Are fungal pathogens manipulating human behavior?

 

Fungal infection of brain tissue (Wikicommons, CDC). Some fungi persist in the human brain for years and begin to harm their host only in old age. What were they doing previously?

 

 

I've published a paper on manipulation of human behavior by fungal pathogens. Here's the abstract:

 

Many pathogens, especially fungi, have evolved the capacity to manipulate host behavior, usually to improve their chances of spreading to other hosts. Such manipulation is difficult to observe in long-lived hosts, like humans. First, much time may separate cause from effect in the case of an infection that develops over a human life span. Second, the host-pathogen relationship may initially be commensal: the host becomes a vector for infection of other humans, and in exchange the pathogen remains discreet and does as little harm as possible. Commensalism breaks down with increasing age because the host is no longer a useful vector, being less socially active and at higher risk of death. Certain neurodegenerative diseases may therefore be the terminal stage of a longer-lasting relationship in which the host helps the pathogen infect other hosts, largely via sexual relations. Strains from the Candida genus are particularly suspect. Such pathogens seem to have co-evolved not only with their host population but also with the local social environment. Different social environments may have thus favored different pathogenic strategies for manipulation of human behavior.

 

Please feel free to comment.

 

Reference

 

Frost, P. (2020). Are Fungal Pathogens Manipulating Human Behavior? Perspectives in Biology and Medicine 63(4): 591-601. https://doi.org/10.1353/pbm.2020.0059

 

Candida and autism

Shamanic ritual (Wikipedia - Idries Shah). There is a correlation between autism and antibodies for Candida albicans. Does a pathogenic strain of this yeast promote the development of autism? Cui bono?


In my previous posts I've argued that certain pathogens have acquired the capacity to manipulate human behavior. Humans are an interesting target for several reasons:

1. The human mind oversees an extensive range of complex behaviors

2. Humans are long-lived, thus providing a useful vehicle for spreading to other potential hosts.

3. Humans have particularly long generation times and are thus less able to develop resistance to short-generation pathogens, which can more easily “outmanoeuvre” the evolution of human resistance.

Among animal hosts in general, behavior can be manipulated by many pathogens, including fungi. Fungi seem to be better able than viruses and bacteria at producing and coordinating the array of chemicals needed for the targeted neural tissue. One of them may be Candida, a genus of yeasts that most often live in the gut but can be found elsewhere in the body. In particular, there seems to be a connection between their presence and the development of autism spectrum disorders (ASD):

We aimed to determine if children with ASD exhibit elevations in antibodies that target C. albicans, indicating current or previous overgrowth of this fungal species. [...] Plasma anti-C. albicans antibody positivity was found in 36.5% (19/52) of children with ASD. Anti-C. albicans antibodies in typically developing controls was (14.3%; 4/28). Overall, ASD children had a higher rate of high-positive values compared to typically developed children with an unadjusted odds ratio of 3.45 (95% confidence interval, 1.0409 to 11.4650; p = 0.041, two-tailed). (Hughes and Ashwood 2018)

The above study takes the line that Candida albicans is a "passive commensal" that "under certain conditions [...] is capable of transitioning to its pathogenic and invasive fungal form" (Hughes and Ashwood 2018). In reality, C. albicans encompasses a variety of strains, some of which live more as a commensal and others more as a pathogen: 

Here, intra-species analyses of C. albicans isolates revealed extensive variation between strains, both at the genotypic and phenotypic level. Substantial genomic differences were observed between the set of 21 clinical strains and included single nucleotide polymorphisms, inversions, copy number changes, LOH events, and whole or partial chromosomal aneuploidies.

[...] The phenotypic plasticity of this species has long been recognized, and our studies reveal the genetic differences underlying phenotypic differences are due to a variety of mechanisms, of which LOH and aneuploidy are major contributors. Furthermore, we uncover a genetic polymorphism responsible for altered phenotypic behavior, including a change in the balance between commensalism and pathogenesis. (Hirakawa et al. 2015)

Some strains of C. albicans have evolved the capacity to adhere to neural tissue:

An ex vivo adhesion assay was used to examine adhesion of Candida albicans yeast cells to brain tissue of the primate Macaca mulata. Tissues from frontal lobes and striatum (caudate, putamen, and portions of the globus pallidus) were used in the assay. Yeast cells adhered to gray matter at about six times the level of adhesion to white matter. The fungus was able to bind to different cell types within the cortex, basal ganglia, and white matter. Binding to neurons, small neurons or glia, endothelial cells, and neuropil was observed. (Denaro et al. 1995)

What's in it for the pathogen?

This is the weakest link in the argument for behavioral manipulation. How does autism benefit the pathogen? Does it help Candida spread to another host? If not, where is the benefit? People have speculated about the evolutionary advantage of autism, but only from the standpoint of the affected person. Perhaps a low dose makes one more inventive and creative (Pickard et al. 2011). Perhaps it gives rise to the "autonomous imagination" of shamans:

[…] “autonomous imagination” [is] a framework for cross-cultural interpretations of inner experience such as dreams, waking visions, trance, spirit possession and mediumship, and shamanistic and meditative states.

[…] Autonomous imagination is characterized by: a) being more freely and richly inventive than ordinary thought; b) emerging into conscious awareness in the form of vivid hallucinatory imagery which is experienced as an external reality; c) possessing a more extensive access to memory; d) exhibiting a special sensitivity to external cues and direction which enables communication to and from deeper levels of the mind, while bypassing conscious awareness, and; e) possessing a capacity to influence somatic and intrapsychic processes usually beyond conscious control (Stephen and Suryani 2000)

Shamans, through their prestige and reproductive success, may have favored a predisposition to autism in the gene pool. This hypothesis assumes that autism is mainly due to a genetic predisposition, i.e., that autism is highly heritable. In fact, heritability is "moderate": 37% for autism and 38% for autism spectrum disorder (Hallmayer et al. 2011). As with male homosexuality, it looks like something in the environment is interacting with a genetic predisposition.

If we take the pathogen's standpoint, we must ask how an autistic person might become an interesting means to spread from one host to another. One possibility is the shaman's role as a community healer. Certain healing practices involve intimate contact. In particular, a shaman's phlegm may be thought to contain the essence of his power. 

A shaman also has a magical phlegm called yachay, lodged in his stomach, which gives him the ability to blow away evil and to such out the sorcery objects (virote) that cause certain forms of illness. (Gow 1996, p. 93)

By targeting people who are likely to fill the position of community healer, a pathogen could greatly increase its opportunities for transmission. 


Parting thought

This example suggests that the evolution of behavioral manipulation can involve more than a pathogen and a host. It may also require a genetic predisposition and a cultural context that create opportunities for behavioral manipulation.


References

Denaro, F.J., J.L. Lopez-Ribot, and W.L. Chaffin. (1995). Adhesion of Candida albicans to brain tissue of Macaca mulata in an ex vivo assay. Infection and Immunity 63(9): 3438-3441.
https://iai.asm.org/content/iai/63/9/3438.full.pdf

Gow, P. (1996). River People: Shamanism and History in Western Amazonia. In Thomas, N., and C. Humphrey (eds). Shamanism, History, and the State (pp. 90-113). Ann Arbor: The University of Michigan Press. 
https://books.google.ca/books?hl=fr&lr=&id=3_inrj3puRQC&oi=fnd&pg=PA90&dq=%22River+People:+Shamanism+and+History+in+Western+Amazonia%22&ots=r2_OIZbV5M&sig=aH8LVaJwqbmFUn3FpuARh3N3UF8#v=onepage&q=%22River%20People%3A%20Shamanism%20and%20History%20in%20Western%20Amazonia%22&f=false

Hallmayer, J., S. Cleveland, A. Torres, et al. (2011). Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Archives of General Psychiatry 68(11): 1095-1102.
http://www.feat.org/Portals/0/Document%20Library/Medical%20Research%20Abstracts/GeneticHeritability_2011_07_04.pdf 

Hirakawa, M.P., D.A. Martinez, S. Sakthikurmar, M.Z. Anderson, A. Berlin, S. Gujja; et al. (2015). Genetic and phenotypic intra-species variation in Candida albicans. Genome Research 25: 413-425.
https://europepmc.org/articles/pmc4352881

Hughes, H.K., and P. Ashwood. (2018). Anti-Candida albicans IgG antibodies in children with autism spectrum disorders. Psychiatry 26 November
https://www.frontiersin.org/articles/10.3389/fpsyt.2018.00627/full

Pickard, C., B. Pickard, and C. Bonsall. (2011). Autistic spectrum disorder in prehistory. Cambridge Archaeological Journal 21(3): 357-364.
https://www.research.ed.ac.uk/portal/files/539348/2011_CAJ_Pickard_etal.pdf

Stephen, M. and L.K. Suryani. (2000). Shamanism, psychosis and autonomous imagination. Culture, Medicine and Psychiatry 24: 5-40.
https://link.springer.com/article/10.1023/A:1005528028869

Yes, demons do exist

 

Chlamydia infection rate, by country (WHO 2004, Wikicommons). Sub-Saharan Africa has been a natural laboratory for the evolution of sexually transmitted pathogens, including strains that can manipulate their hosts.

 

Are we being manipulated by microbes? The idea is not so whacky. We know that a wide range of microscopic parasites have evolved the ability to manipulate their hosts, even to the point of making the host behave in strange ways. A well-known example is Toxoplasma gondii, a protozoan whose life cycle begins inside a cat. After being excreted in the cat's feces, it is picked up by a mouse and enters the new host's brain, where it neutralizes the fear response to the smell of cat urine. The mouse lets itself be eaten by a cat, and the protozoan returns to a cat's gut—the only place where it can reproduce (Flegr, 2013).

T. gondii can also infect us and alter our behavior. Infected individuals have longer reaction times, higher testosterone levels, and a greater risk of developing severe forms of schizophrenia (Flegr, 2013). But there is no reason to believe that T. gondii is the only such parasite we need to worry about. We study it in humans simply because we already know what it does in a non-human species.

Researchers are starting to look at manipulation by another human parasite, a sexually transmitted bacterium called Chlamydia trachomatis. Zhong et al. (2011) have found that it synthesizes proteins that manipulate the signalling pathways of its human host. These proteins seem to facilitate reinfection, although there may be other effects:

Despite the significant progresses made in the past decade, the precise mechanisms on what and how chlamydia-secreted proteins interact with host cells remain largely unknown, and will therefore still represent major research directions of the chlamydial field in the foreseeable future. (Zhong et al., 2011)

What else would a sexually transmitted pathogen do to its host? For one thing, it could cause infertility: 

While several nonsexually transmitted infections can also cause infertility (e.g., schistosomiasis, tuberculosis, leprosy), these infections are typically associated with high overall virulence. In contrast, STIs tend to cause little mortality and morbidity; thus, the effect on fertility seems to be more "targeted" and specific. In addition, several STI pathogens are also associated with an increased risk of miscarriage and infant mortality (Apari et al., 2014)

Chlamydia is a major cause of infertility, and this effect seems to be no accident. Its outer membrane contains a heat shock protein that induces cell death (apoptosis) in placenta cells that are vital for normal fetal development. The same protein exists in other bacteria but is located within the cytoplasm, where it can less easily affect the host's tissues. Furthermore, via this protein, Chlamydia triggers an autoimmune response that can damage the fallopian tubes and induce abortion. This response is not triggered by the common bacterium Escherichia coli. Finally, Chlamydia selectively up-regulates the expression of this protein while down-regulating the expression of most other proteins (Apari et al., 2014).

But how would infertility benefit Chlamydia and other sexually transmitted pathogens? Apari et al. (2011) argue that infertility causes the host and her partner to break up and seek new partners, thus multiplying the opportunities for the pathogen to spread to other hosts. A barren woman may pair up with a succession of partners in a desperate attempt to prove her fertility and, eventually, turn to prostitution as a means to support herself (Caldwell et al., 1989). This is not a minor phenomenon. STI-induced infertility has exceeded 40% in parts of sub-Saharan Africa (Apari et al., 2011).

It gets kinkier and kinkier

Does the manipulation stop there? We know, for instance, that sexual promiscuity correlates with the risk of contracting different STIs, but is this a simple relationship of cause and effect? Could an STI actually promote infidelity by stimulating sexual fantasizing about people other than one's current partner?

Let's look at another pathogen, Candida albicans, commonly known as vaginal yeast, which can cause an itchy rash called vulvovaginal candidiasis (VVC). Reed et al. (2003) found no significant association between VVC and the woman's frequency of vaginal sex, lifetime number of partners, or duration of current relationship. Nor was there any association with presence of C. albicans in her male partner. But there were significant associations with the woman masturbating or practicing cunnilingus in the past month.

VVC is thus more strongly associated with increased sexual fantasizing, as indicated by masturbation rate, than with a higher frequency of vaginal intercourse. This does look like host manipulation, although one might wonder why it doesn't translate into more sex with other men, this being presumably what the pathogen wants. Perhaps the development of masturbation as a lifestyle (through use of vibrators and pornography) is making this outcome harder to achieve.

A sexually transmitted pathogen can also increase its chances of transmission by disrupting mate guarding. This is the tendency of one mate, usually the male, to keep watch over the other mate. If mate guarding can be disabled or, better yet, reversed, the pathogen can spread more easily to other hosts. This kind of host manipulation has been shown in a non-human species (Mormann, 2010).

Do we see reversal of mate guarding in humans? Yes, it's called cuckold envy—the desire to see another man have sex with your wife—and it's become a common fetish. Yet it seems relatively recent. Greco-Roman texts don't mention it, despite abundant references to other forms of alternate sexual behavior, e.g., pedophilia, cunnilingus, fellatio, bestiality, etc. The earliest mentions appear in 17th century England (Kuchar, 2011, pp. 18-19). This was when England was opening up to world trade and, in particular, to the West African slave trade.

Sub-Saharan Africa has been especially conducive to sexually transmitted pathogens evolving a capacity for host manipulation. Polygyny rates are high, in the range of 20 to 40% of all adult males, and the polygynous male is typically an older man who cannot sexually satisfy all of his wives. There is thus an inevitable tendency toward multi-partner sex by both men and women, which sexually transmitted pathogens can exploit ... and manipulate.

What about sexual orientation?

A pathogen can also become more transmissible by giving its host a new sexual orientation. This strategy would disrupt the existing pair bond while opening up modes of transmission that may be more efficient than the penis/vagina one. Some vaginal strains of Candida albicans have adapted to oral sex by becoming better at adhering to saliva-coated surfaces (Schmid et al., 1995). Certain species that cause bacterial vaginosis, notably Gardnerella vaginalis and Prevotella, seem to specialize in female-female transmission (Muzny et al., 2013; Sobel, 2012).

Finally, there is the hypothesis that exclusive male homosexuality has a microbial origin (Cochran et al., 2000). Its main shortcomings are that (a) there is no candidate pathogen and that (b) exclusive male homosexuality has been observed in social environments with limited opportunities for pathogen transmission, such as small bands of hunter-gatherers across pre-Columbian North America (Callender & Kochems, 1983). On the other hand, there seems to have been a relatively recent shift in European societies from facultative to exclusive male homosexuality, so something may have happened in the environment, perhaps the introduction of a new pathogen (Frost, 2009).

Both male and female homosexuality seem to have multiple causes, but it’s likely that various pathogens have exploited this means of spreading to other hosts.

Conclusion

This is a fun subject when it concerns silly mice or zombie ants. But now it concerns us. And that's not so funny. Can microbes really develop such demonic abilities to change our private thoughts and feelings?

It does seem hard to believe. Perhaps this is an argument for intelligent design. After all, only an all-knowing designer could have made creatures that are so small and yet capable of so much ... things like inducing abortion, breaking up marriages, and altering normal sexual desires. Yes, such an argument could be made.

But I don't think anyone will bother.

 

References

Apari, P., J. Dinis de Sousa, and V. Muller. (2014). Why Sexually Transmitted Infections Tend to Cause Infertility: An Evolutionary Hypothesis. PLoS Pathog 10(8): e1004111.

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1004111

Caldwell, J.C., P. Caldwell, and P. Quiggin. (1989). The social context of AIDS in sub-Saharan Africa, Population and Development Review, 15, 185-234.

https://www.soc.umn.edu/~meierann/Teaching/Population/Readings/Feb%209%20Caldwell.pdf

Callender, C. and L.M. Kochems. (1983). The North American Berdache, Current Anthropology, 24, 443-470.

http://www.jstor.org/discover/10.2307/2742448?uid=3739448&uid=2&uid=3737720&uid=4&sid=21104311299061 

Cochran, G.M., P.W. Ewald, and K.D. Cochran. (2000). Infection causation of disease: an evolutionary perspective, Perspectives in Biology and Medicine, 43, 406-448.

http://www.isteve.com/infectious_causation_of_disease.pdf

Flegr, J. (2013). Influence of latent Toxoplasma infection on human personality, physiology and morphology: pros and cons of the Toxoplasma-human model in studying the manipulation hypothesis, The Journal of Experimental Biology, 216, 127-133. http://jeb.biologists.org/content/216/1/127.full 

Frost, P. (2009). Has male homosexuality changed over time, Evo and Proud, March 5

http://evoandproud.blogspot.ca/2009/03/has-male-homosexuality-changed-over.html

Kuchar, G. (2001). Rhetoric, Anxiety, and the Pleasures of Cuckoldry in the Drama of Ben Jonson and Thomas Middleton, Journal of Narrative Theory, 31 (1), Winter, pp. 1-30. 

Mormann, K. (2010). Factors influencing parasite-related suppression of mating behavior in the isopod Caecidotea intermedius, Theses and Disserations, paper 48

http://via.library.depaul.edu/etd/48 

Muzny, C.A., I.R. Sunesara, R. Kumar, L.A. Mena, M.E. Griswold, et al. (2013). Correction: Characterization of the vaginal microbiota among sexual risk behavior groups of women with bacterial vaginosis. PLoS ONE 8(12):

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0080254 

Reed, B.D., P. Zazove, C.L. Pierson, D.W. Gorenflo, and J. Horrocks. (2003). Candida transmission and sexual behaviors as risks for a repeat episode of Candida vulvovaginitis, Journal of Women's Health, 12, 979-989.

http://online.liebertpub.com/doi/abs/10.1089/154099903322643901 

Schmid, J., P.R. Hunter, G.C. White, A.K. Nand, and R.D. Cannon. (1995). Physiological traits associated with success of Candida albicans strains as commensal colonizers and pathogens, Journal of Clinical Microbiology, 33, 2920-2926.

http://jcm.asm.org/content/33/11/2920.short 

Sobel, J.D. (2012). Bacterial vaginosis, Wolters Kluwer, UpToDate

http://www.uptodate.com/contents/bacterial-vaginosis 

Zhong, G., L. Lei, S. Gong, C. Lu, M. Qi, and D. Chen. (2011). Chlamydia-Secreted Proteins in Chlamydial Interactions with Host Cells, Current Chemical Biology, 5, 29-37

http://www.ingentaconnect.com/content/ben/ccb/2011/00000005/00000001/art00004

First, sexual transmissibility and then ...?

Squamous cervix cells covered with rod-shaped bacteria, Gardnerella vaginalis (source)

Bacterial vaginosis is a common disease among reproductive-aged women:

[It] is characterized by the loss of normal vaginal flora, predominantly hydrogen peroxide-producing Lactobacillus spp., and the increase in the number and species of other bacteria in vaginal fluid. The decrease in lactobacilli and increase in numerous facultative and anaerobic bacteria, some of which have only been recently characterized, may lead to changes in the characteristics of vaginal fluid, such as thin discharge and odor. (Koumans etal., 2007)

Its incidence correlates with the number of lifetime sex partners, and this correlation holds true even when one controls for a series of socioeconomic variables: poverty, smoking, body mass index, douching frequency, education, and oral contraceptive use (Koumans et al., 2007). It thus seems to be sexually transmissible, with suspicions falling particularly on the bacterium Gardnerella vaginalis:

Sexual activity is a risk factor for BV, and most experts believe that BV does not occur in women who have never had vaginal intercourse [12,13]. Epidemiologic studies are strongly supportive of sexual transmission of BV pathogens. There is a high occurrence of BV and concordance of flora in women who have sex with women, further suggesting sexual transmission is important in this setting [14-16]. It is not clear, however, whether one type of sexual activity may be more important in the pathogenesis of infection than another. As an example, oral-genital sex may be a more important risk factor than penile intromission into the vagina. (Sobel, 2012)

The incidence of bacterial vaginosis also correlates with ethnicity, being 51.4% of non-Hispanic blacks, 31.9% of Mexican Americans, and 23.2% of non-Hispanic whites. This correlation likewise holds true when the above socioeconomic variables are held constant. High incidences have also been found in sub-Saharan Africa (Pepin et al., 2011).

After studying these ethnic differences in vaginal flora, Ravel et al. (2010) concluded that they were normal and not pathological:

From these data we conclude that vaginal bacterial communities not dominated by species of Lactobacillus are common and appear normal in black and Hispanic women. The data from this study are in accordance with the results of Zhou et al. (17, 18), who studied the vaginal bacterial communities of white, black, and Japanese women. The reasons for these differences among ethnic groups are unknown, but it is tempting to speculate that the species composition of vaginal communities could be governed by genetically determined differences between hosts. These might include differences in innate and adaptive immune systems, the composition and quantity of vaginal secretions, and ligands on epithelial cell surfaces, among others.

The ultimate cause may be vaginal pH, which is higher in blacks and Hispanics than in Asians and non-Hispanic whites (Ravel etal., 2010). Or it may be differences in cytokine concentrations, with differences in vaginal pH being due to the differences in vaginal flora (Nomelini et al., 2010).

There has thus been a co-evolution between the vaginal environment and certain strains of vaginal bacteria. This co-evolution would have followed different trajectories in different human populations. In a monogamous population, possibilities for sexual transmission would have been sporadic and difficult to sustain. The picture is different in a population with a high incidence of polygyny, especially if the males often inherit or steal some of their co-wives from other males. Such a context would have favored bacteria that can spread from one co-wife to another and then to other sets of co-wives when circumstance permit.

But why wait for the right circumstances? Why not make them by manipulating the host’s behavior? Such behavioral manipulation sounds like science-fiction, yet it has been demonstrated in a wide range of animal species, often in surprisingly precise ways. So how could our bacterium manipulate its host? It wants to hop from one set of co-wives to another, but the regular male partner is standing in its way. What should it do?

First, it should facilitate female-to-female transmission among the co-wives. Second, it should disable the male’s propensity for mate guarding. Better yet, it should reverse the polarity, causing him to feel not jealousy but pleasure at the idea of being cuckolded.

This kind of manipulation occurs in the isopod Caecidotea intermedius. A parasite, Acanthocephalus dirus, infects it as a temporary host before infecting one of several freshwater fishes. When the parasite is still soft and immature, it cannot survive a fish eating its isopod host. It thus seeks to reduce this risk by suppressing conspicuous host behaviors, like mate guarding. Later, when the parasite becomes hard and mature, it can survive consumption of its host and now stimulates mate guarding (Galipaud et al., 2011; Mormann, 2010).

Cuckoldry is fatal to reproductive success, so any such tendency would soon flush itself out of the gene pool. For example, the neural networks for mate guarding might become more insensitive to outside tampering. This change, however, would in turn favor those parasites that could maintain such tampering. The eventual outcome would be an evolutionary compromise where mate guarding is impaired, but not enough to prevent reproductive success. The situation is different, though, if the parasite spreads to another population that has never developed such immunity.

Many sexual fetishes have been around for a long time and are often traceable to the ancient Greco-Roman world. Cuckold envy, however, seems relatively recent, the oldest references dating back to 17th century England (Kuchar, 2011, pp. 18-19). We may thus be looking at a sexually transmitted parasite that entered England with the expansion of world trade in the 17th century. But from where? Probably from a highly polygynous culture area, like West Africa.

This parasite might be a vaginal bacterium that first acquired sexual transmissibility and then an ability to manipulate host behavior. It might alternately be a strain of vaginal yeast. Indeed, vaginal strains of Candida albicans show a similar adaptation to sexual transmission via the partner’s mouth, i.e., they adhere better to saliva-coated surfaces than do other strains (Schmid et al., 1995).

References

Gaulipaud, M., Z. Gauthey, and L. Bollache. (2011). Pairing success and sperm reserve of male Gammarus pulex infected by Cyathocephalus truncatus (Cestoda: Spathebothriidea), Parasitology, 138, 11, 1429-1435.

Koumans E.H., M. Sternberg, C. Bruce, G. McQuillan, J. Kendrick, et al. (2007). The prevalence of bacterial vaginosis in the United States, 2001–2004; associations with symptoms, sexual behaviors, and reproductive health, Sexually Transmitted Diseases, 34, 864–869.

http://journals.lww.com/stdjournal/Fulltext/2007/11000/The_Prevalence_of_Bacterial_Vaginosis_in_the.6.aspx

Kuchar, G. (2001). Rhetoric, Anxiety, and the Pleasures of Cuckoldry in the Drama of Ben Jonson and Thomas Middleton, Journal of Narrative Theory, 31 (1), Winter, pp. 1-30.

Mormann, K. (2010). Factors influencing parasite-related suppression of mating behavior in the isopod Caecidotea intermedius, Theses and Disserations, paper 48

http://via.library.depaul.edu/etd/48

Nomelini, R.S., A.P.B. Carrijo, S.J. Adad, A.A. Nunes, E.F.C. Murta. (2010). Relationship between infectious agents for vulvovaginitis and skin color, Sao Paulo Medical Journal, 128, 348-53

http://www.scielo.br/scielo.php?pid=S1516-31802010000600007&script=sci_arttext

Pépin J., S. Deslandes, G. Giroux, F. Sobéla, N. Khonde, et al. (2011). The Complex Vaginal Flora of West African Women with Bacterial Vaginosis. PLoS ONE, 6(9): e25082. doi:10.1371/journal.pone.0025082

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0025082

Ravel J, Gajer P, Abdo Z, Schneider GM, Sara S, et al. (2010). Vaginal microbiome of reproductive-age women. Proceedings of the National Academy of Sciences U SA, 108, 4680-4687.

http://www.pnas.org/content/108/suppl.1/4680.short

Schmid, J., P.R. Hunter, G.C. White, A.K. Nand, and R.D. Cannon. (1995). Physiological traits associated with success of Candida albicans strains as commensal colonizers and pathogens, Journal of Clinical Microbiology, 33, 2920–2926.

Sobel, J.D. (2012). Bacterial vaginosis, Wolters Kluwer, UpToDate

http://www.uptodate.com/contents/bacterial-vaginosis

The demon within. Part III

Sir John Hawkins (1532-1595) was instrumental in bringing England into the slave trade. Was this trade a source of new pathogens for the English population?

Some vaginal strains of Candida albicans have become better at sexual transmission, such as through improved adhesion to saliva-coated surfaces and through displacement of non-vaginal strains in a new host.

But the adaptations don’t stop there. In my last two posts, I argued that these strains have also become better at sexual transmission by manipulating host behavior. They can cross the blood/brain barrier. We know this. Once inside the control room, why not go one step farther?

C. albicans is an ideal candidate for such evolution. First, It’s common. There’s a large pool of genetic variants for natural selection to act upon.

Second, C. albicans has developed the capacity to spread from one host to another through intimate contact. It thus has every reason to enhance this capacity by rewiring its host’s neural circuits, even at the cost of doing much harm.

As biologist Paul Ewald observed:

For decades medical science was dominated by the doctrine of "commensalisms' - the notion that the pathogen-host relationship inevitably evolves toward peaceful coexistence, and the pathogen itself toward mildness, because it is in the germ's interest to keep its host alive. This sounds plausible, but it happens to be wrong.

[…] If you're a germ that can travel from person to person by way of a "vector," or carrier, such as a mosquito or a tsetse fly, you can afford to become very harmful. This is why, Ewald argues, insect borne diseases such as yellow fever, malaria, and sleeping sickness get so ugly. Cholera uses another kind of vector for transmission: it is generally waterborne, travelling easily by way of faecal matter shed into the water supply. And it, too, is very ugly. (Hooper, 1999)

An infectious organism will thus try to turn its host into a launching pad for infection of other hosts. The long-term survival of any one host no longer matters.

Avenues for future enquiry

Where from?

If a pathogen is responsible for cuckold envy, and if the first recorded mention of this fetish comes from 17th-century England, the point of origin is probably extra-European. Specifically, it would have been a society that came into contact with England through that country’s expansion of foreign trade, exploration, and colonization from the 16th century onward. We’re probably looking at the West Indies, West Africa, the eastern American seaboard, or the territories of the Hudson’s Bay Company.

One of my commenters, Jim Bowery, suggested that the pathogen could have entered England via the West African slave trade. Indeed, an argument can be made that sexually transmitted diseases are most likely to develop in high-polygny societies, such as exist among the ‘female-farming’ peoples of sub-Saharan Africa. On the one hand, the polygynous male cannot sexually satisfy all of his wives. On the other, many young males are locked out of the marriage market, the result being a lot of sex on the sly.

As anthropologist Pierre van den Berghe pointed out:

The temporary celibacy of young men in polygynous societies is rarely absolute, however. While it often postpones the establishment of a stable pair-bond and the procreation of children, it often does not preclude dalliance with unmarried girls, adultery with younger wives of older men, or the rape or seduction of women conquered in warfare. Thus, what sometimes looks like temporary celibacy is, in fact, temporary promiscuity. (van den Berghe, 1979, pp. 50-51).

Do other STDs manipulate human sexual behavior?

Is manipulation of sexual behavior a logical adaptation for STDs? If so, have other human STDs evolved in this direction? No one seems to have asked the question. Admittedly, cause and effect are hard to tease apart. Do STDs correlate with sexual promiscuity solely because a promiscuous person is more likely to catch one? Which is the chicken and which is the egg?

Research on insects has turned up several cases of an STD manipulating host behavior in order to facilitate sexual transmission.

Behavioural changes associated with parasitic infection are well known, and at least some of these appear to be adaptations on the part of the parasite to increase transmission (Moore, 1993, 2001; Poulin, 1994a, b, 1998a, 2000). Four recent studies of insect STDs are relevant here. McLachlan (1999) showed that male midges (Paratrichocladius rufiventris) infected with the mite Unionicola ypsilophora were more likely to be in mating pairs than uninfected males. As discussed earlier, the mites rely on female midges to return them to water to complete their life cycle. If they find themselves on a male midge, therefore, they are effectively dead unless their host mates with a female […].

Raina et al. (2000) found that Hz-2V infected female corn earworm moths Helicoverpa zea produce two to three times more sex pheromone than uninfected female moths, possibly enhancing their ability to attract male moths, although they also reported that these animals vigourously resisted mating. Abbot & Dill (2001) found that male Labidomera clivicollis beetles infected with the mite Chrysomelobia labidomera were more likely to displace other males from mating pairs, which again could be interpreted as being adaptive manipulation of the host by the parasite to increase transmission. Webberley et al. (2002), by contrast, found that infection of Adalia bipunctata with Coccipolipus hippodamiae did not have any effect on the mating behaviour of the host. (Knell & Webberley, 2004)

References

Hooper, J. (1999). A new germ theory, The Atlantic Journal, February

http://gc.homeunix.net/

Knell, R.J., and K.M. Webberley. (2004). Sexually transmitted diseases of insects: distribution, evolution, ecology and host behaviour, Biol. Rev., 79, 557–581.

van den Berghe, P.L. (1979). Human Family Systems. An Evolutionary View, New York: Elsevier.

The demon within. Part II

Preferential binding by Candida albicans to various types of cells in a macaque brain (Denaro et al., 1995).

In my last post, I examined the relationship between sexual behavior and vulvovaginal candidiasis (VVC), a condition that occurs when certain strains of vaginal yeast (Candida albicans) become highly virulent. Clearly, the relationship is not a simple one of cause and effect. Occurrence of VVC correlates not with vaginal sex but rather with non-vaginal sex, i.e., fellatio, cunnilingus, and masturbation. There is also no significant association between VVC and the presence of C. albicans in the male partner, including his oral cavity.

The evidence suggests that the direction of causality runs in the opposite direction. These strains of C. albicans do not enter a woman’s vagina via fellatio, cunnilingus, or masturbation, at least not primarily. Instead, they may be manipulating the host’s behavior by weakening her sexual inhibitions and inciting her to maximize contact between vaginal fluids and colonizable sites on her partner’s body.

This scenario is all the more likely because vaginal yeast is common and thus provides a large pool of organisms for natural selection to act upon. Vaginal strains of C. albicans also show evidence of adaptation to saliva-based transmission, i.e., they adhere better to saliva-coated surfaces than do other strains (Schmid et al., 1995). In the male partner, they tend to displace non-vaginal strains (Schmid et al., 1993).

So these vaginal strains became better at spreading from a female host to a new male host. But what then?

Did they then evolve the capacity to make the male host more sexually promiscuous? Perhaps. But keep in mind that male-to-female transmission is much less effective than female-to-male transmission. Although VVC can develop on male body sites, the vagina is by far the primary site for C. albicans colonization and infection.

From the standpoint of C. albicans, the optimal scenario would be one where the female host goes on to infect other males. What can her regular male partner do to bring this about?

He could cease all mate-guarding behavior. In plain English, he could stop being jealous. He could even encourage her to have sex with other men.

This kind of parasite manipulation does occur in one organism, the isopod Caecidotea intermedius. A parasite, Acanthocephalus dirus, infects this isopod as an intermediate host in order to enter its final host, one of several freshwater fishes. When the parasite is still soft and immature, it cannot survive a fish eating its isopod host. It thus seeks to reduce this risk by suppressing conspicuous host behaviors, like mate guarding. Later, when the parasite becomes hard and mature, it can survive consumption of its host and, in fact, seeks this outcome. It now stimulates conspicuous behaviors, like mate guarding, and changes its host’s pigmentation to increase visibility (Mormann, 2010).

‘Cuckold envy’

In humans, suppression of mate guarding seems to match a behavior called “cuckold envy”—a sexual fetish where a man is not only indifferent to being cuckolded but actually derives pleasure from cuckoldry. How prevalent is this fetish? A Google search for the term “wife breeding” turned up 793,000 hits, many of which corresponded to videos that have been specially developed for this market.

Cuckold fetishists tend to center their fantasies on black men, perhaps because darker skin and heavier facial features help evoke the image of a rival male. In fact, some of these fetishists have rebranded themselves as members of the “interracial community,” presumably to gain social acceptance and to blend into the broader antiracist movement. Such individuals may be behind the apparent mainstreaming of interracial porn, as seen for example in the antiracist Swedish video Blanda Upp! (2010). One might draw parallels here between lesbian activists and the feminist movement …

This sexual fetish seems to be sufficiently common to foster speculation about a possible Darwinian (or pseudo-Darwinian) cause:

In his book Sperm Wars, biologist Robin Baker speculated that the excitement and stimulation of the cuckolding fetish emerges from the biology of sexuality and the effects of sexual arousal on the brain. According to his theory, when a man believes that his female mate may have been sexual with another man, he is prompted by biological urges to copulate with the female, in an effort to "compete" with the other man's sperm. (Cuckold – Wikipedia)

Baker’s theory fails to explain why most men have precisely the opposite emotional reaction, i.e., feelings of hurt, anger, and rage.

This seems to be true in all human societies. A search for the term ‘cuckold’ in the Human Relations Area Files (HRAF) turned up references to 32 cultures. All of the references indicated intensely negative feelings in the cuckolded men, as seen in the following examples:

Yanomamö (South America)
Discovery of liaisons by the cuckold inevitably leads to club fighting between the factions of the lover and the husband. The woman involved usually suffers more than either of the male principals in the fighting that follows, as women are severely punished by their husbands. The punishment usually consists of a beating with a club, but men frequently shoot their unfaithful wives with barbed arrows in a non-vital area of the body, such as the buttocks or leg. In one instance I witnessed, the enraged husband struck his wife in the face with a burning log, severely burning her mouth. Burning is a common punishment, and many women bear immense scars from wounds inflicted by enraged husbands. (Chagnon, 1967, pp. 91-92)

Tukano (South America)
Adultery or even flirting with a ceremonial friend’s spouse is a principal cause for a break in this otherwise very stable relationship. A ceremonial friend who has been wronged by his partner retaliates by entering the offender’s house to break or carry off everything belonging to him except the hammock. This act of vandalism declares the friendship broken. Eternal animosity succeeds it. (Goldman, 1963, p. 132).

Quechua (South America)
The two strongest insults that Saraguro males can fling at each other (or curse behind their backs) are maricón (homosexual) and cabrón (literally, he-goat, but meaning cuckold). (Belote, 1978, p. 79)

Pashtun (Asia)
[…] for daows (“cuckold” and by extension “dupe”) is the most serious curse and adultery rather than incest the crime of horror. Among the most serious offenses against Pakhtun social order, adultery causes more trouble, mobilizes more sanctions, and ramifies further than any other Pakhtun delict. (Anderson, 1982, p. 401)

Greeks (Europe)
Conversely, the act of disobedience by which she damages her husband most severely is adultery. In adultery she makes her husband a cuckold (κερατ□ς), one who wears a horn. ‘She puts horns on him’ (το□ βάζει κέρατα), it is said. The implication that the cuckold wears a horn may be an ironical allusion to the sexual potency which his wife's action suggests he does not possess (Campbell, 1964, p. 152)

Azande (Africa)
[…] he is certain that she has a lover and he broods in dark anger till he can discover who has made him a cuckold. (Evans-Pritchard, 1937, p. 268)

Men seem to tolerate cuckoldry the most in societies with low paternal investment, i.e., ‘female farming’ societies of sub-Saharan Africa and Papua-New Guinea. But I found no HRAF reference to men actually feeling pleasure at the idea of being cuckolded. The closest match was the custom of ‘wife exchange’ among the Inuit and some Amerindian peoples, like the Comanche:

In many cases, the levirate as practiced by the Comanches approximated polyandry, for brothers lent each other their wives. This “anticipatory levirate” reflected an attitude of camaraderie and denial of sexual jealousy between two brother-warriors.

[…] Women, however, were not free to initiate liaisons. Adulterous men could be sued for damages and customarily made payments in horses or other goods, but the women in question bore the brunt of the shame, and her punishment might include disfigurement (usually slitting of the nose) or death at the hands of her husband. When pressing his case, the cuckold would address his wife's lover as “brother,” an ironic reference to the proper conditions for wife sharing. (Gelo, 1986, pp. 29-30)

When I switched from a cross-cultural search to a cross-historical one, the oldest references to cuckold envy seemed to be in plays from 17th-century England. In these plays, the cuckold anxiety of earlier periods gives way to cuckold envy:

In A Mad World, My Masters Middleton fully realizes some of the subtle psycho/social details that Jonson develops with the potential cuckold Kitely in Every Man in His Humor. The perverse pleasure that Jonson's acquiescent cuckold derives from his subject position is latent, as Martin Semour-Smith notes, in the etymology of Kitely's name: "Mr. Sale draws attention in his edition to the dialect word 'kittle', meaning 'ticklish' ie. 'hard to deal with, touchy'; but he has missed the verb 'to kittle': 'to stir, with feeling or emotion, usually pleasurable.'" Seymour-Smith continues, noting that it "was also clear to Jonson that Kitely perversely enjoyed his wife less as a direct sexual object than as the indirect object by which he might be cuckolded" (xii, xiii). (Kuchar, 2001, p. 18)

In Every Man in His Humor, the lead character notes the strangeness of his fetish:

Who will not judge him worthy to be robbed,
That sets his doors wide open to a thief,
And shows the felon, where his treasure lies?
(Kuchar, 2001, p. 19)

If 17th-century England is the ground zero for cuckold envy, where was it beforehand? In some yet unknown human population? Or was it in a nonhuman species? Perhaps we are looking at an evolutionary trajectory similar to that of the AIDS virus, i.e., a lengthy period of co-adaptation in a nonhuman population followed by transfer to a human population and increased virulence.

References

Anderson, J.W. (1982). Social structure and the veil: comportment and the composition of interaction in Afghanistan, Anthropos, 77 (3/4), 397.

Belote, L. (1978). Prejudice and pride: Indian-White relations in Saraguro, Ecuador,
Ann Arbor, Michigan: University Microfilms International.

Campbell, J.K. (1964). Honour, family and patronage: a study of institutions and moral values in a Greek mountain community, Oxford: Clarendon Press.

Chagnon, N. (1967). Yanomamö warfare, social organization and marriage alliances,
Ann Arbor, Mich.: University Microfilms.

Cuckold – Wikipedia, http://en.wikipedia.org/wiki/Cuckold

Denaro, F.J., J.L. Lopez-Ribot, and W.L. Chaffin. (1995). Adhesion of Candida albicans to brain tissue of Macaca mulata in an ex vivo assay, Infection and Immunity, 63, 3438-3441.

Evans-Pritchard, E.E. (1937). Witchcraft, oracles and magic among the Azande,
Publisher: Oxford: Clarendon Press.

Gelo, D. (1986). Comanche belief and ritual, Ann Arbor, Mich.: University Microfilms International.

Goldman, I. (1963). The Cubeo: Indians of the Northwest Amazon, Urbana, Illinois: University of Illinois Press.

Kuchar, G. (2001). Rhetoric, Anxiety, and the Pleasures of Cuckoldry in the Drama
of Ben Jonson and Thomas Middleton, Journal of Narrative Theory, 31 (1), Winter, pp. 1-30.

Mormann, K. (2010). Factors influencing parasite-related suppression of mating behavior in the isopod Caecidotea intermedius, Theses and Disserations, paper 48
http://via.library.depaul.edu/etd/48

Schmid, J., P.R. Hunter, G.C. White, A.K. Nand, and R.D. Cannon. (1995). Physiological traits associated with success of Candida albicans strains as commensal colonizers and pathogens, Journal of Clinical Microbiology, 33, 2920–2926.

Schmid, J., M. Rotman, B. Reed, C.L. Pierson, and D.R. Soll. (1993). Genetic similarity of Candida albicans strains from vaginitis patients and their partners, Journal of Clinical Microbiology, 31, 39-46.

The demon within

Candida albicans. Some strains have adapted to sexual transmission. Have they gone so far as to manipulate host behavior?

Vulvovaginal candidiasis (VVC), commonly known as vaginal yeast infection, affects 70-75% of sexually active women at least once and 5-8% recurrently (Li et al., 2008). It is usually caused by Candida albicans, a single-celled fungus that reproduces asexually.

Although C. albicans can colonize many body sites, some strains have specifically adapted to the vagina. This evolutionary trajectory seems to have gone through three levels of adaptation:

Adaptation to vaginal environments

Vaginally adapted strains are a small subset of C. albicans. In China, two strains account for almost 60% of all VVC cases, yet neither is present at extragenital sites (Li et al., 2008). In the United States, C. albicans strains are much more diverse in the male partners of women without VVC than in the vaginas of women with or without VVC (Schmid et al., 1993).

Adaptation to sexual transmission

These vaginal strains seem to have also adapted to sexual transmission, specifically female-to-male transmission. Once VVC develops, they can spread to the host’s male partner by colonizing his glans penis via vaginal intercourse (Li et al., 2008) or his oral cavity via cunnilingus (Schmid et al., 1995). Vagina-to-vagina transmission has also been attested in lesbian couples (Bailey et al., 2008).

There is evidence of genetic changes for sexual transmissibility. Vaginal strains adhere better to saliva-coated surfaces than do other strains (Schmid et al., 1995). In the male partner, they tend to displace non-vaginal strains of C. albicans (Schmid et al., 1993).

Adaptation to certain sexual behaviors

Although a relationship clearly exists between sexual behavior and VVC, it is not a simple one of cause and effect. This is the conclusion of two research teams, Hellberg et al. (1995) and Reed et al. (2003), who sought to identify those aspects of sexual behavior that correlate with VVC.

Hellberg et al. (1995) found no significant association between VVC and the main indicators of vaginal sexual activity: (1) frequency of vaginal sex; (2) history of multiple sexual partners (more than 10 lifetime partners); and (3) sex with more than one partner during the last six months.

There were, however, significant associations with (1) early age of first intercourse, (2) casual sex with previous unknown partners in the past month, (3) vaginal sex during menstruation, (4) oral sex (fellatio), and (5) receptive anal sex.

Reed et al. (2003) reported similar findings. VVC was not significantly associated with frequency of vaginal sex, lifetime number of partners, and duration of current relationship. But there were significant associations with cunnilingus in the past month and masturbation in the past month. Unlike Hellberg et al. (1995), there were no significant associations with early age of first intercourse or frequency of receptive anal sex.

Reed et al. (2003) also found two risk factors in the male partner: early age of first intercourse and masturbation in the past month. There were no significant associations with his marital status, lifetime number of partners, previous partners with VVC, personal history of yeast infections, or reported fellatio or cunnilingus in the past month.

This is all rather puzzling. Occurrence of VVC was related not to vaginal sex but rather to non-vaginal sex, i.e., fellatio, cunnilingus, and masturbation. Even more puzzling, Reed et al. (2003) failed to find any association between VVC and the presence of C. albicans in the male partner, including his oral cavity. The authors concluded that the relationship between VVC and sexual behavior is not primarily one of sexual transmission:

If the association between orogenital contact and recurrent Candida vulvovaginitis is not mediated by transmission of the organism, how might increased risk be conferred? Previous study of the immunopathogenesis of recurrent Candida vulvovaginitis suggests that a delicate equilibrium exists among C. albicans, vaginal bacterial flora, and vaginal defense mechanisms, and that changes in the host environment promote the transformation of C. albicans from a saprophytic to a pathogenic existence. We suggest that the effects of genital washing with saliva—from either the male or the female—might upset this balance […] (Reed et al., 2003)

But how would this vaginal equilibrium be upset by the woman fellating her male partner? And how would it be upset by her male partner masturbating—alone and by himself?

Manipulation of host behavior?

To make sense of all this, we should perhaps reverse the direction of causality. Perhaps some vaginal strains of C. albicans have reached a third level of adaptation, i.e., manipulation of host behavior to increase opportunities for sexual transmission. Perhaps they somehow weaken the host’s sexual inhibitions and incite her to maximize contact between her vaginal fluids and colonizable sites on her partner’s body.

Does this sound like science fiction? Keep in mind that parasites manipulate host behavior in many non-human animals, and some of these parasites are likewise fungi (see here). Moreover, C. albicans has evolved the ability to cross the blood-brain barrier and colonize sites in the human brain (Jong et al., 2001). According to an autopsy of macaque brains, this microbe can recognize different kinds of neural tissue:

An ex vivo adhesion assay was used to examine adhesion of Candida albicans yeast cells to brain tissue of the primate Macaca mulata. Tissues from frontal lobes and striatum (caudate, putamen, and portions of the globus pallidus) were used in the assay. Yeast cells adhered to gray matter at about six times the level of adhesion to white matter. The fungus was able to bind to different cell types within the cortex, basal ganglia, and white matter. (Denaro et al., 1995)

One can imagine a multi-stage process of development:

1. “Behavior-modifying” C. albicans colonizes the vagina as a commensal organism with low virulence and no VVC. The ensuing period of latency might last a long time.

2. Meanwhile, the microbe spreads to other sites within the host’s body, including certain areas of the brain that influence sexual behavior.

3. Once this secondary colonization is complete, the area of primary colonization enters a highly infectious stage, i.e., VVC. The microbe is now ready to spread to her sexual partner.

And how will it influence her partner’s behavior? We cannot find the answer by studying his behavior before and during VVC—as in current studies. We must examine his subsequent behavior, i.e., once this strain of C. albicans has spread to his body and replaced other strains. Are there any behavioral changes?

But, then, what sort of changes should we expect?

(to be cont’d)

References

Bailey, J.V., R. Benato, C. Owen, and J. Kavanagh. (2008). Vulvovaginal candidiasis in women who have sex with women, Sexually Transmitted Diseases, 35, 533–536

Brainwashed by a parasite, Neurophilosophy, August 9, 2007
http://scienceblogs.com/neurophilosophy/2007/08/brainwashed_by_a_parasite.php

Denaro, F.J., J.L. Lopez-Ribot, and W.L. Chaffin. (1995). Adhesion of Candida albicans to brain tissue of Macaca mulata in an ex vivo assay, Infection and Immunity, 63, 3438-3441

Hellberg, D., B. Zdolsek, S. Nilsson, and P-A. Mårdh. (1995). Sexual behavior of women with repeated episodes of vulvovaginal Candidiasis, European Journal of Epidemiology, 1, 575-579, 1995

Jong, A.Y., M.F. Stins, S-H. Huang, S.H.M. Chen, K.S. Kim. (2001). Traversal of Candida albicans across human blood-brain barrier in vitro, Infection and Immunity, 69, 4536-4544.

Li, J., S-R. Fan, X-P. Liu, D-M Li, Z-H. Nie, F. Li, H. Lin, W-M. Huang, L-L. Zong, J-G. Jin, H. Lei, and F-Y. Bai. (2008). Biased genotype distributions of Candida albicans strains associated with vulvovaginal candidosis and candidal balanoposthitis in China, Clinical Infectious Diseases, 47, 1119–25.

Reed, B.D., P. Zazove, C.L. Pierson, D.W. Gorenflo, and J. Horrocks. (2003). Candida transmission and sexual behaviors as risks for a repeat episode of Candida vulvovaginitis, Journal Of Women’s Health, 12, 979-989.

Schmid, J., P.R. Hunter, G.C. White, A.K. Nand, and R.D. Cannon. (1995). Physiological traits associated with success of Candida albicans strains as commensal colonizers and pathogens, Journal of Clinical Microbiology, 33, 2920–2926.

Schmid, J., M. Rotman, B. Reed, C.L. Pierson, and D.R. Soll. (1993). Genetic similarity of Candida albicans strains from vaginitis patients and their partners, Journal of Clinical Microbiology, 31, 39-46.