Integrative and Comparative Biology Integrative and Comparative Biology, Volume 54, Number 2, Pp

Home , Sickness behavior

Integrative and Comparative Biology Integrative and Comparative Biology, volume 54, number 2, pp. 159–165 doi:10.1093/icb/icu036 Society for Integrative and Comparative Biology

SYMPOSIUM

Parasitic Aphrodisiacs: Manipulation of the Hosts’ Behavioral Defenses by Sexually Transmitted Parasites Shelley A. Adamo1 Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2 From the symposium ‘‘Parasitic Manipulation of Host Phenotype, or How to Make a Zombie’’ presented at the annual

meeting of the Society for Integrative and Comparative Biology, January 3–7, 2014 at Austin, Texas. Downloaded from 1E-mail: [email protected]

Synopsis Animals have a number of behavioral defenses against infection. For example, they typically avoid sick con- http://icb.oxfordjournals.org/ specifics, especially during mating. Most animals also alter their behavior after infection and thereby promote recovery (i.e., sickness behavior). For example, sick animals typically reduce the performance of energetically demanding behaviors, such as sexual behavior. Finally, some animals can increase their reproductive output when they face a life-threatening immune challenge (i.e., terminal reproductive investment). All of these behavioral responses probably rely on immune/ neural communication signals for their initiation. Unfortunately, this communication channel is prone to manipulation by parasites. In the case of sexually transmitted infections (STIs), these parasites/pathogens must subvert some of these behavioral defenses for successful transmission. There is evidence that STIs suppress systemic signals of immune activation (e.g., pro-inflammatory cytokines). This manipulation is probably important for the suppression of sickness behavior at Bora Laskin Law Library on November 7, 2016 and other behavioral defenses, as well as for the prevention of attack by the host’s immune system. For example, the cricket, Gryllus texensis, is infected with an STI, the iridovirus IIV-6/CrIV. The virus attacks the immune system, which suffers a dramatic decline in its ability to make proteins important for immune function. This attack also hampers the ability of the immune system to activate sickness behavior. Infected crickets cannot express sickness behavior, even when challenged with heat-killed bacteria. Understanding how STIs suppress sickness behavior in humans and other animals will significantly advance the field of psychoneuroimmunology and could also provide practical benefits.

Introduction increase their chance of recovery (i.e., sickness Parasites must infect new hosts for successful trans- behavior; Hart 1988). Sickness behavior usually in- mission. Sexually transmitted infections (STIs) have cludes a reduction in sexual behavior (Hart 1988). special requirements for transmission; the infected These behavioral defenses reduce the animal’s risk of host must engage in sexual contact with potential disease-induced mortality (e.g., Hart 1988; Dantzer new hosts (Lockhart et al. 1996). Unfortunately for 2004; Adelman and Martin 2009). However, if exe- STIs, this mode of transmission pits them against the cuted, they also would prevent the transmission of host’s behavioral defenses against infection. STIs. STIs must suppress such defenses for successful Hosts have a number of behavioral defenses transmission of the parasite to occur. The success against infection (Schmid-Hempel 2011). These of STIs at circumventing these behavioral defenses often are overlooked, but they play an important has ramifications for the evolution of sexually se- role in preventing infection and in promoting sur- lected signals as well as for our understanding of vival after infection (Schmid-Hempel 2011; de Roode immune/neural connections. and Le`fevre 2012). These defenses include the avoid- In this article, the term parasite is used very ance of sick conspecifics (e.g., Able 1996; Kavaliers broadly and includes not just traditional parasites et al. 2004) and the rejection of infected mates (Able such as parasitic worms (e.g., tapeworms, Cestoda), 1996; Møller et al. 1999). Once infected, animals but all organisms that require a host for its nutrition typically alter their behavior in such a way as to and home (e.g., pathogens such as viruses, bacteria,

Advanced Access publication May 9, 2014 ß The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: [email protected]. 160 S. A. Adamo and fungi). Both vertebrate and invertebrate animals also reject immune-challenged mates (e.g., Fedorka have immunological and behavioral defenses against and Mousseau 2007). parasites across this phylogenetic range (Roitt et al. One reason infected animals become less desirable 2001; Beckage 2008; Schmid-Hempel 2011). as mates is that infection often induces a decline in the attractiveness of sexually selected ornaments/traits Behavioral defense No. 1. Avoid sick (e.g., see Møller et al. 1999; Lawniczak et al. 2007; conspecifics Hasselquist and Nilsson 2012). These traits often act as advertisements of a male’s current health (e.g., Disease is a major source of mortality in animals. birds, Faivre et al. 2003; rodents, Kavaliers et al. Therefore, behaviors that reduce the risk of disease 2004). The sensitivity of many sexually selected traits should provide individuals with a substantial advan- to a male’s health status should usually prevent fe- tage. For example, animals from a range of vertebrate males from mating with diseased males. However, and invertebrate species help prevent contagion by immune challenge does not always decrease sexual avoiding sick conspecifics (Able 1996; Kavaliers

signaling (e.g., Copeland and Fedorka 2012; Jacobs Downloaded from et al. 2004, 2005; de Roode and Le`fevre 2012). In and Zuk 2012). There is also some debate as to many species, animals recognize signs of immune whether sexually selected traits advertise a male’s cur- activation in conspecifics, even if no parasite is rent health (direct benefits), or his heritable resistance present. For example, the ant, Formica polyctena, re- to disease (indirect benefits) to females, or some com- duces mouth-to-mouth exchanges of fluid (trophal-

bination of the two (Lawniczak et al. 2007; Adamo http://icb.oxfordjournals.org/ laxis) with nest-mates that have had their immune and Spiteri 2009; Jacobs and Zuk 2012). This issue is systems activated by injecting lipopolysaccharides somewhat complex (e.g., see Lindstro¨m et al. 2009; (LPS), a major chemical component of bacterial Jacobs and Zuk 2012). Minimally it can be concluded cell membranes (Aubert and Richard 2008). Some that there are species differences in how strongly in- of these cues are olfactory (Kavaliers et al. 2004, dividuals avoid infected mates. STIs may have fewer 2005; Arakawa et al. 2010). These cues are thought defenses to overcome in species in which females do to be ‘‘cheat-proof,’’ in part because adopting not pay attention to a male’s health when choosing an inflammatory immune state may necessitate the at Bora Laskin Law Library on November 7, 2016 a mating partner. Whether this makes them more production and shedding of certain metabolites vulnerable to STIs remains to be tested. (Arakawa et al. 2010). In support of this hypothesis, Regardless of this ongoing debate, STIs must not injecting an anti-inflammatory cytokine, interleukin make its host unattractive or it runs the risk of (IL)-10, prevented the production of the odor cue achieving little or no transmission. In some species signaling illness to conspecifics in rats (Arakawa (i.e., the ones that signal health to prospective part- et al. 2010). This observation suggests that in species ners), this will require that STIs induce their hosts to that are sensitive to a conspecific’s health status, an falsely advertise that they are disease-free. This will STI will need to suppress at least some aspects of the degrade the accuracy of the sexual ornament adver- host’s immune response, or its host will be shunned, tising this trait. STIs are not uncommon infections in reducing mating opportunities. animals (Lockhart et al. 1996) and their presence may exert an under-appreciated impact on the evo- Behavioral defense No. 2. Reject lution of sexually selected traits (Knell 1999; Kokko infected mating partners et al. 2002; Knell and Webberley 2004). Unfortunately for STIs, the avoidance of infected con- As would be predicted by the strong evolutionary specifics is most marked within the context of mating. forces acting on STIs, they tend to produce few Animals avoid mating with potential partners suffering symptoms in their hosts (Knell 1999; MacKey and from contagious diseases (Able 1996; Kavaliers et al. Immerman 2003; Antonovics et al. 2011). A hallmark 2004). For example, male mice avoid the urine odors of STIs is that they do not appear to put their hosts of females infected with parasites (Kavaliers et al. at a disadvantage in terms of attractiveness to mates 2004). Animals from a range of species are also sensi- (e.g., Lockhart et al. 1996; Knell and Webberley tive to the immune status of a potential mating part- 2004). This lack of discernment on the part of pro- ner, and will reject potential mates with ongoing spective mates is surprising given the costs to females immune responses, even if no parasite is present. For if they mate with males infected with an STI. Most example, male rats spend less time courting females STIs carry fitness penalties, including reduced fertil- injected with LPS or IL-1 (a pro-inflammatory cyto- ity and premature death (e.g., Lockhart et al. 1996; kine that induces immune activation) (Avitsur and see Knell and Webberley 2004, table 1; MacKey and Yirmiya 1999; Roitt et al. 2001). Some invertebrates Immerman 2003). In many mating systems, males STIs and host behavioral defenses 161 are abundant; therefore, it would be to a female’s male and in female rats (Avitsur and Yirmiya 1999). advantage to avoid males with fitness-reducing However, male rats are able to ‘‘conceal’’ sickness be- STIs. Females in a number of species can avoid havior when courting a female (Avitsur and Yirmiya males undergoing robust immune responses, as was 1999). Similarly, male song sparrows (Melospiza discussed above. In these species, STIs will need to molida) inhibit sickness behaviors (such as reduction avoid strongly activating the host’s immune re- in territorial aggression) when immune-challenged sponses in order to fool a prospective partner into during the breeding season (Owen-Ashley and mating with an infected host. Wingfield 2006). In zebra finches (Taeniopygia gut- tata), LPS induces sickness behaviors in males Behavioral defense No. 3: Initiate housed alone, but it is suppressed if males are in sickness behavior the presence of the breeding colony (Lopes et al. 2012). The mechanisms mediating this suppression As well as a decline in the attractiveness of sexually are partly known. Immune-generated reductions in selected ornaments, infected animals often show a

sexual behavior can be modulated by the presence Downloaded from decline in their motivation for sexual behavior of other signaling molecules (Adelman and Martin (Hart 1988; Dantzer 2004; Lawniczak et al. 2007). 2009). For example, testosterone plays a role in the This decline in libido can be induced by injecting suppression of sickness behaviors during the breeding compounds that activate the immune system; no season in white-crowned sparrows (Zonotrichia leu- pathogen is required (e.g., Avitsur and Yirmiya cophrys gambelii) (Ashley et al. 2009). The adaptive http://icb.oxfordjournals.org/ 1999; Jacot et al. 2004). In vertebrates, sickness be- suppression of sickness behavior does not appear to haviors also can be induced by injections of pro- be due to a general suppression of the immune re- inflammatory cytokines such as IL-1 (Dantzer sponse. Plasma levels of the pro-inflammatory cyto- 2004). This suppression of energetically expensive kine IL-6 were the same in male zebra finches sexual behaviors shifts resources toward immune de- regardless of whether the breeding colony was present fense (Hart 1988; Dantzer 2004). This shift optimizes or not (Lopes et al. 2012). immune function, increasing the chance that the Animals infected with STIs continue to mate; animal will survive the infection (Hart 1988; therefore, STIs must have evolved ways of inhibiting at Bora Laskin Law Library on November 7, 2016 Dantzer 2004). Immune activation also reduces immune-generated declines in sexual behavior in sexual behavior in invertebrates, even though they their hosts. STIs could use at least two possible do not use the same pro-inflammatory cytokines methods to produce this inhibition. First, they (Adamo 2008). For example, immune challenge could directly inhibit sickness behavior by reducing with LPS lowers calling rates in adult male crickets immune activation (e.g., in vertebrates by decreasing (Gryllus campestris) (Jacot et al. 2004) and bush pro-inflammatory cytokine production) (Roitt et al. crickets (Cyphoderris strepitans) (Leman et al. 2001). Second, they could, in some species, exploit 2009), thereby reducing their opportunities for the methods hosts use to adaptively reduce the mating (Jacot et al. 2004). Immune challenge also effects of immune activation on sexual behavior. reduces a male cricket’s propensity to mate with Exploiting pre-existing host mechanisms is a females (e.g., G. texensis; Adamo et al. 2014). common method parasites use to manipulate hosts’ However, given the importance of mating for re- behavior (Adamo 2013). productive success, the effect of immune activation on Unfortunately, how STIs circumvent sickness be- sexual behavior is sometimes modulated by other fac- havior remains unknown. However, at least in some tors. For example, in rats it is sex-specific; injection of cases, reducing the production of pro-inflammatory LPS suppresses sexual behavior in females, but not in cytokines appears to be involved. Pro-inflammatory males (Avitsur and Yirmiya 1999). For males in this cytokines such as IL-1 and IL-6 are potent activators species, the cost of forgoing a limited opportunity to of sickness behavior (Dantzer 2004). Some non-STI reproduce is thought to be greater (in terms of fit- parasites induce little or no sickness behavior in their ness) than the risk of possible death due to not opti- hosts (Kavaliers et al. 2004), in part by suppressing mizing conditions for the immune system. However, pro-inflammatory cytokine production (Duell et al. female rats may be unlikely to produce healthy off- 2012). Some non-STIs accomplish this by inducing spring when infected, and, therefore, there is little an increase in the generation of anti-inflammatory benefit for them in not optimizing immune function cytokines (Duell et al. 2012). For example, IL-10 is (Avitsur and Yirmiya 1999). Physiologically, immune an anti-inflammatory cytokine that reduces the pro- activation induces a rapid and sustained suppression duction of pro-inflammatory cytokines such as IL-1 of the hypothalamic/pituitary/gonadal axis both in and IL-6 (Roitt et al. 2001; Duell et al. 2012). 162 S. A. Adamo

IL-10 injected into the brain can prevent LPS- to produce molecules important for immune func- induced sickness behavior in rats, e.g., social with- tion is probably responsible for the loss of sickness drawal (Bluthe´ et al. 1999) and illness-induced behavior in infected animals (Fig. 1) (Adamo et al. anorexia (Hollis et al. 2010). Intriguingly, most 2014). The signal between the immune system and STIs increase IL-10 production in their hosts, e.g., nervous system appears to be disconnected in in- human immunodeficiency virus, human papilloma fected crickets (Adamo et al. 2014). virus, Chlamydia trachomatis, and Neisseria gonor- rhoeae (Duell et al. 2012). If IL-10 is produced too Behavioral defense No. 4. Activate early in infection it prompts an inappropriate tran- terminal reproductive investment sition from cell-mediated immunity to humoral responses, leading to chronic infections (Duell et al. In some species, activating an immune response leads 2012) with low pathology (Couper et al. 2008). to increased sexual behavior (see Reaney and Knell This description fits the clinical course of many 2010) (Table 1). This behavioral defense maximizes reproductive output when death appears to be immi-

STIs (Lockhart et al. 1996; Antonovics et al. 2011). Downloaded from The source, timing, and magnitude of IL-10 produc- nent (Clutton-Brock 1984). This defense is called ter- tion can sculpt the parasite/host interaction (Couper minal reproductive investment (Clutton-Brock 1984). et al. 2008) and is likely to be a key factor mediating Infected animals perceive their dwindling future repro- manipulation of the host by STIs. However, many ductive potential (e.g., due to infection) and shift their molecular and energetic resources toward reproduc- STIs also induce local inflammation despite increas- http://icb.oxfordjournals.org/ ing IL-10 production, e.g., Chlamydia (Zhong 2009). tion. For example, injection of LPS into female crickets For example, syphilis, caused by the spirochete induces oviposition (Adamo 1999). Female crickets Treponema pallidum, produces local inflammation, carry both stored sperm and fully formed eggs but no systemic activation of cytokine (Cruz et al. (Loher and Dambach 1989); therefore, the LPS 2012). The vertebrate immune system is extremely allows females to lay as many of her stored eggs as complex, and the details of how STIs are able to possible before she dies. Because there is no parental remain relatively asymptomatic (i.e., not induce sick- care in crickets, an increased number of eggs can im- ness behavior), despite activating some inflammatory prove a female’s reproductive success, even if she dies at Bora Laskin Law Library on November 7, 2016 processes, remains unclear (Mackern-Oberti et al. soon after oviposition (Adamo 1999). Terminal repro- 2013). ductive investment also exists in males (e.g., Copeland A reduction in some immune functions also may and Fedorka 2012; Nielsen and Holman 2012). One of be involved in curtailing sickness behavior in inver- the best-studied systems on this issue is the effect of tebrates infected with STIs. For example, an irido- immune challenge on the male beetle, Tenebrio moli- virus, insect iridovirus type 6, cricket variant, tor. Males challenged with LPS change the cuticular IIV-6/CrIV (Jakob et al. 2002), is an STI that attacks hydrocarbon profile of their sexual pheromones, crickets (G. texensis) (Adamo et al. 2014). The virus making them more attractive to females (Nielsen and enhances male sexual behavior and suppresses the Holman 2012). Terminal reproductive investment is decline in sexual behavior that usually occurs during also observed in some vertebrates (e.g., Adelman immune activation (Adamo et al. 2014). In fact, all and Martin 2009). Whether an immune challenge sup- sickness behaviors are suppressed. Crickets usually presses sexual behavior (sickness behavior) or en- show illness-induced anorexia when the immune hances it (terminal reproductive investment) depends system is activated (Adamo et al. 2010). However, on a number of factors, such as the age of the host illness-induced anorexia is absent in crickets infected (Copeland and Fedorka 2012; Wilson and Cotter with the virus, even if the immune system is artifi- 2013). cially stimulated with heat-killed bacteria (Adamo Like the three other forms of behavioral defense, et al. 2014). terminal reproductive investment due to infection is The virus invades the cricket’s fat body (Adamo probably initiated by immune/neural signaling. These et al. 2014), an organ that makes most of the connections could provide a potential mechanism for immune-related proteins (Chapman 1998). The STIs to exploit. In some STIs, infected animals virus also infects hemocytes (Kleepsies et al. 1999), become more desirable as mating partners and/or the insects’ immune cells of the blood. Therefore, the show increased sexual behavior compared with entire immune system is largely under viral control. healthy controls. These effects occur both in verte- The infected fat body sharply reduces its production brates (Schwanz 2008; Dass et al. 2011) and inverte- of host proteins, including immune-related proteins brates (Abbot and Dill 2001; Adamo et al. 2014). As (Adamo et al. 2014). The loss of the cricket’s ability the host’s mating rate is the main determinant of an STIs and host behavioral defenses 163 Downloaded from http://icb.oxfordjournals.org/

Fig. 1 Hypothesized method used by IIV-6/CrIV, an STI in crickets, to suppress sickness behavior. The hexagons represent the virus. Dashed lines indicate data that have been inferred, but not directly measured. The virus redirects the fat body to make viral particles instead of the host’s proteins. Egg production drops due to lack of the egg-yolk protein vitellogenin. The lack of immune-related proteins/peptides, e.g., phenoloxidase (PO), leads to reduced immune attack against the virus and a suppression of sickness behavior. Sickness behavior would normally reduce sexual behavior; there is no reduction in sexual behavior in crickets infected with IIV-6/CrIV. These changes benefit the virus. Based on Adamo et al. (2014). at Bora Laskin Law Library on November 7, 2016

STI’s transmission rate (Webberley et al. 2006), such to the immunosuppression the parasite must use to a change in hosts’ behavior would benefit an STI. prevent attack by the host’s immune system, remains However, given that enhanced sexual behavior to be discovered. Some mechanisms are likely to be could also benefit the host, the STI may not require species-specific, as the effect of different immune sig- any mechanisms dedicated for this manipulation. naling molecules can vary across species, even within Even in hosts rendered sterile by the STI, the host mammals (McCusker and Kelley 2013). The ability may not ‘‘know’’ that it is sterile, and simply re- of STIs to alter immune signaling has ramifications spond to the initiating stimulus (i.e., an infection) for the evolution of traits that advertise the male’s with enhanced reproduction. Therefore, in species health (e.g., see Kokko et al. 2002). Increased study that show terminal reproductive investment, STIs of how STIs alter immune/neural connections will might encourage some inflammatory responses. also significantly advance psychoneuroimmunology, and possibly provide practical benefits. For example, Conclusions pro-inflammatory cytokines are now used to treat diseases such as viral hepatitis (Foster 2009). These STIs must overcome a number of the hosts’ behav- treatments induce serious side-effects, including ioral defenses in order to achieve successful transmis- sexual dysfunction (Foster 2009). If STIs can selec- sion. As these defenses are probably induced by tively target and suppress sickness behavior, knowing immune/neural signaling molecules, subverting this these mechanisms might help patients tolerate im- communication channel might be a common mech- munotherapy, without depressing immune function. anism among STIs. STIs may be pre-adapted for this type of manipulation, as interference with the hosts’ immune systems, and, therefore, with the hosts’ Funding immune signaling systems (e.g., cytokines), is neces- This work was supported by a Natural Science and sary for successful parasitism. The molecular details Engineering Research Council of Canada (NSERC) of how STIs inhibit the hosts’ behavioral defenses, grant to S.A.A. Support for participation in this sym- and whether any of these mechanisms are in addition posium was provided by the Society for Integrative 164 S. A. Adamo and Comparative Biology (Divisions of Invertebrate lipopolysaccharide in rats. Psychoneuroendocrinology Biology, Animal Behavior, and Neurobiology), the 24:301–11. American Microscopical Society and the National Chapman RF. 1998. The insects. 4th ed. Cambridge: Cambridge University Press. Science Foundation (IOS 1338574). Clutton-Brock TH. 1984. Reproductive effort and terminal investment in iteroparous animals. Am Nat 123:212–29. Copeland EK, Fedorka KM. 2012. The influence of male age References and simulated pathogenic infection on producing a dishon- est sexual signal. Proc R Soc B Biol Sci 279:4740–6. Abbot P, Dill LM. 2001. Sexually transmitted parasites and Couper KN, Blount DG, Riley EM. 2008. IL-10: The mas- sexual selection in the milkweed leaf beetle, Labidomera ter regulator of immunity to infection. J Immunol clivicollis. Oikos 92:91–100. 180:5771–7. Able DJ. 1996. The contagion indicator hypothesis for para- Cruz AR, Ramirez LG, Zuluaga AV, Pillay A, Abreu C, site-mediated sexual selection. Proc Natl Acad Sci U S A Valencia CA, La Vake C, Cervantes JL, Dunham-Ems S, 93:2229–33. Cartun R, et al. 2012. Immune evasion and recognition

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