defences against infectious disease. We suspect no one has thought to look at this potential relationship between fertilisation and immunity. Here, we would like to point out the need for such studies. We are convinced that investigating post-fertilisation immunity in plants will lead to some very interesting research and add a completely new topic area to the field of reproductive immunity.

reproducing organisms needed a system to recognise potential and interactions between sexually transmitted infection and the partners. Early unicellular organisms are thought to have evolved genital microbiome and their respective effects on reproduction. a cell-to-cell recognition system for mate selection, which then By providing a framework for studying reproductive immu- has formed the basis for immune recognition systems (Boehm, nity and identifying different selection pressures we would like 2006a,2006b). Therefore, sexual reproduction might be at the to ignite new research avenues within the field of reproductive heart of immunity itself. The fundamental links between immu- immunity. Here, we review the association of mating and immunity and reproduction are further intertwined by the presence of nity from the early beginning of sexual reproduction to higher

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organisms. We will explore the question of how and why the link (Siva-Jothy et al., 2019), and failing to mount a suitable immune is maintained in such a wide range of organisms and propose three response could be catastrophic to a female’s survival or repro- different selection pressures that might play a role in maintaining ductive success. However, the cost of reproduction induced by and driving the evolution of reproductive immunity. the wound healing processes is completely understudied. Inter- estingly, in a single mated species, such as the bumblebee, copulatory wounding has been shown to be beneficial for the female Reproductive Immunity (Barribeau and Schmid-Hempel, 2017). The immune response triggered by wounding lead to higher resistance to a gut para- Reproductive immunity involves all immune traits, local and sys- site in the bumblebee Bombus terrestris. In this case, copulatory temic, that assist the process of reproduction. These immune wounding seems to be a signal for the female immune system and responses serve diverse functions, such as the protection and provides females with protective immunity against parasites (see repair of reproductive tissue from mating wounds and transmitted section titled ‘ Reproductive Immune Protection’). microbes that can potentially lead to sexually transmitted infec- Males might also be exposed to high wounding risk depend- tions, and can also directly bias fertilisation, such as by producing ing on the intensity of pre-copulatory male–male competition sperm antibodies or other responses that favour fertilisation by (Clutton-Brock and Huchard, 2013) or aggressive male–female some sperm over others. We propose that the study of reproduc- interactions (e.g. biting while mating in Tasmanian devils tive immunity will benefit from applying an ecological immunol- (Hamilton et al., 2019)). Infections from wounds induced by ogy framework, which is founded on the basic premise that the male–male competition or aggressive male–female interactions evolution and use of the immune system are costly and thus must can result in harmful local or systemic infections, which can kill be traded off against other traits, such as survival and repro- or reduce fertility (Losdat et al., 2011; Tremellen, 2008). As a duction, to balance an organism’s investment into all the traits consequence, males should be selected to invest in immunity needed to promote evolutionary fitness (Sheldon and Verhulst, to secure fertilisation success, and this would be especially true 1996; Boots et al., 2013). While we assume that the same is under intense pre-copulatory male–male competition and when likely true for reproductive immunity, the actual costs might be males have the opportunity to mate multiply in one or more hard to measure as reproductive immune responses protect the breeding seasons. reproduction itself. Therefore, the costs would be hard to mea- Sexual selection theory predicts, to some extent, the invest- sure in fecundity, for example. However, hosts still will benefit ment in immunity by both sexes. We hypothesise that selection if immune responses are induced only when really necessary, to for the evolution of reproductive immune defence will be stronger k conserve resources. Thus, localising the expression of immune in females than males (Oku et al., 2019) as females invest more k agents in and surrounding attacked tissues of the host are likely resources into each reproductive event than males do. In most to be less costly than globalised/systemic immune responses. This mating systems, females are more likely to secure matings than reduces energetic costs by keeping production of immune agents males, as fewer males may monopolise mating opportunities. at a minimum and agents are used when and where they are Furthermore, the time between successive reproductive events needed (Broderick et al., 2009) and self-harm is minimised (Sadd is dictated by the physiological constraints of producing those and Siva-Jothy, 2006). As with the rest of the immune response, gametes, which are more expensive and thus slower to be pro- we predict that the evolution of induced and localised immune duced in females. Thus, investing in immune defence is more responses (relative to constitutive and global responses) are deter- important to females’ lifetime reproductive success than males’. mined by the predictability of exposure, here being wounding The differential investment in reproductive immunity should be and/or parasite exposure (Mayer et al., 2016; Westra et al., 2015) stronger in polygamous systems than in monogamous systems, and virulence (Boots and Best, 2018). To better understand the where sexual conflict is comparatively low. However, the risk of link between reproduction and immunity as well as its mainte- infection per mating will interact with selection on reproductive nance we need to investigate the main selection pressures linking immunity induced by sexual conflict. Species with multiple mat- both biological functions and the factors, such as mating rate that ing may have fundamentally different immunological responses will modulate the investment in reproductive immunity. to mating than singly mating species. As an opportunity for sexual conflict increases, the damage caused by mating will likely increase, although it is unclear as to the specific nature of these Three Selection Pressures Linking increasing costs. For example, data are lacking on whether mating Reproduction and Immunity costs due to wounds increase linearly over consecutive matings or in some other fashion (asymptotically, with additional mat- Mating harm ing resulting in diminishing costs; exponentially with increasing costs). The shape of these cost curves may reflect the intensity In species with copulatory mating, wounding is common and of sexual conflict or the current status of sexually antagonistic provides an obvious link between reproduction and immunity coevolution. (Reinhardt et al., 2015). We think it is safe to assume that each copulatory wound triggers an immune response, as signs Sexual transmission of microbes of wound repair can be easily detected, for example mating scars in flies (Kamimura, 2007), velvet worms (Blaxter and Sun- In addition to direct mating induced wounding, ecological fac- nucks, 2011), seed beetles (Van Haren et al., 2017) and bedbugs tors, such as microbe presence/absence in and on reproductive

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organs and the probability of sexually transmitted infections of regular copulatory wounding, mating-induced infections or might directly affect the investment in both immune and repro- increased mating-related infection risk. ductive traits (Otti, 2015). Microbes are sexually transmitted in many species (Afzelius et al., 1989; Lockhart et al., 1996). Reproductive immune protection While we tend to only think of classically sexually transmitted infections (STIs), opportunistic and beneficial microbes, which Mating harm can trigger an immune response and give protec- inhabit the genitalia (Marius-Jestin et al., 1987; Reinhardt and tive immunity, so harm could paradoxically represent a benefit, Siva-Jothy, 2005), can also be transferred (Bellinvia et al., 2019, and females may then be selected to allow a certain degree of 2020). The reproductive organs of a variety of species often har- harm. This might represent the start of antagonistic sexual con- bour more than ten different bacterial species. Microbes have flict evolution. Interestingly, in a single mated species, such asthe been found on male reproductive organs and semen in verte- bumblebee, copulatory wounding has been shown to be benefi- brates (González-Marin et al., 2011; Skau and Folstad, 2003; cial for the female (Barribeau and Schmid-Hempel, 2017). The Virecoulon et al., 2005; Lombardo and Thorpe, 2000; Hupton immune response triggered by wounding lead to higher resis- et al., 2003), and female reproductive organs harbour a rich tance to parasites in the bumblebee B. terrestris. In this case, microbial flora in birds and mammals (Hirsh, 1999; Hickey et al., copulatory wounding provides females with protective immu- 2012, Hupton et al., 2003; Ravel et al., 2011; White et al., nity against a parasite that is particularly virulent to queens after 2011). Humans are among those vertebrates with characterised mating and diapause (Brown et al., 2003). Because this will prob- and transmissible genital microbiota (Chen et al., 2017). The few ably improve female colony founding success and survival in studies that have looked for microbes on or in genitals of insects the following year, wounding the female will improve male fit- have reported an infestation on both the male intromittent organ ness as well. The induction of protective immunity, therefore, and within the female reproductive organs (Otti, 2015; Bellinvia seems based on mutual male and female interests. However, to et al., 2019). Pollen too has distinct species-specific micro- understand which sex is in the driving seat and whether protec- biomes, which can also have unexpectedly high titers of bacte- tive immunity is found commonly further work in monogamous ria (Manirajan et al., 2016). However, we still lack knowledge species is needed. about the exact composition of the genital or gamete associated microbiomes in most species and whether the sexes har- Reproductive immune anticipation bour distinct microbial communities, how they are transmitted, or the effect these microbiomes have on reproduction or host Depending on how predictable mating is one could assume that k health. females would evolve to anticipate the male harm or risk of k Direct selection pressures such as mating harm and sexual STI by increasing reproductive immunity in advance of mating transmission of microbes will align reproductive physiology (Zhong et al., 2013; Siva-Jothy et al., 2019) either constitutively with immunity. Mating rate, mating system and sexual conflict or to induce a response pre- or post-mating. A signal or trait that will further define the predictability of immune system usedin informs an individual about when and where mating is happening relation to mating and thus the strength of the selection pressure. will facilitate the evolution of reproductive immune anticipa- High rates of mating are predicted to induce high rates of wound- tion. For example, in bedbugs, mating is linked to blood-feeding, ing and increase the risk of sexually transmitted infections (STIs). because females cannot avoid being mated, when fully fed (Rein- Females could, therefore, be selected for a strong and fast wound hardt et al., 2009). Therefore, the timing of mating can be antici- healing and reproductive immune response. The predictability of pated and the risk of infection due to mating or copulatory wound- risk for harm and infection will select for optimal immune sys- ing is more or less predictable. Indeed, bedbug females prepare tem regulation during reproduction. Under stereotyped sublethal their immune system for the upcoming challenges associated with damage, such as gland feeding or hemolymph drinking (Gwynne, mating (Siva-Jothy et al., 2019). Even if no obvious signal exists 2008; Sakaluk et al., 2004), we would predict the evolution of that can be linked to the predictability of mating, we assume that prophylactic responses because the immune system is assumed high incidences of STIs or high risk of mating harm can lead to to be ready. Therefore, such damage is likely less costly, in anticipatory immunity. Female Drosophila shows immune antic- comparison to unexpected or intermittent costs. For example, a ipation by upregulating immune genes against sexually trans- sudden attack by a rival, rape/harassment, situation exploitation mitted fungal infections (Zhong et al., 2013). For Drosophila, come with greater harm, because the immune system is not ready. a signal or trait inducing reproductive immune anticipation is However, even if regular sublethal harm occurs, the variation unknown. We assume that bedbugs and Drosophila are not the in inflicted damage between males will impose higher costs, only species in which reproductive immune anticipation occurs because the extent to which the immune system has to respond and therefore would like to highlight here also the need for further is difficult to predict. The evolved investment in reproductive research in this area. immunity will likely follow the theoretical predictions described in immune system evolution in general, that is more frequent Gamete recognition encounter and poor condition (Westra et al., 2015; Mayer et al., 2016) will lead to greater investment in constitutive protection Gamete recognition with the help of the immune system, for and greater virulence will lead to greater investment in induced example specific immunity to sperm, could provide females with responses (Boots and Best, 2018). Below we outline two possible a means to optimise fertilisation and presents a third selection adaptations of the female immune system to reduce the costs pressure for aligning reproduction and immunity. At the basis

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Box 3 What could be the function of immunity to sperm? In several cases, the female immune system is downregulated after mating (Oku et al., 2019) supposedly to avoid a reduction in sperm number and fertilisation success, especially if females are sperm-limited and every sperm is sacred. However, the female immune system might also function as a selective filter of sperm. Recent syntheses on the effects of sperm age (Pizzari et al., 2008; Reinhardt, 2007) concluded that females would benefit not only from choosing a compatible sperm genotype but also from selecting beneficial sperm phenotypes, that is between sperm of the same male. Given that sperm cells undergolarge surface, structural and functional changes (Reinhardt, 2007) in response to age, there is ample opportunity for the possibility of cellular recognition. To avoid fertilisation with low-quality sperm the female immune response to sperm could act as a filter for dead or deficient sperm and also for killing microbe/pathogen-‘contaminated’ ejaculates. Using selective spermicide female immunity to sperm could function as a cryptic choice mechanism to bias fertilisation towards high-quality sperm (female choice immunity). In human females, immunity seems to cause reproductive incompatibility by selecting against males that express foreign cell-surface antigens and, thereby, determining antigen polymorphism. Incompatibilities due to antigen mismatch may affect the evolution of the female immune response itself (Ghaderi et al., 2011). Studies from different invertebrates have shown that their immune systems can act specifically (Kurtz and Franz, 2003; Sadd and Schmid-Hempel, 2006). The degree of specificity canbe extremely high, as for instance, the copepod immune system is able to differentiate between individuals from the same species of pathogen (Kurtz and Franz, 2003). However, the mechanisms that can produce such specificity remain largely speculative. To characterise the specificity of reproductive immunity towards sperm, we suggest two concepts that have been developed to explain the evolution of the immune system. The danger model states that the immune system has evolved to recognise dangerous factors (e.g. pathogens, cancer cells) within the organism (Matzinger, 2002), whereas the SNS model suggests that nonself, mostly thought of as infectious nonself (Bretscher and Cohn, 1970), is targeted by the immune system. Both models postulate that the recognition system has evolved to target and destroy pathogens. Just as with pathogens, females recognise and destroy damaged sperm (housekeeping immunity), and also the sperm of nonpreferred males (female choice immunity). We hypothesise that housekeeping immunity corresponds to the danger/nondanger model for the evolution of the immune system, while female choice immunity is equivalent to the SNS model, that is recognition of genetic distance. Aged sperm can produce k unviable or otherwise impaired offspring (Reinhardt, 2007; Tarín et al., 2000). Therefore, females that selectively remove old, k damaged or unviable sperm from the fertilisation set will benefit by having increased zygote and offspring viability (Reinhardt, 2007). As this mechanism works not only between males but also between the sperm of one ejaculate, recognition of damaged sperm would be selected under the danger/nondanger immune system model. Sexual selection predicts that females benefit from choosing compatible sperm for the fertilisation of their gametes. Female choice immunity would, therefore, be a mechanism underlying cryptic choice after a mating has occurred. By choosing the best-suited sperm genotype for her gametes, a female could benefit in terms of offspring quality. In mammals, sperm and seminal fluid compounds can produce an antisperm immune response, and strong responses can result in infertility. Understanding the mechanisms underlying reproductive immunity could help to circumvent problems of infertility, for example genetic incompatibility, old or nonfunctional sperm. In an applied sense such studies could help to improve in vitro fertilisation in humans and livestock (Suri, 2004) but would also shed light on potential sperm choice mechanisms in higher animals.

of this, we suspect to be the ancient link between reproduction opportunity if the response is harmful to ‘good’ sperm (Sadd and and immunity (Box 1) that could provide females with a means Siva-Jothy, 2006). to control fertilisation by establishing immunological barriers to Females here face yet another trade-off. On one hand, elevating sperm after copulation, that is mounting an immune response to immune responses can limit harm from copulatory wounds or sperm (Poiani, 2002). In humans and other vertebrates, females transmitted infections, on the other, these responses are energet- produce antisperm antibodies (Clarke, 2009; Jarora et al., 2014; ically costly and risk auto-immune self-harm. One solution is the separation of immune responses to spatially constrained and Risvanli, 2011). Females might benefit from such an immune relevant organs like the reproductive and sperm storage organs response to sperm by incapacitating damaged sperm, absorbing (Orr and Brennan, 2015; Wigby et al., 2019). In addition, the dead sperm or even potentially select sperm (Drobnis and Over- evolution of reproductive organs probably made the process of street, 1992; Box 3). Female immunity to sperm might even be reproduction more efficient and reduced potential interference able to alter sperm competition outcomes in the female’s favour with other physiological processes beyond the immune system. by selecting for stronger sperm. Such immunological responses Consistent with these ideas, the human female reproductive tract to sperm are unlikely to be free, and much like the costs of immu- presents reduced innate and adaptive immune protection when nity more generally can represent energetic costs of mounting conditions are most amenable to fertilisation; during secretion of the response, autoimmunological self-harm, or harm in reduced eggs (Wira et al., 2015).

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A Potential Regulation of the Link in reproduction benefits most from longer lifespan and maintenance mechanisms, such as immunity (McKean and Nunney, between Reproduction 2005; Rolff, 2002). Hence, sexual dimorphism in immune func- and Immunity tion is commonly observed in vertebrates and some invertebrates with females often being the more immunologically protected sex Several original studies and some extensive reviews have shown (Nunn et al., 2008; McKean and Nunney, 2005). To conclude, that the reproductive system and the immune system are tightly we think the current evidence suggests a link between neuro- linked (Siva-Jothy, 2009; Lawniczak et al., 2007; Oku et al., logical, endocrinological and immunological pathways and even 2019; Schwenke et al., 2016; Wigby et al., 2019), but are crosstalk between them seems possible. However, many more they coupled to a degree that the physiological or molecular studies are needed to show strict connections and interactions pathways involved in both use the same pathways or crosstalk between these pathways, especially whether these are also related between them? Neurological–endocrinological–immunological to reproductive physiology. Nevertheless, if these pathways are interactions have been described in vertebrates and invertebrates coupled, the next salient question is ‘why?’, that is what selec- and may shed light on the simultaneous regulation of immunity tion pressures have led to the coupling and why have they been and reproduction. In crickets, for instance, the immune system is maintained? connected to the nervous system via octopamines (Adamo, 2014) and in Drosophila mating seems to regulate similar neuromodulators in the female reproductive tract (Heifetz et al., 2014). It Conclusion remains to be shown if such neuromodulators could regulate both immunity and reproduction. In bees, a connection similar to the Immunity and sexual reproduction appear to be tightly connected one in crickets has indirectly been shown by neurotoxins having processes that emerge from the shared requirement of self-nonself immunosuppressive effects (Pamminger et al., 2018). However, recognition. Here, we explored a number of aspects of these these studies only provide a link between two parts this potential shared features and the evolutionary implications and predictions tripartite interaction and do not investigate reproductive physi- of their relationship. Throughout this article, there are tantalis- ology per se. Future studies should investigate simultaneously ing glimpses of how these systems of identifying pathogens and all three parts of the interaction and include its link to repro- reproductive partners are linked, but these data are often sparse. ductive processes to provide more information on the pathways Further empirical and theoretical work into, among other things, the cost/benefit relationship of consecutive matings in relation to k linking immunity with reproduction. Hormones are plausible can- k didates to regulate several physiological processes at the same mating harm, potential sexually transmitted infections, the costs time, as postulated by the theory of hormonal pleiotropy (Flatt of immune activation upon mating, and the putative tripartite et al., 2005; Rolff and Siva-Jothy, 2002). For example, juvenile mechanistic links between hormone, reproduction and immunity hormone (JH) both regulates reproduction (Flatt et al., 2005) and are sorely needed. Studies that begin to address these questions in suppresses immunity in Drosophila (Flatt et al., 2008; Schwenke plants would be particularly welcome to explore the generality of and Lazzaro, 2017). As an antagonist to JH, the hormone 20E is the relationships described in this article. These studies could be involved in the induction of antimicrobial peptides (Flatt et al., helpful to determine the conditions for the evolution of optimal 2008). Interestingly, the opposite is the case in Bombyx mori,JH investment in immunity and the thresholds at which multiple mat- activates immunity whereas 20E inhibits it (Tian et al., 2010), ing becomes prohibitively expensive. Finally, the investigation of indicating variation in the link between hormonal regulation of reproductive immunity across various mating systems might also the immune system across taxa. To date, we only have circum- reveal different immune strategies (Mayer et al., 2016). stantial evidence for potential mechanistic links between immunity and reproduction and thus, more direct evidence is sorely needed. Acknowledgements In vertebrates, steroid hormones seem to drive immune function differences between the sexes and also between mating sys- We are grateful to Janis Antonovics for discussions on plant tems (Klein, 2000). Vertebratemales often exhibit reduced immu- immunity and reproduction and to Klaus Reinhardt for ideas nity and suffer more often from infections than females (Klein, which we finally incorporated in this article. We also thank Sara 2000). Sexual dimorphism in immune function seems more pro- Bellinvia for comments on earlier versions of the paper. O.O. nounced among polygamous than monogamous species (Klein, was supported by the German Research Foundation to O.O. 2000), much as other traits vary more among sexes in polyga- (OT 521/2-1). S.B. and O.O. conceived the idea for this review mous species, such as ornamentation. Further, originally polyan- article and jointly wrote the manuscript contributing equally to drous females evolving under monandry reduce their investment all sections. in immunity (Hangartner et al., 2015). Such evolution indi- cates a need for females to constantly invest in immunity under Glossary polyandry (Oku et al., 2019). These observations suggest that immunity, like other life history (see also: Life History The- Life history traits These are characteristics or traits that affect ory) traits, is affected by sexual selection and can be understood the fitness of an organism, and can be imagined as various through Bateman’s principle, where the sex that invests most investments in growth, reproduction, and survivorship.

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Major histocompatibility complex (MHC) A group of genes Boehm T (2006a) Quality control in self/nonself discrimination. Cell that code for proteins found on the surfaces of cells that help 125: 845–858. DOI: 10.1016/j.cell.2006.05.017. the immune system to recognise foreign substances. In Boehm T (2006b) Co-evolution of a primordial peptide-presentation humans, this complex is also called the human leukocyte system and cellular immunity. Nature Reviews Immunology 6: antigen (HLA) system. 79–84. DOI: 10.1038/nri1749. Mating system A description of who mates with whom in the Boots M, Donnelly R and White A (2013) Optimal immune defence animal kingdom. Definitions of different mating systems are in the light of variation in lifespan. Parasite Immunology 35: based on how many mates an individual acquires during a 331338. DOI: 10.1111/pim.12055. breeding season. In monogamous mating system a female and Boots M and Best A (2018) The evolution of constitutive and induced a male only have one mate at a time. In polygamous mating defences to infectious disease. Proceedings of the Royal Society of London B 285 systems, individuals of one or the other sex have more than : 20180658. DOI: 10.1098/rspb.2018.0658. Bretscher P and Cohn M (1970) A theory of self-nonself one mate during the breeding season. discrimination. Science 169: 1042–1049. DOI: 10.1126/sci- Pleiotropy This occurs when one gene codes and controls the ence.169.3950.1042. phenotype or expression of several different unrelated traits. Broderick NA, Welchman DP and Lemaitre B (2009) Recognition Self incompatibility The general name for several genetic and response to microbial infection in Drosophila.In:RolffJ mechanisms in angiosperms, which prevent selffertilisation and Reynolds SE (eds) Insect Infection and Immunity, pp 13–33. and thus encourage outcrossing. Oxford University Press: Oxford. Sexual conflict An evolutionary theory within the framework Brown MJ, Schmid-Hempel R and Schmid-Hempel P (2003) Strong of sexual selection based on the observation that a trait that is context-dependent virulence in a host–parasite system: reconciling beneficial for the reproductive success of one sex can reduce genetic evidence with theory. The Journal of Animal Ecology 72: the fitness of the other sex. 994–1002. DOI: 10.1046/j.1365-2656.2003.00770.x. Chae E, Bomblies K, Kim S-T, et al. (2014) Species-wide genetic incompatibility analysis identifies immune genes as References hotspots of deleterious epistasis. Cell 159: 1341–1351. DOI: 10.1016/j.cell.2014.10.049. Adamo SA (2008a) Bidirectional connections between the immune Chen C, Song X, Wei W, et al. (2017) The microbiota con- system and the nervous system in insects. In: Beckage NE (ed.) tinuum along the female reproductive tract and its relation to Insect Immunology, pp 129–149. Academic Press: San Diego. uterine-related diseases. Nature Communications 8: 875. DOI: Adamo SA (2008b) Norepinephrine and octopamine: linking stress k 10.1038/s41467-017-00901-0. k and immune function across phyla. Invertebrate Survival Journal Clarke GN (2009) Etiology of sperm immunity in women. Fertility 5: 12–19. and Sterility 91: 639–643. DOI: 10.1016/j.fertnstert.2007.11.045. Adamo SA (2014) The effects of stress hormones on immune func- Clutton-Brock TH and Huchard E (2013) Social competition and tion may be vital for the adaptive reconfiguration of the immune selection in males and females. Philosophical Transactions of the system during fight-or-flight behavior. Integrative and Compara- Royal Society B 368: 20130074. DOI: 10.1098/rstb.2013.0074. tive Biology 54: 419–426. DOI: 10.1093/icb/icu005. Drobnis EZ and Overstreet JW (1992) The natural history of sperma- Afzelius BA, Alberti G, Godula DJ and Witalinski W (1989) Virus- tozoa in the female reproductive tract. Oxford Reviews of Repro- and Rickettsia-infected sperm cells in arthropods. Journal of Inver- tebrate Pathology 53: 365–377. ductive Biology 14: 1–45. Andersson MB (1994) Sexual Selection. Princeton University Press: Eberhard WG (1996) Female Control: Sexual selection and Cryptic Princeton. Female Choice. Princeton University Press: Princeton. Antonovics J (2005) Plant venereal diseases: insights from a Firman RC, Gasparini C, Manier MK and Pizzari T (2017) messy metaphor. The New Phytologist 165: 71–80. DOI: Postmating female control: 20 years of cryptic female 10.1111/j.1469-8137.2004.01215.x. choice. Trends in Ecology & Evolution 32: 368–382. DOI: Barribeau S and Schmid-Hempel P (2017) Sexual healing: mating 10.1016/j.tree.2017.02.010. induces a protective immune response in bumblebees. Journal of Flatt T, Tu M-P and Tatar M (2005) Hormonal pleiotropy and the Evolutionary Biology 30: 202–209. DOI: 10.1111/jeb.12964. juvenile hormone regulation of Drosophila development and life Bellinvia S, Johnston PR, Mbedi S and Otti O (2019) Mating history. BioEssays 27: 999–1010. DOI: 10.1002/bies.20290. changes the genital microbiome in both sexes of the common bed- Flatt T, Heyland A, Rus F, et al. (2008) Hormonal regulation of bug Cimex lectularius across populations. bioRxiv: 819300. DOI: the humoral innate immune response in Drosophila melanogaster. 10.1101/819300. The Journal of Experimental Biology 211: 2712–2724. DOI: Bellinvia S, Johnston PR, Reinhardt K and Otti O (2020) Bacte- 10.1242/jeb.014878. rial communities of the reproductive organs of virgin and mated Ghaderi D, Springer SA, Ma F, et al. (2011) Sexual selection common bedbugs Cimex lectularius. Ecological Entomology. DOI: by female immunity against paternal antigens can fix loss of 10.1111/een.12784. function alleles. Proceedings of the National Academy of Sci- Birkhead TR and Møller AP (1998) Sperm competition, sexual selec- ences of the United States of America 108: 17743–17748. DOI: tion and different routes to fitness. In: Birkhead TR and Møller AP 10.1073/pnas.1102302108. (eds) Sperm Competition and Sexual Selection, pp 1–10. Academic González-Marín C, Roy R, López-Fernández C, et al. (2011) Bacteria Press: San Diego. in bovine semen can increase sperm DNA fragmentation rates: a Blaxter M and Sunnucks P (2011) Velvet worms. Current Biology 21: kinetic experimental approach. Anim. Reprod. Sci. 123: 139–148. R268–R240. DOI: 10.1016/j.cub.2011.02.017. DOI: 10.1016/j.anireprosci.2010.11.014.

k k

Sexual Reproduction and Immunity

Gwynne DT (2008) Sexual conflict over nuptial gifts in optimal MHC immune genes. Evolution 72: 2478–2490. DOI: insects. Annual Review of Entomology 53: 83–101. DOI: 10.1111/evo.13591. 10.1146/annurev.ento.53.103106.093423. Lihoreau M, Zimmer C and Rivault C (2008) Mutual mate choice: Hamilton DG, Jones ME, Cameron EZ, et al. (2019) Rate of when it pays both sexes to avoid inbreeding. PLoS ONE 3: e3365. intersexual interactions affects injury likelihood in Tasmanian DOI: 10.1371/journal.pone.0003365. devil contact networks. Behavioral Ecology 30: 1087–1095. DOI: Lockhart AB, Thrall PH and Antonovics J (1996) Sexually trans- 10.1093/beheco/arz054. mitted diseases in animals: ecology and evolutionary implications. Hangartner S, Michalczyk L, Gage MJG and Martin OY (2015) Biological Reviews of the Cambridge Philosophical Society 71: Experimental removal of sexual selection leads to decreased 415–471. investment in an immune component in female Tribolium cas- Lombardo MP and Thorpe PA (2000) Microbes in tree swallow taneum. Infection, Genetics and Evolution 33: 212–218. DOI: semen. Journal of Wildlife Diseases 36: 460–468. 10.1016/j.meegid.2015.05.005. Losdat S, Richner H, Blount JD and Helfenstein F (2011) Immune Hart MW, Stover DA, Guerra V, et al. (2018) Positive selec- activation reduces sperm quality in the great tit. PLoS ONE 6: tion on human gamete-recognition genes. PeerJ 6: e4259. DOI: e22221. DOI: 10.1371/journal.pone.0022221. 10.7717/peerj.4259. Løvlie H, Gillingham MAF, Worley K, Pizzari T and Richard- He J, Ma L, Kim S, Nakai J and Yu CR (2008) Encoding gender and son DS (2013) Cryptic female choice favours sperm from individual information in the mouse vomeronasal organ. Science major histocompatibility complex-dissimilar males. Proceed- 320: 535–538. DOI: 10.1126/science.1154476. ings of the Royal Society of London B 280: 20131296. DOI: Heifetz Y, Lindner M, Garini Y and Wolfner MF (2014) Mating 10.1098/rspb.2013.1296. regulates neuromodulator ensembles at nerve termini innervating Manirajan AB, Ratering S, Rusch V, et al. (2016) Bacte- the Drosophila reproductive tract. Current Biology 24: 731–737. rial microbiota associated with flower pollen is influenced by DOI: 10.1016/j.cub.2014.02.042. pollination type, and shows a high degree of diversity and Hickey RJ, Zhou X, Pierson JD, Ravel J and Forney LJ (2012) species-specificity. Environmental Microbiology 18: 5161–5174. Understanding vaginal microbiome complexity from an ecological DOI: 10.1111/1462-2920.13524. perspective. Translational Research 160: 267–282. Marius-Jestin V, Le Menec M, Thibault E, et al. (1987) Normal Hirsh DC (1999) The genital tract as a microbial habitat. In: Hirsh phallus flora of the gander. Journal of Veterinary Medicine, Series DC and Zee YC (eds) Veterinary Microbiology, pp 190–191. B 34: 67–78. Wiley-Blackwell: Oxford. Matzinger P (2002) The danger model: a renewed sense of self. Hosken DJ and Stockley P (2004) Sexual selection and geni- Science 296: 301–305. DOI: 10.1126/science.1071059. k tal evolution. Trends in Ecology & Evolution 19: 87–93. DOI: k Mayer A, Mora T, Rivoire O and Walczak AM (2016) Diver- 10.1016/j.tree.2003.11.012. sity of immune strategies explained by adaptation to pathogen Hupton G, Portocarrero S, Newman M and Westneat DF (2003) statistics. Proceedings of the National Academy of Sciences Bacteria in the reproductive tracts of red-winged blackbirds. The of the United States of America 113: 8630–8635. DOI: Condor 105: 453–464. 10.1073/pnas.1600663113. Jarora V, Gandotra VK, Cheema RS, Bansal AK and Dhindsa SS McKean KA and Nunney L (2005) Bateman’s principle and immu- (2014) Relationship of in vitro cervical mucus penetration assay with IgA and IgG type antibodies in cross-bred cows. Advances in nity: phenotypically plastic reproductive strategies predict changes Animal and Veterinary Sciences 2: 606–611. DOI: 10.14737/jour- in immunological sex differences. Evolution 59: 1510–1517. DOI: nal.aavs/2014/2.11.606.611. 10.1554/04-657. Jennions MD and Petrie M (1997) Variation in mate choice Milinski M, Griffiths S, Wegner KM, et al. (2005) Mate choice and mating preferences: a review of causes and consequences. decisions of stickleback females predictably modified by MHC Biological Reviews 72: 283–327. DOI: 10.1111/j.1469-185X. peptide ligands. Proceedings of the National Academy of Sci- 1997.tb00015.x. ences of the United States of America 102: 4414–4418. DOI: Kalbe M, Eizaguerre C, Dankert I, et al. (2009) Lifetime repro- 10.1073/pnas.0408264102. ductive success is maximized with optimal MHC diversity. Pro- Milinski M (2006) The major histocompatibility complex, ceedings of the Royal Society of London B 276: 934–925. DOI: sexual selection, and mate choice. Annual Review of 10.1098/rspb.2008.1466. Ecology, Evolutionn and Systematics 37: 159–186. DOI: Kamimura Y (2007) Twin intromittent organs of Drosophila 10.1146/annurev.ecolsys.37.091305.110242. for traumatic insemination. Biology Letters 3: 401–404. DOI: Mondragón-Palomino M, John-Arputharaj A, Pallmann M and Dres- 10.1098/rsbl.2007.0192. selhaus T (2017) Similarities between reproductive and immune Klein S (2000) Hormones and mating system affect sex and species pistil transcriptomes of Arabidopsis species. Plant Physiology 174: differences in immune function among vertebrates. Behavioural 1559–1575. DOI: 10.1104/pp.17.00390. Processes 51: 149–166. DOI: 10.1016/S0376-6357(00)00125-X. Morrow EH and Innocenti P (2012) Female postmating Kurtz J and Franz K (2003) Evidence for memory in invertebrate immune responses, immune system evolution and immuno- immunity. Nature 425: 37–38. DOI: 10.1038/425037a. genic males. Biological Reviews 87: 631–638. DOI: Lawniczak MKN, Barnes AI, Linklater JR, et al. (2007) Mating 10.1111/j.1469-185X.2011.00214.x. and immunity in invertebrates. Trends in Ecology & Evolution 22: Nunn CL, Lindenfors P, Pursall ER and Rolff J (2008) On sex- 48–55. DOI: 10.1016/j.tree.2006.09.012. ual dimorphism in immune function. Philosophical Transactions Lenz TL, Hafer N, Samonte IE, Yeates SE and Milinski M (2018) of the Royal Society B: Biological Sciences 364: 61–69. DOI: Cryptic haplotype-specific gamete selection yields offspring with 10.1098/rstb.2008.0148.

k k

Sexual Reproduction and Immunity

Oku K, Price TAR and Wedell N (2019) Does mating negatively Sasu MA, Wall KL and Stephenson G (2010) Antimicrobial nectar affect female immune defences in insects? Animal Biology 69: inhibits a florally transmitted pathogen of a wild Cucurbita pepo 117–136. DOI: 10.1163/15707563-20191082. (Cucurbitaceae). American Journal of Botany 97: 1025–1030. Orr TJ and Brennan PLR (2015) Sperm storage: distinguishing selec- DOI: 10.3732/ajb.0900381. tive processes and evaluating criteria. Trends in Ecology & Evolu- Schwenke RA, Lazzaro BP and Wolfner MF (2016) tion 30: 261–272. DOI: 10.1016/j.tree.2015.03.006. Reproduction-immunity trade-offs in insects. Annual Review Otti O (2015) Genitalia-associated microbes in insects. Insect Science of Entomology 61: 239–256. DOI: 10.1146/annurev-ento-010715- 22: 325–339. DOI: 10.1111/1744-7917.12183. 023924. Pamminger T, Botías C, Goulson D and Hughes WOH (2018) Schwenke RA and Lazzaro BP (2017) Juvenile hormone suppresses A mechanistic framework to explain the immunosuppressive resistance to infection in mated female Drosophila melanogaster. effects of neurotoxic pesticides on bees. Functional Ecology 32: Current Biology 27: 596–601. DOI: 10.1016/j.cub.2017.01.004. 1921–1930. DOI: 10.1111/1365-2435.13119. Sheldon BC and Verhulst S (1996) Ecological immunology: Pizzari T, Dean R, Pacey A, Moore H and Bonsall MB (2008) costly parasite defences and trade-offs in evolutionary ecol- The evolutionary ecology of pre- and post-meiotic sperm senes- ogy. Trends in Ecology & Evolution 11: 317–321. DOI: cence. Trends in Ecology & Evolution 23: 131–140. DOI: 10.1016/0169-5347(96)10039-2. 10.1016/j.tree.2007.12.003. Siva-Jothy MT (2009) Reproductive immunity. In: Rolff J and Poiani A (2002) Sperm competition promoted by sexually transmit- Reynolds SE (eds) Insect Infection and Immunity: Evolution, Ecol- ted pathogens and female immune defences. Ethology Ecology and ogy, and Mechanisms, pp 1–10. Oxford University Press: Oxford. Evolution 14: 327–340. DOI: 10.1080/08927014.2002.9522734. Siva-Jothy MT, Zhong W, Naylor R, et al. (2019) Female bed bugs Ravel J, Gajer P, Abdo Z, et al. (2011) Vaginal microbiome of (Cimex lectularius L) anticipate the immunological consequences reproductive-age women. Proceedings of the National Academy of traumatic insemination via feeding cues. Proceedings of the of Sciences of the United States of America 108 (Suppl. 1): National Academy of Sciences of the United States of America 116: 4680–4687. 14682–14687. DOI: 10.1073/pnas.1904539116. Reinhardt K and Siva-Jothy MT (2005) An advantage for young Skau PA and Folstad I (2003) Do bacterial infections cause reduced sperm in the house cricket Acheta domesticus. The American Nat- ejaculate quality? A meta-analysis of antibiotic treatment of male uralist 165: 718–723. infertility. Behavioral Ecology 14: 40–47. Reinhardt K (2007) Evolutionary consequences of sperm cell Suri A (2004) Sperm specific proteins-potential candidate molecules aging. The Quarterly Review of Biology 82: 375–393. DOI: for fertility control. Reproductive Biology and Endocrinology 2: 10.1086/522811. 10. DOI: 10.1186/1477-7827-2-10. Reinhardt K, Naylor RA and Siva-Jothy MT (2009) Situa- Tarín JJ, Pérez-Albalá S and Cano A (2000) Consequences on off- k tion exploitation: higher male mating success when female k spring of abnormal function in ageing gametes. Human Reproduc- resistance is reduced by feeding. Evolution 63: 29–39. DOI: tion Update 6: 532–549. DOI: 10.1093/humupd/6.6.532. 10.1111/j.1558-5646.2008.00502.x. TianL,GuoE,DiaoY,et al. (2010) Genome-wide regulation of Reinhardt K, Anthes N and Lange R (2015) Copulatory wounding innate immunity by juvenile hormone and 20-hydroxyecdysone and traumatic insemination. Cold Spring Harbor Perspectives in Bombyx BMC Genomics 11 Biology 7: a017582. DOI: 10.1101/cshperspect.a017582. in the fat body. : 549. DOI: Risvanli A (2011) Reproductive immunology in mares. 10.1186/1471-2164-11-549. Asian Journal of Animal and Veterinary 6: 547–554. DOI: Tremellen K (2008) Oxidative stress and male infertility – a clini- 10.3923/ajava.2011.547.554. cal perspective. Human Reproduction Update 14: 243–258. DOI: Rolff J (2002) Bateman’s principle and immunity. Proceed- 10.1093/humupd/dmn004. ings of the Royal Society of London B 269: 867–872. DOI: Van Haren MM, Liljestrand Rönn J, Schilthuizen M and Arnqvist G 10.1098/rspb.2002.1959. (2017) Postmating sexual selection and the enigmatic jawed geni- Rolff J and Siva-Jothy MT (2002) Copulation corrupts immunity: talia of Callosobruchus subinnotatus. Biology Open 6: 1008–1012. a mechanism for a cost of mating in insects. Proceedings of the DOI: 10.1242/bio.025684. National Academy of Sciences of the United States of America 99: Virecoulon F, Wallet F, Fruchart-Flamenbaum A, et al. (2005) Bac- 9916–9918. DOI: 10.1073/pnas.152271999. terial flora of the low male genital tract in patients consulting for Sadd BM and Schmid-Hempel P (2006) Insect immunity shows infertility. Andrologia 37: 160–165. specificity in protection upon secondary pathogen exposure. Cur- Westra ER, van Houte S, Oyesiku-Blakemore S, et al. (2015) rent Biology 16: 1206–1210. DOI: 10.1016/j.cub.2006.04.047. Parasite exposure drives selective evolution of constitutive ver- Sadd BM and Siva-Jothy MT (2006) Self-harm caused by an insect’s sus inducible defense. Current Biology 25: 1043–1049. DOI: innate immunity. Proceedings of the Royal Society of London B 10.1016/j.cub.2015.01.065. 273: 2571–2574. DOI: 10.1098/rspb.2006.3574. White BA, Creedon DJ, Nelson KE and Wilson BA (2011) The Sakaluk SK, Campbell MTH, Clark AP, Johnson JC and Keorpes vaginal microbiome in health and disease. Trends in Endocrinology PA (2004) Hemolymph loss during nuptial feeding constrains male & Metabolism 22: 389–393. mating success in sagebrush crickets. Behavioral Ecology 15: Wigby S, Suarez SS, Lazzaro BP, Pizzari T and Wolfner MF 845–849. DOI: 10.1093/beheco/arh113. (2019) Chapter eight – Sperm success and immunity. Cur- Sanabria N, Goring D, Nürnberger T and Dubery I (2008) rent Topics in Developmental Biology 135: 287–313. DOI: Self/nonself perception and recognition mechanisms in plants: 10.1016/bs.ctdb.2019.04.002. a comparison of self-incompatibility and innate immunity. Wira CR, Rodriguez-Garcia M and Patel MV (2015) The role of sex The New Phytologist 178: 503–514. DOI: 10.1111/j.1469-8137. hormones in immune protection of the female reproductive tract. 2008.02403.x. Nature Reviews Immunology 15: 217–230. DOI: 10.1038/nri3819.

k k

Sexual Reproduction and Immunity

Ylönen H and Haapakoski M (2016) Risk of inbreeding: problem Further Reading of mate choice and fitness effects? Israel Journal of Ecology and Evolution 62: 155–161. DOI: 10.1080/15659801.2015.1073452. Otti O, Naylor RA, Siva-Jothy MT and Reinhardt K (2009) Bacteri- Zhang X, Liu W, Nagae TT, et al. (2017) Structural basis for receptor olytic activity in the ejaculate of an insect. The American Naturalist recognition of pollen tube attraction peptides. Nature Communica- 174: 292–295. tions 8: 1331. DOI: 10.1038/s41467-017-01323-8. Otti O, McTighe AP and Reinhardt K (2013) In vitro antimicrobial Zhong W, McClure CD, Evans CR, et al. (2013) Immune antic- sperm protection by an ejaculate-like substance. Functional Ecol- ipation of mating in Drosophila: Turandot M promotes immu- ogy 27: 219–226. DOI: 10.1111/1365-2435.12025. nity against sexually transmitted fungal infections. Proceed- Otti O, Deines P, Hammerschmidt K and Reinhardt K (2017) Regular ings of the Royal Society of London B 280: 20132018. DOI: wounding in a natural system: bacteria associated with reproduc- 10.1098/rspb.2013.2018. tive organs of bedbugs and their quorum sensing abilities. Frontiers Zhou Y, Li M, Zhao F, et al. (2016) Floral nectary morphology in Immunology 8: 1855. DOI: 10.3389/fimmu.2017.01855. and proteomic analysis of nectar of Liriodendron tulipifera Linn. Frontiers in Plant Science 7: 826. DOI: 10.3389/fpls.2016.00826. Ziegler A, Kentenich H and Uchanska-Ziegler B (2005) Female choice and the MHC. Trends in Immunology 26: 496–502. DOI: 10.1016/j.it.2005.07.003.

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