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.
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 http://via.library.depaul.edu/etd/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.
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)
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. https://www.sciencedirect.com/science/article/abs/pii/S0065266016300049
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) https://www.nature.com/articles/srep15015
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.
HAND and HAART
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.
References
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. https://insights.ovid.com/article/00006114-199806000-00048
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.
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 https://link.springer.com/article/10.1007/s00415-017-8503-2
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) https://science.sciencemag.org/content/365/6456/eaat7693
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. https://www.ncbi.nlm.nih.gov/pubmed/10963370
