Infectious diseases that have the ability to evade the immune system are quite difficult to treat. One such disease is the African sleeping sickness. It is caused by the parasite Trypanosoma brucei and is transmitted by the tsetse fly. The parasite gets transmitted to mammals through fly bites. If left untreated for prolonged period the disease can get fatal as it invades major organs such as the brain, disrupting the sleep cycle, among other symptoms.
There are different forms of trypanosomes. When they house themselves in a fly, they are covered with proteins called procyclins. Once they enter the bloodstream of a mammal, they acquire a dense layer of glycoproteins that continually change, which enables the parasite to dodge an attack from the host’s immune system.
Postdoctoral scientists Danae Schulz and Erik Debler, working in Nina Papavasiliou’s and GÃ¼nter Blobel’s labs at Rockefeller University have innovated 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 details of the study were published recently in PLOS Biology. Their findings suggest that by inhibiting specific proteins that interact with chromatinthe mass of DNA and proteins that packages a cell’s genetic informationcan trick the parasite into differentiating to a different stage of its lifecycle.
Nina Papavasiliou, head of the Laboratory of Lymphocyte Biology said that when these chromatin-interacting proteins are blocked, the parasite becomes visible to the immune system. Since, the bloodstream form of the parasite constantly switches protein coats to evade the immune, this new method works as it makes the parasite think it’s in the fly, where it doesn’t need to worry about the immune system attacking it.
Regulatory proteins interact with chromatin to either package it more tightly or unwind it, which affects the genes that 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. It is known that in mice bromodomains are involved in cell differentiation, which led the researchers to hypothesize that such epigenetic mechanisms may drive the trypanosome to change from one form to another.
Schulz, the lead author of the study remarked that to investigate if chromatin-altering mechanisms might be important for differentiation, 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 known to block bromodomains in mammals.
When these changes were introduced the investigators observed changes in gene expression levels that resembled those seen in cells differentiating from the bloodstream form to the fly form. Also a procyclin coat normally found on the fly form developed on it. The results of the study made the researchers believe bromodomains could serve as a potential therapeutic target to treat African sleeping sickness.
The researchers then used drug-treated trypanosomes to infect mice to find if I-BET151 could be used to combat the disease. The results revealed that the parasite's ability to invade the host was diminished in the presence of I-BET151.
I-BET151 is not effective enough to be used in the clinic, but a crystal structure determined by Debler and published as part of this study provides direct clues for how an optimized drug could be designed to bind parasite bromodomains in a highly specific manner, limiting side effects.
Papavasiliou said that since the current treatments for this disease are limited and they have substantial side effects, including very high mortality rates, this study offers a promising new avenue to develop therapeutics. She also remarked that this could the findings will be helpful for not only African sleeping sickness, but also a number of related parasitic diseases like Chagas or malaria.