You are what you're infected with?

Rats infected with the parasite Toxoplasma gondii do crazy things.  They find the scent of cat urine sexy and attractive, they don't run from the actual beasts; they are more active in running wheels, which might indicate that the parasite induces increased activity which may more readily attract a cat's attention. When an infected rat is eaten by a cat, the T. gondii is passed on in the cat's feces to infect again.  T. gondii can only reproduce inside the cat.  Great survival strategy on the part of the parasite, this trick of making the rat no longer fear cats -- now that's really building a better mouse-trap! Did this strategy evolve by adaptive selection, or is it just something that happened?

Czech biologist, Jaroslav Flegr, thinks T. gondii infections do much the same to humans -- his story is told in the March 2012 Atlantic Monthly.  Toxoplasmosis, the infection caused by T. gondii, infects a significant segment of the world's population -- perhaps 20% of Americans, but 55% of French people are infected, probably because the French diet includes more rare or raw meat than the American diet.  The usual mode of transmission is from a member of the cat family to another warm-blooded animal via ingestion of feces from an infected cat, but raw or rare meat can be another source.  It can also be transmitted from mother to fetus, and can result in serious complications in an infected fetus, including stillbirth.  This is why pregnant women are told to avoid litter boxes.

Infection has long been supposed to cause mild flu-like symptoms in otherwise healthy individuals, but then it was assumed that the parasite lay dormant in cysts sequestered away inside brain cells.  People with weakened immunity were at greater risk, however; in the days before antiretroviral drugs for treating HIV, toxoplasmosis infections are thought to have caused much of the dementia in patients with end-stage AIDS.

But maybe the parasite actually does more damage than has been thought.

...if Flegr is right, the “latent” parasite may be quietly tweaking the connections between our neurons, changing our response to frightening situations, our trust in others, how outgoing we are, and even our preference for certain scents. And that’s not all. He also believes that the organism contributes to car crashes, suicides, and mental disorders such as schizophrenia. When you add up all the different ways it can harm us, says Flegr, “Toxoplasma might even kill as many people as malaria, or at least a million people a year.” 

Flegr's hypothesis comes directly from his own experience.  He wondered for years why he was willing to take risks that others wouldn't, like crossing a street in the middle of traffic, or speaking out against communism in Communist Czechoslovakia.  Entirely by fluke, he was tested for T. gondii by someone in his institution looking for infected people to study a diagnostic kit they were developing, and he was discovered to be positive. To him, this explained his bizarre risk-taking behavior.

He reasons that T. gondii is not the only parasite that affects behavior.  The rabies virus incites fury in infected animals, ensuring that they bite others, and thus pass on the infection.  Ants infected with parasitic Cordyceps fungi do all kinds of bizarre, self-destructive things, including climbing onto a blade of grass and then clamping on with their mandibles. Soon the fungus consumes the ant's brain, and fungal fruiting bodies sprout from the ant's head (as in the video) and burst, releasing spores into the air, to settle and find a home in another unsuspecting, soon to be robotic ant. Apparently the Cordyceps fungi release chemicals that change an ant's pheromone reception, which alters their sense of navigation. Is this coincidence, not specific enough to have evolved per se?  Or is it a specific adaptation?



Another example of zombie ants involves infection by the lancet liver fluke, Dicrocoelium dendriticum.  When infected, the ant again climbs onto a blade of grass where it clamps on, there to be eaten by a grazing sheep or cow.  The ant does this only in the evening, when the air cools, and if it survives the night uneaten, it climbs down and behaves normally again until the following evening, when the fluke regains control. Again, this is remarkable, but it is it specific enough and frequent enough to be a Darwinian adaptation?  And what's in it for the poor manipulated ant? 

Things that seem (to human observers) so bizarre probably would be expected to have a balance, or else the victim species would have evolved resistance.  So many questions are raised by these examples.  And there are many more like them. 

But in any case, parasite-induced behavior changes are not unprecedented.  Could T. gondii really do the same?

In the Soviet-stunted economy, animal studies were way beyond Flegr’s research budget. But fortunately for him, 30 to 40 percent of Czechs had the latent form of the disease, so plenty of students were available “to serve as very cheap experimental animals.” He began by giving them and their parasite-free peers standardized personality tests—an inexpensive, if somewhat crude, method of measuring differences between the groups. In addition, he used a computer-based test to assess the reaction times of participants, who were instructed to press a button as soon as a white square popped up anywhere against the dark background of the monitor.

The subjects who tested positive for the parasite had significantly delayed reaction times. Flegr was especially surprised to learn, though, that the protozoan appeared to cause many sex-specific changes in personality. Compared with uninfected men, males who had the parasite were more introverted, suspicious, oblivious to other people’s opinions of them, and inclined to disregard rules. Infected women, on the other hand, presented in exactly the opposite way: they were more outgoing, trusting, image-conscious, and rule-abiding than uninfected women.

Flegr confirmed these surprising findings with further research, finding that infected men were suspicious, sloppy dressers, and introverted, while infected women were well-dressed and gregarious.  Reaction times of infected people were considerably slower than uninfected, and he found that they were 2 1/2 times more likely to be in traffic accidents -- this statistic has been replicated in other countries.  Flegr says that the personality changes are generally subtle, only detectable on a statistical basis.  But, it turns out that a fairly substantial percentage of people diagnosed with schizophrenia are T. gondii positive. 



What's the mechanism? 

Many schizophrenia patients show shrinkage in parts of their cerebral cortex, and Flegr thinks the protozoan may be to blame for that. He hands me a recently published paper on the topic that he co-authored with colleagues at Charles University, including a psychiatrist named Jiri Horacek. Twelve of 44 schizophrenia patients who underwent MRI scans, the team found, had reduced gray matter in the brain—and the decrease occurred almost exclusively in those who tested positive for T. gondii.

That's not clearly a mechanism, however, as the shrinkage could be entirely unrelated to schizophrenia.  Indeed, since only 1/4 of the patients tested showed reduced gray matter.  Anything more convincing?

Apparently, sequencing of the T. gondii genome suggests that it has 2 genes that can make the infected animal increase production of dopamine, and elevated dopamine levels are a mark of schizophrenia. Infection also, apparently, increases the infected animal's gregariousness, and in humans, increases sociability -- even infection with the influenza virus.  Infection can, apparently, even increase a person's (or a rat's) sex drive, and because many of these infections can be transmitted sexually, this improves their chances of being passed on.  This relates to any kind of infection that has been tested, not just T. gondii.

As it turns out, schizophrenia has been associated with a number of infections ("maternal rubella (German measles), influenza, Varicella zoster (chicken pox), Herpes (HSV-2), common cold infection with fever, or poliovirus infection while in childhood or adulthood, coxsackie virus infection (in neonates) or Lyme disease (vectored by the Ixodes tick and Borrelia Burgdorferri) or Toxoplasmosis" -- from a 2011 paper by C.J. Carter), and in fact, while genomewide association studies haven't found genes with major effects, or reliably replicated what they have found, for schizophrenia, itself, they have found 600 genes with small effect, many associated with inflammatory response, others implicated in the life cycle of the associated pathogens.  The same paper suggests that:

Schizophrenia may thus be a “pathogenetic” autoimmune disorder, caused by pathogens, genes, and the immune system acting together, and perhaps preventable by pathogen elimination, or curable by the removal of culpable antibodies and antigens.

That is, the authors suggest that the susceptibility genes code for proteins that are homologous to the pathogen's proteins, and that the latter might be intermingling or replacing endogenous proteins, and they are different enough to disrupt normal function, and lead to disease.

Pathogens' proteins may act as dummy ligands, decoy receptors, or via interactome interference. Many such proteins are immunogenic suggesting that antibody mediated knockdown of multiple schizophrenia gene products could contribute to the disease, explaining the immune activation in the brain and lymphocytes in schizophrenia, and the preponderance of immune-related gene variants in the schizophrenia genome. 

Further,

All of the pathogens implicated in schizophrenia express proteins with homology to multiple schizophrenia susceptibility gene products. The profile of each individual pathogen is again specific for different types of gene product, but all target key members of the schizophrenia network including dopamine, serotonin and glutamate receptors as well as neuregulin and growth-related or DISC1 related pathways.

So, the idea is that our genomes, our particular DNA variants, determine which human/viral matches we carry, and thus which pathogens we're susceptible to damage from.  So, in that sense, Carter, and others, suggest, schizophrenia and other behavioral disorders may be 'genetic', but environmental exposures, our vaccination history and so on determine the pathogens we might be infected with, and our immune system determines how we respond.

To be sure, these are statistical findings and there are so many genes associated with schizophrenia -- or perhaps more accurately so many genes not clearly but weakly, possibly, maybe, but not replicably associated, that it is possible one could almost always find some potential association with these pathways.  That makes it hard to evaluate the infectious scenario.

One clear point, though, is that even when what we are is genetic, the genes need not be those we were born with.  Bacteria, and hence their genes are vital to our survival and that appears just to be for starters.  When parasites affect our gene expression or function, their genomes become part of ours.  And from a biological point of view, our genetic battle for persistence -- for staying alive -- may have more to do with microbial challenges than with wearing out, which is basically what many GWAS targets are about (cancer, diabetes, etc.)

Even more important, perhaps, and a hint that we need to pay more attention to, is that many GWA kinds of studies are finding genes in immune-related systems, or those related to 'inflammation' for what appeared to be totally non-infectious and non-behavioral diseases, even including diabetes, intestinal disorders, retinal disorders of the eye, and many others.  These would be genetic in the sense that genetic susceptibility is involved, but not in the sense of intrinsically harmful genetic variants.

Is this behavioral parasite work definitive?  Do we now know that schizophrenia, and other disorders, are infectious in origin?  No.  Many questions have yet to be answered.  Maternal or early childhood exposure seem to be associated with risk, but why does schizophrenia have such a relatively late age of onset, given early age of exposure?  And why so stereotypically in late adolescence?  And so on.

But, it's intriguing that many GWAS have found an albeit small proportion of risk of many diseases explained by immune genes.