There are many examples of infectious agents that are capable of modifying the behavior of their host organism. Pathogens typically co-opt their host in ways that create an opportunity to spread into another host. For example, the rabies virus is transmitted through saliva, so the virus transforms its host into an unusually aggressive beast that is prone to bite other animals.
The single-celled parasite known as Toxoplasma gondii is another clever puppeteer of its host. Rodents infected with this microbe not only lose their fear of cats, but also become sexually attracted to cat odors, transforming them into easy prey for their feline predator. The startling twist in this tale is that cats are the only known species in which the Toxoplasma parasite can undergo the sexual stage of its life cycle.
But that is only the beginning of Toxoplasma’s impressive reach. The parasite can infect any warm-blooded animal, including humans. The CDC estimates that one fourth of Americans are infected, carrying this parasite in their brain as a latent tissue cyst. Given the sheer number of people infected, the discovery that Toxoplasma also alters human behavior would have profound implications. But this is a very challenging question to address and the evidence to support the idea is only correlative to date.
Working in a cell-based culture system, researchers have been able to confirm that cells infected with the Toxoplasma parasite exhibit dramatic changes in gene expression. The parasite appears to modulate host gene expression through the activities of secreted proteins that it injects into the host cell. Toxoplasma can bewitch its host cell to arrest the cell cycle, block apoptosis, or, in the case of certain immune cells, cause them to become motile, thereby helping the parasite disseminate throughout the body.
So how might Toxoplasma hijack the host cell to do the parasite’s bidding? It has been shown that some of these parasite-secreted proteins alter signal transduction cascades that ultimately change gene expression, presumably through an epigenetic component. Recent studies lend support to this idea by showing how Toxoplasma infection has the potential to alter both DNA histone, modifications that repress or activate genes, respectively.and
In a 2014 study, Hari Dass and Vyas noted diminished DNA methylation of the arginine vasopressin promoter in the medial amygdala of infected male rats, which may contribute to the loss of fear in response to cat odors. Interestingly, the aversion to cat odors in infected rats can be reversed with systemic hypermethylation.
Our recent studies of cortical astrocytes demonstrate that host histones become differentially acetylated upon Toxoplasma infection, undoubtedly contributing to changes in host cell gene expression. However, histones were just one protein group of many found to be acetylated differently in Toxoplasma-infected astrocytes. These findings are consistent with earlier studies showing that mRNA levels for several histone acetyltransferases (HATs) and histone deacetylases (HDACs) are altered in Toxoplasma-infected cells. The ability of Toxoplasma to alter the acetylation profile of brain cells provides another possible method the parasite may use to manipulate its host.
If Toxoplasma reprograms the host genome by commandeering the epigenetic machinery, then treatment of infected cells with inhibitors of chromatin remodeling machinery should be detrimental to parasite propagation. Several studies have shown this to be the case. In fact, the HDAC inhibitor apicidin was first described in 1996 as a potent anti-protozoal agent that had broad-spectrum activity against parasites in the phylum Apicomplexa (this includes Toxoplasma, Cryptosporidium, and Plasmodium (malaria), just to name a few). The compound, which was isolated from fermentations of a Costa Rican fungus, received its name because it kills (is CIDAL) APIcomplexan parasites. While apicidin has activity against a parasite HDAC, it could also be acting on HDACs belonging to the host cell. HDAC inhibitors that lack specificity may be a double-whammy for the parasitic invader: not only could parasite-mediated epigenetic changes be reversed in the host cell, but parasite epigenetics could also be disrupted.
You can read more about the Toxoplasma parasite and how it alters host behavior in the March 2015 issue of Scientific American MIND. Ongoing research will eventually illuminate how the parasite alters its host at the epigenetic level and if such changes translate into behavioral anomalies that can be reversed.
- Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, Cannova C, Meinke PT, Colletti SL, Bednarek MA, Singh SB, Goetz MA, Dombrowski AW, Polishook JD, Schmatz DM. Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13143-7.
- Hari Dass SA, Vyas A. Toxoplasma gondii infection reduces predator aversion in rats through epigenetic modulation in the host medial amygdala. Mol Ecol. 2014 Dec;23(24):6114-22. doi: 10.1111/mec.12888. Epub 2014 Sep 16.
- McConkey GA, Martin HL, Bristow GC, Webster JP. Toxoplasma gondii infection and behaviour – location, location, location? J Exp Biol. 2013 Jan 1;216(Pt 1):113-9. doi: 10.1242/jeb.074153. Review.
- Bougdour A, Tardieux I, Hakimi MA. Toxoplasma exports dense granule proteins beyond the vacuole to the host cell nucleus and rewires the host genome expression. Cell Microbiol. 2014 Mar;16(3):334-43. doi: 10.1111/cmi.12255. Epub 2014 Jan 20. Review.
- Bouchut A, Chawla AR, Jeffers V, Hudmon A, Sullivan WJ Jr. Proteome-Wide Lysine Acetylation in Cortical Astrocytes and Alterations That Occur during Infection with Brain Parasite Toxoplasma gondii. PLoS One. 2015 Mar 18;10(3):e0117966. doi: 10.1371/journal.pone.0117966. eCollection 2015.