Sunday, October 27, 2019

Behavioral manipulation: population differences in virulence

Helicobacter pylori (Wikicommons – NIH). Some human populations have become resistant to this bacterium; others have not. Could the same be true for pathogens that manipulate human behavior?

Humans are behavioral creatures par excellence. Our brains oversee a large repertoire of behaviors, each of which is vulnerable to manipulation. We can be manipulated by psychological means, like the parasite who lives off the altruism of others.  There's also ideological manipulation. 

And then there's hardwired manipulation—an organism enters your mind and rewires some of its circuitry. That kind of manipulation is poorly known. We know a lot about short-term infections that make you sick. We know much less about long-term infections where the pathogen hangs around in your body without triggering an immune response. There’s no fever, no rash, no abscess. Yet it may be doing something to the most important organ of your body, perhaps to increase its chances of spreading to another host. Not surprisingly, the adverse effects become worse when you're no longer of much help. It no longer has anything to lose from trashing its host.

So if a pathogen is screwing with your mind, the symptoms will be especially severe in two cases: 

- You’re approaching the end of your life. The pathogen has less incentive to keep you healthy. You’re also less active socially and sexually, and thus less useful as a vehicle for transmission to other hosts.

- The pathogen is spreading out of its original host population and into new hosts that have not had time to develop resistance to its worse effects

This post is about the second case. You pay a cost when a pathogen monkeys around with your mental circuitry. Over time, there will be selection for humans who better resist such manipulation. Eventually, an equilibrium is reached: the pathogen still screws around with your mind, but the negative consequences are kept to a minimum. In most cases. And until it spreads to people who have no resistance.

The latter situation has been covered by a recent review article:

[...] the effects of susceptibility and virulence alleles in the respective gene pools of humans and pathogens are often contingent upon each other. The evolution of virulence is a dynamic process, easily perturbed by extrinsic variables over space and time, and therefore unlikely to follow the same trajectory in every population. [...] Whether the result is a steady-state equilibrium due to a perpetual "arms race" or a commensal detente, the same genes and pathways are unlikely to be involved in every population. As a consequence, when humans and pathogens migrate to new environments or admix, the ensuing disruption of co-evolutionary equilibria and loss of complementarity between host and pathogen genotypes may yield unpredictable and potentially deleterious biomedical consequences. (Kodaman et al. 2014)

The authors cite the example of Helicobacter pylori, a bacterium that lives in the stomach lining. It is a risk factor for gastric cancer, but the level of risk varies according to the population it infects:

Studies of human or H. pylori genetics in isolation have generally failed to explain why populations with similar rates of H. pylori infection exhibit strikingly different susceptibilities to gastric cancer. For example, in many African and South Asian countries, the low incidences of gastric cancer in the presence of almost universal rates of H. pylori infection remain a source of much speculation, and have been referred to collectively as the "African enigma" and the "Asian enigma" [...] In Latin America, where H. pylori strains native to Amerindian populations have been largely displaced by European strains [...], the predominantly Amerindian populations living at high altitudes suffer disproportionately from gastric cancer relative to other populations with similar infection rates [...]. These and other points of evidence raise the possibility that the pathogenicity of a given H. pylori strain may vary with human genomic variation, and that some individuals may be better adapted to their infecting strains than others. (Kodaman et al. 2014)

Manipulating sexual behavior

Pathogens thus differ in their virulence from one human population to another. The same should be true for those pathogens that manipulate human behavior to improve their chances of spreading from one human to another. For them, our most interesting behavior is sex, and the most interesting human populations are "leaky" polygynous ones with high rates of infidelity. In that kind of context they can spread rapidly from one household to another.

Polygyny rates are highest among the tropical farming peoples of sub-Saharan Africa (Dalton and Leung 2011; Pebley and Mbugua 1989). Traditionally, 20 to 40% of all marriages are polygynous, and most women live in polygynous households. Not surprisingly, many men, particularly young men, are single. Their opportunities for sex are limited to rape, affairs with the wives of other men, or abduction of women during times of war:

Typically, the more men are polygynous in a given society, the greater the age difference between husbands and wives. [...] 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)

Cuckold envy: a case of behavioral manipulation?

This is the environment in which a sexually transmitted pathogen can leapfrog from one polygynous household to another. The main obstacle is male jealousy and male "guarding behavior." The pathogen can increase its chances of transmission by disabling mate guarding or, better yet, reversing it. This kind of host manipulation has been shown in a non-human species: male isopods no longer guard their mates when they get infected by a certain parasite (Mormann, 2010).

In a human context, a pathogen may reverse male jealousy and make its host want to be cuckolded, as a means to gain access to more hosts (Frost 2013). Many sexual fetishes are mentioned in ancient writings: pedophilia, cunnilingus, fellatio, and bestiality, but not cuckold envy. The oldest mentions go back to seventeenth-century England (Kuchar, 2011, pp. 18-19).

Perhaps a sexually transmitted pathogen came to England from West Africa during the early days of the slave trade. Such a pathogen would have evolved in a context where most women were in polygynous marriages and where cuckoldry was the main route for invading one set of wives after another. Meanwhile, the human hosts may have evolved some kind of resistance, perhaps through “overwiring.” Or perhaps a certain level of cuckoldry became socially accepted. No such resistance, however, had evolved in England or elsewhere in the Western world.

As time goes on, we will discover that many STDs have evolved a capacity for behavioral manipulation, specifically by making the host either more promiscuous or less jealous.


Dalton, J.T., and T.C. Leung. (2011). Why is Polygyny More Prevalent in Western Africa?
An African Slave Trade Perspective,

Frost, P. (2013). First, sexual transmissibility and then …? Evo and Proud, January 5 

Kodaman, N., R.S. Sobota, R. Mera, B.G. Schneider, and S.M. Williams. (2014). Disrupted human-pathogen co-evolution: a model for disease. Frontiers in Genetics 25 August

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): 1-30.

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

Pebley, A. R., and W. Mbugua. (1989). Polygyny and Fertility in Sub-Saharan Africa. In R. J. Lesthaeghe (ed.), Reproduction and Social Organization in Sub-Saharan Africa, Berkeley: University of California Press, pp. 338-364.

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

Friday, October 18, 2019

I was really something

I was really something (2016), by Judith Carlin. A fungus may live in your brain for years while meddling only as much as necessary with your neurons. Beyond a certain age it gets less benefit and has less incentive to keep you mentally healthy. One result may be Alzheimer's.

Behavior manipulation has been perfected by many organisms: viruses, bacteria, worms, and insects. Fungi, however, seem to be the champions:

Fungi probably represent a special case study in this general field because of several unique factors peculiar to this Kingdom. The first and most prominent is the range and complexity of behavioral manipulation by fungi of arthropods. [...] It is difficult and perhaps futile to rank manipulation across different kingdoms of life and argue that fungal manipulation is more complex than that observed when the manipulator is in the Kingdom Animalia (eg, trematodes). However, what is clear is that the diversity of strategies is greater than that observed in other groups. In addition, it is evident that behavioral manipulation has arisen multiple times independently. (Hughes et al. 2016)

You've probably heard about "zombie ants." A fungus invades an ant's brain and makes it leave its nest, climb up a plant, and fix itself in place with its mandibles. The fungus then kills the ant, and a fruiting body sprouts from behind the ant's head and showers spores onto the forest floor below.

There are other examples. A fungus invades the body of a flying insect and causes a hole to form on the side of the abdomen. It then releases spores through that hole while its host is flying. The infected body gradually falls apart, except for its nervous system and its wings. Is the insect still alive? Not really. The bits and pieces that remain have become extensions of the fungus (Hughes et al. 2016).

Other fungi imitate the smell or visual appearance of a sexually receptive female to lure male insects, who then become infected (Hughes et al. 2016).

In the above cases, the fungus mutilates and kills its host in ways that are not only ghastly but also easy to observe and study. But what about the more subtle cases where the host's behavior is simply altered? Those are the ones we know much less about. Our knowledge is biased toward the most obvious cases of infection. As Greg Cochran observed:

The most conspicuous transmission chains occur when disease manifestations are externally apparent in a high proportion of infected individuals, when they occur soon after the onset of infection, and when contact between infected and susceptible individuals is easy to observe. Under these circumstances chains of transmission are apparent through everyday experience. (Cochran et al. 2000)

Even when we can detect the presence of a pathogen, the causal link with certain effects is far from obvious because the effects are either subtle or long-term:

Pathogens are often classified as relatively harmless or even commensal without sufficient long-term study to warrant such a classification. The historical record illustrates the consequences of this error. Epstein-Barr viruses and human papillomaviruses were once thought of as relatively harmless on the basis of their linkage to relatively benign diseases that occur soon after infection (infectious mononucleosis and warts respectively). But each virus can cause lethal cancers. Bacteroides was once thought to be a harmless commensal, but recent evidence indicates that it may be linked to ulcerative colitis. (Cochran et al. 2000)

Many slowly developing diseases are probably of pathogenic origin. This seems especially the case with various forms of senile dementia. The pathogen targets your brain and gains some benefit while you’re still socially and sexually active. At that stage, it’s living in a commensal relationship with you and confines its neuronal meddling to the minimum necessary. Beyond a certain age, however, it gets less benefit from you and has less incentive to keep you mentally healthy. One result may be Alzheimer's:

The possibility that Alzheimer's disease (AD) has a microbial aetiology has been proposed by several researchers. Here, we provide evidence that tissue from the central nervous system (CNS) of AD patients contain fungal cells and hyphae. Fungal material can be detected both intra- and extracellularly using specific antibodies against several fungi. Different brain regions including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus and choroid plexus contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi. Fungal infection is also observed in blood vessels, which may explain the vascular pathology frequently detected in AD patients. Sequencing of fungal DNA extracted from frozen CNS samples identifies several fungal species. Collectively, our findings provide compelling evidence for the existence of fungal infection in the CNS from AD patients, but not in control individuals. (Pisa et al. 2015)

Alzheimer's is a late onset disease. What is the fungus doing to your brain during the long time when you’re not mentally impaired? 

Another example may be multiple sclerosis:

Many biomarkers of MS are consistent with fungal infections, such as IL-17, chitotriosidase, and antibodies against fungi. Dimethyl fumarate (DMF), first used as an industrial fungicide, was recently repurposed to reduce MS symptoms. Its mechanisms of action in MS have not been firmly established. The low risk of MS during childhood and its moderate association with herpes simplex virus type 2 suggest genital exposure to microbes (including fungi) should be investigated as a possible trigger. (Benito-Leon and Laurence 2017)


Benito-Leon, J. and M. Laurence. (2017). The Role of Fungi in the Etiology of Multiple Sclerosis. Frontiers in Neurology 16 October

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

Hughes, D.P., J.P.M. Araujo, R.G. Loreto, L. Quevillon, C. de Bekker, and H.C. Evans. (2016). Chapter Eleven - From So Simple a Beginning: The Evolution of Behavioral Manipulation by Fungi. Advances in Genetics 94: 437-469.

Pisa, D., R. Alonso, A. Rabano, and I. Rodal. (2015). Different Brain Regions are Infected with Fungi in Alzheimer's Disease. Scientific Reports 5(15015) 

Thursday, October 10, 2019

Is this the Gay Germ? Part II

Courtyard with Lunatics, Francisco Goya (1746-1828). Why is HIV much more likely to cause cognitive impairment in the body of a gay man than in the body of an intravenous drug user? Has an unknown pathogen been caught in the dragnet of AIDS studies?

My last post focused on certain discrepancies in data on AIDS victims: as antiretroviral therapy becomes more widespread, there has been a decline in opportunistic infections, but the decline hasn't been the same for all pathogens. In particular, some brain infections have shown modest declines or no change at all. 

Has an unknown pathogen been caught in the dragnet of AIDS studies? This pathogen would coexist with HIV only because it, too, is associated with the gay lifestyle. It would not be a "cofactor" that makes the HIV infection worse. In fact, it probably precedes the HIV infection by many years. This unknown pathogen may target certain sites in the brain of its host early in life in order to change his sexual orientation and thereby increase its chances of transmission to another host. It thereafter remains in the background until its host has reached an age when he ceases to be useful. The pathogen is then no longer penalized if it causes damage to surrounding neural tissues. Various neurocognitive disorders could therefore develop in its host from late middle age onward.

AIDS in gay men and intravenous drug users

This post will focus on discrepancies in data from two other papers. The first one is a study of AIDS victims in the Italian city of Bologna. Some of them contracted AIDS via homosexual/bisexual behavior, and some via intravenous drug use. One finding strikes me as unusual: "Compared with injecting drug users, homosexual/bisexual and heterosexual participants had ORs of 9.6 (95% CI, 2.2-42.7) and 6.3 (95% CI, 2.2-18.3), respectively, for cognitive impairment" (De Ronchi et al. 2002).

In other words, when the researchers looked at AIDS victims, they found that cognitive impairment was ten times more strongly associated with homosexuality/bisexuality than with intravenous drug use. That finding is curious because the ratio of ten to one doesn't correspond at all to the ratio of homosexuals/bisexuals to intravenous drug users among Italian AIDS cases. In fact, intravenous drug users made up about 60% of those cases in 1997 (Wikipedia 2019). The Bologna study took place between 1994 and 1997.

Why is HIV much more likely to cause cognitive impairment in the body of a gay man than in the body of an intravenous drug user? Do druggies take better care of their mental health? The evidence actually suggests the reverse: HIV-associated dementia seems to progress more rapidly in intravenous drug users (Bouwman et al. 1998). The latter finding also points to a qualitative difference between the two groups: dementia seems to develop more slowly in gay men.


The second paper is a review of studies on HAND [HIV-associated neurocognitive disorders]. It notes that HAND can develop even in individuals on HAART [Highly active antiretroviral therapy] with no detectable traces of HIV:

Furthermore, 21% [of individuals in the CHARTER study] developed HAND despite effective HAART (although the precise number who were aviremic is unclear). Similarly, in a cohort of individuals with AIDS, 21% of aviremic individuals (who also had undetectable CSF HIV RNA) progressed to HAD [HIV-associated dementia]. A third prospective study also identified HAND in 8-34% (depending on the time point of the assessment) of aviremic patients without comorbidities and with a nadir CD4 cell count less than 200 cells/µl (McArthur and Brew 2010)

The authors suggest that HIV can produce irreversible neural damage that becomes noticeable only much later in life. Well, perhaps. Nonetheless, it seems to me more parsimonious to postulate a second pathogen.

Parting thoughts

Clearly, HIV does cause cognitive impairment. The Bologna study showed a strong association between HAND and low white cell counts. But it looks like a certain proportion of HANDs are due to a cause that exists independently of HIV infection.

Please note: I'm not arguing that HIV is interacting with an unknown pathogen to cause cognitive impairment. I am arguing that these two pathogens impair cognition independently of each other and in different ways. They share only one thing in common: they have a much higher incidence among gay men than in the general population.

Finally, I'm not arguing that this unknown pathogen is the only cause of male homosexuality. There are likely multiple causes. In a nutshell, male homosexuality seems to be due to a genetic predisposition interacting with something in the environment. The genetic predisposition is a smaller-than-average neuronal population that promotes a heterosexual orientation. Normally, natural selection keeps it from falling below the threshold needed to sustain attraction to women. Certain environmental agents, however, can cause this neuronal population to fall below the threshold: fraternal birth order effects, stressful events during pregnancy, exposure to environmental estrogens during childhood, and, yes, a pathogen.

I don't know whether my views on the "gay germ theory" are consistent with Greg Cochran's. I hope he will deign to provide his comments.


Bouwman, F., R. Skolasky, D. Hes, O. Selnes, J. Glass, T. Nance-Sproson, W. Royal, G. Dal Pan,  and J. McArthur. (1998). Variable progression of HIV-associated dementia. Neurology 50(6): 1814-1820. 

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

De Ronchi, D., I. Faranca, D. Berardi, et al. (2002). Risk Factors for Cognitive Impairment in HIV-1-Infected Persons with Different Risk Behaviors. Archives of Neurology 59(5): 812-818.

McArthur, J.C., and B.J. Brew. (2010). HIV-associated neurocognitive disorders: is there a hidden epidemic? AIDS 24(9): 1367-1370|aidsonline:2010:06010:00017|| 

Wikipedia (2019). HIV/AIDS Public Health Campaigns in Italy

Wednesday, October 2, 2019

Is this the Gay Germ?

Poster for 1997 World AIDS Day (Wikicommons - Neil Curtis, Christian Michelides). Antiretroviral therapy has reduced infections in AIDS victims, but the decline hasn't been the same for all pathogens. Some infections have shown modest declines or no change at all. Could they be due to the "gay germ"?

Male homosexuality has low to moderate heritability (30 to 45%). A recent study in the UK Biobank and 23andMe has identified a number of genetic variants associated with same-sex sexual behavior. Together, they account for 8 to 25% of variation in male and female same-sex behavior (Ganna et al. 2019). There is thus a genetic predisposition, but it's weak and may simply reflect a smaller population of neurons for heterosexual orientation.

So this genetic predisposition seems to be interacting with something in the environment. But what?

There may be different environmental factors. One possibility would be a pathogen that alters its host's sexual orientation in order to enhance its chances of spreading to other hosts. This is Greg Cochran's "gay germ" theory (Cochran et al. 2000).

With the introduction of antiretroviral therapy for AIDS, we may have a chance to identify candidates for the "gay germ." Over time this therapy should reduce the incidence of infections in AIDS victims. Indeed it has, but the decline has been uneven.  A retrospective study of AIDS autopsies in Vienna between 1984 and 1999 found a lower rate of decline for infections due to fungi and most bacteria than for infections due to protozoa, viruses, and mycobacteria:

Extracerebral protozoal (Pneumocystis carinii, toxoplasmosis), Mycobacterium avium complex, viral [e.g., cytomegalovirus (CMV)], multiple opportunistic organ and CNS infections, and Kaposi sarcoma significantly decreased over time. There was less decrease in fungal infections, while bacterial organ and CNS infections (except for mycobacteriosis), lymphomas, HIV-associated CNS lesions (around 30%), non HIV-associated changes (vascular, metabolic, etc.) and negative CNS findings (10-11%) remained unchanged. (Jellinger et al. 2000)

These findings are in line with those of a retrospective study of AIDS autopsies in San Diego between 1982 and 1998:

Pneumocystis carinii pneumonia and Mycobacterium avium complex decreased, whereas bacterial infections increased and the frequency of fungal infection remained unchanged over time. (Eliezer et al. 2000)

After the lungs, such pathogens most often target the brain:

This study suggests that despite the beneficial effects of antiretroviral and anti-opportunistic infection therapy, involvement of the brain by HIV continues to be a frequent autopsy finding. (Eliezer et al. 2000).

Similar to a recent autopsy study from San Diego, these data suggest that despite the beneficial effects of modern antiretroviral combination therapy, involvement of the brain in AIDS subjects continues to be a frequent autopsy finding. (Jellinger et al. 2000)

Subjects with brain alterations at an early stage otherwise seemed almost normal:

Of the cases with early brain alterations, systemic opportunistic infections were present in only 5.9% of the cases, neoplasms in 0.5%, and neoplasms and opportunistic infections in 1.7%. (Eliezer et al. 2000)

A few caveats

The change in incidence over time partly reflects differences between fast-developing infections and slow-developing ones. By definition, people succumb more quickly to the former than to the latter. When antiretroviral therapy was still unavailable those infections were the ones that generally killed people with AIDS. Better control of aggressive infections may have also created a better environment for the growth of less aggressive infections.

But ...

It is harder to explain why the brain should remain a major pathogenic target. It is especially hard to explain why subjects with brain alterations at an early stage otherwise seemed almost normal.

Eggers et al. (2017) pointed out another apparent contradiction: HIV-associated neurocognitive disorders (HAND) are continuing to develop in people whose HIV infection is under control.

Despite the brain infection taking place in the days after primary infection, the development of HAND takes years. As an explanation for this ostensible contradiction, it has been suggested that initially, the brain infection is relatively well controlled, while later, there is a quantitative and qualitative breakdown of immune control in the CNS (Eggers et al. 2017)

Some authors have suggested co-infection by the Hepatitis C virus, but Eggers et al. (2017) ruled this out:

While some authors implicated HCV co-infection in the pathogenesis of HAND, a recent large and well-controlled study found no evidence for worse cognitive function in HCV co-infected patients, at least in the absence of liver dysfunction. (Eggers et al. 2017)

Pathogen "X"

Could we be looking at an unknown pathogen that exists independently of HIV? Over the years some have suggested that HIV is not the only pathogen involved in AIDS. In this case, pathogen "X" may cause adverse effects that get blamed on HIV, but its relationship with HIV is incidental, the only common denominator being the gay lifestyle.

I would propose the following scenario. Pathogen "X" enters its host early in life, just in time to alter that person's psychosexual development. From then on it remains in the background and reaps whatever benefit it gets from its behavior manipulation. Past the age of 40 the host becomes less useful, and the pathogen begins to cause more adverse effects, including neurocognitive disorders that are wrongly attributed to HIV.

Pathogen "X" is most likely a fungus. If we go back to the two retrospective studies, the fungal infections were the ones that seemed the least influenced by the introduction of antiretroviral therapy.


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

Eggers, C., G. Arendt, K. Hahn, K., I.W. Husstedt, M. Mashke, et al. (2017). HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment. Journal of Neurology 264: 1715-1727

Eliezer, M., R.M. DeTeresa, M.E. Mallory, and L.A. Hansen. (2000). Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 14(1): 69-74.

Ganna, A., K.J.H. Verweij, M.C. Nivard, R. Maier, R. Weddow, et al. (2019). Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior. Science 365(6456) 

Jellinger, K.A., U. Setinek, M. Drlicek, G. Böhm, A. Steurer, and F. Lintner. (2000). Neuropathology and general autopsy findings in AIDS during the last 15 years. Acta Neuropathologica 100(2): 213-220.