How some trypanosomes cause sleeping sickness while others don't

Protozoan parasite increases risk of colitis, study reveals

Researchers from the University of Toronto have discovered that mice infected with the common gut parasite Tritrichomonas muris are at an increased risk of developing inflammatory colitis. Their findings, which have been published online in The Journal of Experimental Medicine, expand the type of gut-resident microorganism that can affect the health of their host and suggest that related parasites may cause gastrointestinal disease in humans.

In recent years, researchers have discovered that the trillions of bacteria that reside in the gastrointestinal tract have an enormous impact on human health and disease. But the effects of other types of microorganisms that live in the gut, such as the unicellular eukaryotes known as protozoans, are less well understood. Though some protozoan species, which are part of the protist kingdom of life, cause diseases like malaria and leishmaniasis, the protozoa that commonly live in the gut are generally thought to be harmless.

While studying the inflammatory mechanisms underlying colitis in rodents, a team of researchers led by Dana Philpott and Thierry Mallevaey realized that their laboratory mice were more susceptible to developing the disease if their intestines were already infected with the protozoan Tritrichomonas muris. This parasite is commonly found in the intestines of mice, and the researchers observed that its presence raised the levels of pro-inflammatory T cells and cytokines in the host animal's gut. These inflammatory factors may "prime" the intestinal tissue to become inflamed, leaving it more susceptible to colitis.

A recent study published in Cell revealed that, while the related parasite Tritrichomonas musculis makes the intestine susceptible to both colitis and colorectal cancer, it induces an immune response that protects mice against Salmonella infection. This may be why host animals tolerate protozoans such as T. muris living in their intestines. Several species of protozoa reside in the human gut, and some of them are prevalent in patients with gastrointestinal disease, suggesting that similar host-parasite interactions could affect human health. "Our findings highlight the need for a better understanding of cross-kingdom interactions between host and protozoa within the gastrointestinal tract," says Philpott.

How some trypanosomes cause sleeping sickness while others don't

Trypanosome parasites transmitted by tsetse flies cause devastating diseases in humans and livestock. Different subspecies infect different hosts: Trypanosoma brucei brucei infects cattle but is non-infectious to humans, whereas T. b. gambiense and T. b. rhodesiense cause sleeping sickness in humans. A study published on May 15th in PLOS Pathogens reveals how humans can fight off some trypanosomes but not others.

Sam Alsford, from the London School of Hygiene and Tropical Medicine, UK, and colleagues, undertook a comprehensive search for genes that make T. b. brucei sensitive to the innate (the first-line, non-specific) defenses of the human immune system. The hope is that understanding the molecular basis of sensitivity would enable the development of strategies to sensitize resistant trypanosome subspecies. And new drugs are badly needed because existing ones have serious side effects.

The researchers systematically inactivated T. b. brucei genes and looked for parasites which could survive exposure to human blood serum (factors in which can kill this subspecies, making it harmless to humans). Three genes thought to sensitize T. b. brucei to human defenses had been previously identified by other methods, and the researchers re-discovered all three -- plus they found a previously unknown fourth gene in this study.

One of the known genes codes for a protein called inhibitor of cysteine peptidase (or ICP), and the researchers further analyzed its role. Using chemical and genetic approaches, they show that ICP sensitizes T. b. brucei to human serum by dampening the activity of a specific cysteine peptidase (a protein that can cut other proteins) called CATL. In the absence of ICP, CATL is fully active and can counteract components of human serum responsible for killing trypanosomes.

Discussing the findings, Alsford commented: "CATL is under consideration as a potential drug target, and our results suggest that its inactivation could indeed support the human defense system in fighting off disease-causing trypanosome strains. However, as CATL might also be involved in the generation or break-down of other factors involved in parasite-host interactions, it will be important to develop an improved understanding of the complex interplay of all of these factors in human-infective trypanosomes."

The researchers also plan work on the new (fourth) gene they discovered. It codes for a protein that appears to be a so-called transmembrane channel. Studying this channel (which is likely to be involved in the uptake of human defense factors by the parasite) should further improve the understanding of the interaction between the parasite and the anti-trypanosomal components of human serum.