Creative Minds: Interrogating a Master of Disguise

Posted on February 16th, 2017 by Dr. Francis Collins

When I volunteered several years ago as a physician in a small hospital in West Africa, one of the most frustrating and frightening diseases I saw was sleeping sickness. Now, an investigator supported by the NIH Common Fund aims to figure out how this disease pathogen manages to evade the human immune system.

Monica Mugnier’s fascination with parasites started in college when she picked up the book Parasite Rex, a riveting, firsthand account of how “sneaky” parasites can be. The next year, while studying abroad in England, Mugnier met a researcher who had studied one of the most devious of parasites—a protozoan, spread by blood-sucking tsetse flies, that causes sleeping sickness in humans and livestock across sub-Saharan Africa.

From her British colleague, Mugnier learned that after a tsetse fly infected with Trypanosoma brucei bites a person, the invading parasitic protozoans cloak themselves in a dense coat of molecules called glycoproteins. When the human immune system detects T. brucei, it marks the protozoans with antibodies that target them for destruction. However, T. brucei possesses the ability to evade such destruction by sweeping off the antibodies and disguising itself in a new set of glycoproteins. This immunological “cat and mouse” game can go on for years. Eventually, the parasite crosses the blood-brain barrier, triggering excessive sleep and life-threatening seizures and coma.

Using a gene-expression approach that she helped to adapt to T. brucei, Mugnier extrapolated that the parasite runs through the 2,000 or so genes that code for its glycoprotein disguises in a matter of months [1]. This raises a perplexing question: How can this parasite outsmart the human immune system for years, if it has “nothing new to wear” for most of that time?

Now an assistant professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, Mugnier recently received a 2016 NIH Director’s Early Independence award to look for answers. One possibility is the parasite has learned how to combine bits of one gene with another to weave together an almost inexhaustible supply of disguises. To test this idea, Mugnier will use the CRISPR/Cas9 gene editing tool to create targeted breaks into a disguise gene. Then she’ll see which snippet of another gene gets inserted and whether a working hybrid gene emerges.

Another possibility is that the disguise genes hypermutate to keep the immune system guessing. Mugnier will apply advanced next-generation DNA sequencing for one of the first times on T. brucei to see if that’s the case. If so, what’s being mutated might also suggest how the parasite avoids the immune system, suggesting possible targets for new therapies and vaccine development.

The young scientist’s work will also take into account a relatively new discovery by other researchers [2,3]. In findings that shook up the field of sleeping sickness research, those investigators found that, in addition to infecting blood, T. brucei also resides in skin and fat. Whether these newfound, “extravascular” reservoirs of the parasite contribute to neurological disease is yet to be determined. For her part, Mugnier will investigate whether these extravascular parasites might don a different set of disguises than those lurking in the bloodstream. This will provide vital information in the ongoing effort to combat a disease that each year claims the lives of about 9,000 people [4], and affects the health and economic well-being of many more through its destructive effect on vital herds of livestock.

References:

[1] The in vivo dynamics of antigenic variation in Trypanosoma brucei. Mugnier MR, Cross GA, Papavasiliou FN. Science. 2015 Mar 27;347(6229):1470-1473.

[2] The skin is a significant but overlooked anatomical reservoir for vector-borne African trypanosomes. Capewell P, Cren-Travaillé C, Marchesi F, Johnston P, Clucas C, Benson RA, Gorman TA, Calvo-Alvarez E, Crouzols A, Jouvion G, Jamonneau V, Weir W, Stevenson ML, O’Neill K, Cooper A, Swar NK, Bucheton B, Ngoyi DM, Garside P2, Rotureau B, MacLeod A. Elife. 2016 Sep 22;5.pii: e17716.

[3] Trypanosoma brucei parasites occupy and functionally adapt to the adipose tissue in mice. Trindade S, Rijo-Ferreira F, Carvalho T, Pinto-Neves D, Guegan F, Aresta-Branco F, Bento F, Young SA, Pinto A, Van Den Abbeele J, Ribeiro RM, Dias S, Smith TK, Figueiredo LM. Cell Host Microbe. 2016 Jun 8;19(6):837-848.

[4] Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lozano R, Naghavi M, Foreman K, et al. Lancet. 2012 Dec 15;380(9859):2095-2128.

Links:

African Trypanosomiasis (Centers for Disease Control and Prevention, Atlanta)

Mugnier Lab (Johns Hopkins Bloomberg School of Public Health, Baltimore)

Mugnier Project Information (NIH RePorter)

NIH Director’s Early Independence Award Program (Common Fund)

NIH Support: Common Fund