Mancini, Patricia E.

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Bridgewater ReviewVolume 21 | Issue 1 Article 11Jun-2002The Deadly Trypanosome: Understanding theParasite that causes Sleeping SicknessPatricia E. ManciniBridgewater State CollegeThis item is available as part of Virtual Commons, the open-access institutional repository of Bridgewater State University, Bridgewater, Massachusetts.Recommended CitationMancini, Patricia E. (2002). The Deadly Trypanosome: Understanding the Parasite that causes Sleeping Sickness. Bridgewater Review,21(1), 24-27.Available at: http://vc.bridgew.edu/br_rev/vol21/iss1/11THE DEADLY TRYPANOSOMEPATRICIA E. MANCINIAfrican sleeping sickness. Tsetse fly. Trypanosomes. Tosome, these words may sound exotic, menacing or evenhumorous, but not to me. The biochemistry and physi-ology of African trypanosomes, and particularlyTrypanosoma brucei, the protozoan agent of this deadlyscourge, has been the main focus of my research life andthought for almost 25 years. My current work focuseson the mechanisms by which trypanosomes attach toand interact with host cells, and the potentially toxicmolecules involved in such interactions. As a new facul-ty member at BSC, I’d like to introduce you to thisorganism and the disease it causes, and point out waysin which the study of these parasites by students canoffer them valuable research experience. Training in microbiology and biochemistry prepared me well for the study of trypanosomes, but lab-benchscientific studies are only one aspect of  understandingthis disease and the problems it causes throughoutmuch of the African continent. Geography, colonial his-tory, ethnic conflicts, and cultures of the region allinfluence the toll this disease takes. HISTORY AND EPIDEMIOLOGYOF AFRICAN SLEEPING SICKNESSAfrican sleeping sickness in humans is caused by a pro-tozoan, Trypanosoma brucei, and, throughout much ofsub-Saharan Africa, is transmitted by the bite of thetsetse fly. Although mortality is relatively low in num-bers compared to diseases caused by other infectiousagents, it is sufficient for the disease to be a majorhealth threat and concern. Trypanosoma brucei, the parent species, is found in antelopes and other gameanimals, but these native animals (and even some localbreeds of domestic cattle) can tolerate the infectionwithout showing symptoms. However, they may serve as reservoirs of infection for the trypanosome subspecies which attack humans. We do not knowwhat makes the wild antelope population resistant, but assume that millions of years of co-evolution haveallowed it to reach a stale-mate with the parasite.Almost as important as the disease in humans is the dis-ease in domestic animals which, by killing animals ofEuropean (i.e., non-native) stock, prevents cultivationof, or grazing on, millions of acres of fertile land in the“tsetse belt.” Some trypanosome species affect cattle;others, horses and camels. Together these organismsmake farming and ranching difficult in the most poten-tially productive area of the continent. A major proteindeficiency in the African diet, caused by the inability toproduce sufficient food for the population, might beaverted if some of this land (in an area the size of theUS) could be maintained for farming and grazing. THE VECTORTsetse fly is a general name for any of the eight speciesof the genus Glossina which may carry and transmit theparasite. The flies are generally divided into two broadgroups—those which live in the riverine areas of therain forests of West Africa  and are associated with thechronic form of the disease caused by T. brucei gambi-ense, and the woodland tsetses,  which inhabit driergrasslands and forests of the east coast of Africa  and arevectors for the more acute, and more rapidly fatal, formof the disease caused by T. brucei rhodesiense. Indigenouspeoples have known for centuries that the presence ofthe tsetse fly is associated with high incidence of dis-ease. Regions which are endemic for the flies are alsoendemic for sleeping sickness, which is essentially 100%fatal if untreated. Traditionally, native herdsmen havemoved their cattle away from the rivers during thetsetse season, minimizing  the effects of the disease.Colonial powers actually helped spread the diseaseacross the continent by providing host animals in theirhorses and cattle, so what was once a contained,endemic problem soon became widespread throughoutthe continent.The Deadly Trypanosome:Understanding the Parasite that causesSleeping Sicknessby Patricia E. ManciniBRIDGEWATER REVIEW                        JUNE 2002 25PATHOLOGY OF THE DISEASEAND CURRENT DRUG TREATMENTSAfter the fly bites, trypanosomes enter the mammalianhost, multiply in the skin, then migrate through the tis-sues to the bloodstream. Most of their life cycle in themammalian host occurs in the blood and tissues, withrapid cell division leading to high parasite levels. This isthe primary stage of the disease, when available drugtreatments are most likely to be effective. It is also atime when the bite of another tsetse fly can transmitthese parasites to the next host. However, the diseasemay progress to the secondary stage when the parasitesmigrate from the blood into the central nervous system,including the brain and cerebrospinal fluid. Early indica-tors may be mild episodes of disorientation which thenprogress to an increasingly altered sleep cycle resultingin long periods of “sleep” and eventually coma anddeath. The drugs available to treat the primary infection havenot changed in 100 years. Pentamidine and suramin,which kill the parasite, are still effective against thebloodstream forms (although some strains have becomeresistant) but have side effects. Melarsoprol, an arseni-cal which until recently was the only drug for treatingcerebral involvement, is toxic enough on its own toaccount for a 5% fatality rate. The only drug recentlydeveloped (in the 1980’s) to treat secondary stage dis-ease, eflornithine, an inhibitor of an essential pathwayof parasite metabolism, was discontinued by its manu-facturer after a company merger. This points up a criti-cal problem in the development of new treatments forthe disease. Pharmaceutical companies are unwillingand/or unable to devote resources to research and devel-opment of new drugs because the disease strikes in areaswhere the infected individuals are unable to afford theprice of medication. In addition, an effective distribu-tion system may be unavailable even if the drug isdonated free of charge by the manufacturer. STRATEGIES FOR PREVENTION AND CONTROLAlthough the latest  World Health Organization statis-tics record only about 40,000 reported cases, this isprobably a gross under-representation. As many as halfa million people may currently be infected, but mostcases go unreported and untreated because the ruralpopulations which are most at risk may have minimalcontacts with healthcare personnel. Also, infected indi-viduals may seek treatment only at later stages of thedisease or not at all. Many are children who die of  try-panosomiasis without ever causing a blip on the sur-veillance radar. Surveillance andscreening of infectedindividuals in localareas have been  suc-cessful strategies forcontrol in the past,almost eradicating the disease in the halfcentury prior to the1970’s. Unfortunately,surveillance as a con-trol measure relies onsuccessful administra-tive infrastructures andeconomics because it is a  labor-intensive activity.Surveillance teams must cover vast areas to diagnosethe disease where infection rates are highest, must takeblood samples from individuals in  villages where, insome cases, 70% of the population may be infected, andfinally, must arrange for contact with healthcare deliv-ery systems which are often inadequate. Patients mustbe transported to hospitals where the drugs are general-ly administered intravenously. This removal of infectedpersons from a community has the public health effectof removing a reservoir of infection, and may help cutdown on transmission but may be a “hard sell” to fami-lies of infected individuals. In the past, successful con-trol strategies have also involved the labor-intensivecollection and removal of the flies when they are activeduring the daylight hours.  Broader strategies such asspraying insecticides or converting riverine areas andwoodlands into farmland have also been effective.However, these are often threatening to the delicateecological balance of an area and, in any case, also relyupon an administrative infrastructure and a robusteconomy.Dr. Mancini with studentsThe life cycle of theAfrican trypanosomein the mammalian hostand in the tsetse fly host.Shown are the variousmorphological formsseen in each, as well asthe phenomenon of anti-genic variation (alteredsurface proteins) seen inthe mammalian host.Figure courtesy of  Dr.James E. Strickler ©1980. Modified with permission. THE DEADLY TRYPANOSOMEPATRICIA E. MANCINITHE GEOPOLITICS AND DEVASTATING CONSEQUENCESOF THE DISEASEIn the past 40 years the legacy of colonial rule hasresulted in economic and political changes, ethnicunrest, civil wars, population migrations due to famineand other non-biological events which have subjectedthe population in sub-Saharan Africa to reduced levelsof surveillance, minimal treatment, and subsequentdramatic increases in the incidence and mortality ofsleeping sickness. The boundaries of countries whichare affected by these problems, including (but not limit-ed to) the Democratic Republic of the Congo, Sudan,Uganda and Angola, can be superimposed upon recentdata recording epidemic resurgence of this disease.Even countries with stable political and economicstructure are at risk of increased incidence due to thethousands of refugees who may carry the disease acrossnational borders. Few countries are equipped to dealwith the magnitude of such a problem.HOW UNDERGRADUATES BENEFITFROM RESEARCH ON MICROBIAL SYSTEMSLaboratory research with trypanosomes provides ameaningful experience for undergraduate students forseveral reasons. Trypanosomes offer a system for studyvery similar to that of other biological systems: non-infectious laboratory strains of the parasites can now bestudied using all the methods of modern biochemistryand molecular biology to grow and manipulate try-panosomes, and these methods are applicable toresearch on other organisms. Students entering the jobmarket directly after college will be well prepared with“hands-on” experience for jobs in biotechnology orpharmaceutical companies, or in academic research,hospital and/or government labs. And some undergrad-uate research is almost always a prerequisite for admis-sion to good graduate and professional programs.Admissions committees are impressed by the level oftechnical expertise and commitment exemplified bystudents who do “bench level” research. Additionally,the ability to think logically in order to design, execute,analyze and write up experiments is useful for manyfuture scientific or nonscientific endeavors.  Studies ontrypanosomes overlap with research in genetics, celland molecular biology, immunology and biochemistrycurrently being undertaken in the Biology andChemistry departments at BSC. This promotes a levelof camaraderie here among undergraduate researcherswhich is useful when they enter the professional world.But there is a more important reason for doing researchon any parasite agent of diseases which afflict primarilydeveloping countries. Microorganisms have alwaysaffected the course of human society—consider theeffects of  plague, typhus, typhoid, dysentery, andtetanus during wars, or cholera epidemics in cities andrural areas, or the Irish potato famine, which brought somany individuals to the United States during the mid-19th century. Students at BSC studying trypanosomeslearn valuable lessons in public health. Increased aware-ness of public health and environmental issues bothlocally and worldwide helps them understand the inter-play between individual actions within the society andthe spread of microorganisms and disease, as well as theeffect that microorganisms have on the course of a soci-Tsetse Fly Mammalian HostReproducingVariant AMetacyclic Trypomastigote SlenderVariant BEpimastigote       IntermediateVariant CMidgut Stumpy Etc.Trypomastigote  BRIDGEWATER REVIEW                        JUNE 2002 27ety’s progress as a whole. Ultimately the control andeventual eradication of African sleeping sickness and itscompanion diseases, malaria, hookworm, leishmaniasis,schistosomiasis, and more, will depend  both on the sci-ence and on the social factors which influence how indi-viduals in a community or a country interact with oneanother and with the disease agent. WHAT TO DO? STRATEGIES FOR UNDERSTANDING THEPARASITE AS A MEANS OF COMBATING THE DISEASEUnderstanding  the parasite’s physiology and biochem-istry  (in other words, “know thine enemy”), can helpresearchers to develop a rational approach to preventionor therapy. Trypanosomes have so far evaded mostattempts to control and  understand them. Throughmillions of years of co-evolution with their mammalianhosts, the parasites which survive rely on “immunocon-fusion” and “immunoevasion,” mechanisms whichallow them to be overlooked by the immune system. Inaddition, the metabolism of the parasite closely mimicsthe metabolism of its mammalian hosts, another sur-vival advantage, so drugs for treating the disease have avery narrow window of effectiveness for eradicating theparasite without causing damage to the patient. In order to develop new and effective drugs, we willhave to find an Achilles’ Heel in the parasite, i.e., ametabolic variation found only in the parasite and notin the host, which might be exploited for drug therapywithout damage to the host physiology. A thoroughknowledge of the parasite’s physiology and biochem-istry is one way to find this difference, but even thisstraightforward approach has been hampered for manyyears by the inability to study the parasite effectively.Once removed from the host animal, the trypanosomeis a fragile creature, difficult to keep alive in the lab. Inrecent years there have been advances in the ability toculture the parasite and to study its genes and theirexpression or activation using molecular biological tech-niques in addition to traditional biochemical andimmunological methods. This has allowed us to pro-duce sufficient quantities of this organism or its proteincomponents to examine their functions more carefully,a first step in designing specific drugs to block thosefunctions and kill the parasite. However, we still havefew clues as to how the parasite actually kills its host. Isits simple presence in large numbers sufficient to inter-fere with the host’s own metabolism? Does it producetoxic substances that directly kill host cells, damagingfunctions of critical organs ? Does it actively inhibit cer-tain components of the immune system? How does itmigrate through tissues to the small capillaries of thebloodstream, and from there to the brain?  These aresome of the questions which need to be addressed bystudying the biochemistry of the trypanosome’s com-ponents and how they work. Any projects undertaken by BSC students must  be safe,and there are now culture systems which use a form ofthe parasite which is non-infectious for humans. Theseallow growth of sufficient numbers of cells for studentsto study their interactions with mammalian or insectcells in culture. Special dyes can now be used to staindifferent physiological states of parasite or host toassess adherence or production of toxic substances. Inaddition, students can learn how to clone and detectspecific parasite genes and produce their proteins in the lab to help in identifying novel drugs to inhibit well known proteins, or to find unique proteins as novel drug targets in the parasite. Newer purificationmethods allow both isolation of the proteins and identi-fication of their functions, providing many potentialprojects for student focus. In the past ten years, severaltypes of cell surface enzymes, receptor molecules, adhe-sion proteins, stress-related proteins and other impor-tant molecules have been identified in trypanosomes as potential targets. Unraveling the components of theparasite provides enough work for many students toparticipate in helping us to understand and control this disease.—Patricia E. Mancini is Assistant Professor of Biological Sciences

The Deadly Trypanosome: Understanding the Parasite that causes Sleeping Sickness

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The Deadly Trypanosome: Understanding the Parasite that causes Sleeping Sickness

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