Some infectious diseases are particularly difficult to treat because of their ability to evade the immune system. One such illness, African sleeping sickness, is caused by the parasite Trypanosoma brucei, transmitted by the tsetse fly, and is fatal if left untreated. The trypanosome parasite is transmitted to mammals through fly bites and eventually invades major organs such as the brain, disrupting the sleep cycle, among other symptoms.
Trypanosomes exist in different forms. When inhabiting a fly, they are covered with proteins called procyclins. But upon entering the bloodstream of a mammal, they acquire a dense layer of glycoproteins that continually change, allowing the parasite to dodge an attack from the host’s immune system.
Now, new research reveals a method to manipulate trypanosomes in the mammalian bloodstream to acquire fly stage characteristics, a state that makes it easier for the host immune system to eliminate the invader.
The findings suggest that inhibiting specific proteins that interact with chromatin—the mass of DNA and proteins that packages a cell’s genetic information—can “trick” the parasite into differentiating to a different stage of its lifecycle. The study was published on December 8 in PLOS Biology.
Regulatory proteins interact with chromatin to either unwind it or package it more tightly, affecting which genes are expressed. Some of these regulatory proteins contain a region called the bromodomain, which recognizes a specific signal on chromatin and induces changes in gene expression.
Recent findings in mice have indicated that bromodomains are involved in cell differentiation, which led researchers to hypothesize that such epigenetic mechanisms may drive the trypanosome to change from one form to another.
The researchers inhibited bromodomain proteins in cells by introducing genetic mutations in their DNA or by exposing the cells to a small-molecule drug called I-BET151, which is known to block bromodomains in mammals. When these perturbations were made, the investigators observed changes in gene expression levels that resembled those seen in cells differentiating from the bloodstream form to the fly form. They also saw that the parasites developed a procyclin coat normally found on the fly form.
To explore whether I-BET151 could be used to combat the disease, the researchers used drug-treated trypanosomes to infect mice. The mice infected with drug-treated trypanosomes survived significantly longer than those infected with untreated trypanosomes, indicating that the virulence of the parasite—its ability to invade the host—was diminished in the presence of I-BET151.
Based on these findings, researchers suggest that proteins with bromodomains maintain the bloodstream form of trypanosomes, and inhibiting them causes the parasite to progress in its development toward the fly form. They believe bromodomains could serve as a potential therapeutic target to treat African sleeping sickness.