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African Trypanosomiasis (Sleeping Sickness; Trypanosoma brucei Complex)
Sixty million people in 36 countries are at risk for infection with Trypanosoma brucei complex, the causative agent of sleeping sickness. Also known as human African trypanosomiasis (HAT) , this disease is restricted to sub-Saharan Africa, the range of the tsetse fly vector. It is a disease of extreme poverty, with the highest disease burden observed in remote rural areas. HAT comes in 2 geographically and clinically distinct forms. Trypanosoma brucei gambiense causes a chronic infection and affects people who live in western and central Africa ( West African sleeping sickness , Gambian trypanosomiasis ). Trypanosoma brucei rhodesiense is a zoonosis that presents as an acute illness lasting several weeks and usually occurs in residents or travelers from eastern and southern Africa ( East African sleeping sickness , Rhodesian trypanosomiasis ).
Etiology
HAT is a vector-borne disease caused by parasitic, extracellular, flagellated kinetoplastid protozoans of 2 subspecies of Trypanosoma brucei . It is transmitted to humans through the bite of Glossina , commonly known as the tsetse fly .
Humans usually contract East African HAT when they venture from towns to rural areas to visit woodlands or livestock, highlighting the importance of zoonotic reservoirs in this disease. West African HAT is contracted closer to settlements and only requires a small vector population, making it difficult to eradicate. Animal reservoirs occur, but the main source of infection remains chronically infected human hosts.
Life Cycle
Trypanosoma brucei undergoes several stages of development in the insect and mammalian host. On ingestion with a blood meal, nonproliferative short stumpy (SS) forms of the parasite transform into procyclic forms in the insect's midgut. These procyclic forms proliferate and undergo further development into epimastigotes, which then become infective metacyclic forms that migrate to the insect's salivary glands. The life cycle within the tsetse fly takes 15-35 days. On inoculation into the mammalian host, the metacyclic stage transforms into proliferative long slender (LS) forms in the bloodstream and the lymphatics, eventually penetrating the central nervous system (CNS). LS forms appear in waves in the peripheral blood, with each wave followed by a febrile crisis and heralding the formation of a new antigenic variant. Once a critical density of LS forms is reached, a quorum-sensing mechanism causes most of these to transform into nonproliferative SS forms that are ingested by Glossina and start the cycle anew. Some LS forms remain to maintain the infection in the human host.
Direct transmission to humans has been reported, either vertically to infants or mechanically through contact with tsetse flies with viable LS forms on their mouthparts from a recent blood meal from an infected host.
Epidemiology
HAT remains a major public health problem in sub-Saharan Africa. It occurs in the region between latitudes 14 degrees north and 29 degrees south, where the annual rainfall creates optimal climatic conditions for Glossina . In 2009, because of intensive control efforts spearheaded by the World Health Organization (WHO), the number of new HAT cases annually fell below 10,000. In 2015, this further fell to 2,804 cases, with 84% of cases coming from the Democratic Republic of Congo. Gambian trypanosomiasis is targeted for sustainable elimination as a public health problem by 2030.
T. brucei rhodesiense infection is restricted to the eastern third of the endemic area in tropical Africa, stretching from Ethiopia to the northern boundaries of South Africa. T. brucei gambiense , which accounts for 98% of HAT cases, occurs mainly in the western half of the continent's endemic region. Rhodesian HAT, which has an acute and often fatal course, greatly reduces chances of transmission to tsetse flies. The ability of T. brucei rhodesiense to multiply rapidly in the bloodstream and infect other species of mammals helps maintain its life cycle.
Pathogenesis
At the site of the Glossina bite, tsetse fly salivary antigens, peptides, and proteins promote an immune-tolerant microenvironment that facilitates parasite invasion. Injected metacyclic parasites transform into LS forms, which rapidly divide by binary fission. The parasites, along with the attendant inflammation, cellular debris, and metabolic products, may give rise to a hard, painful, red nodule known as a trypanosomal chancre . Dissemination into the blood and lymphatic systems follows, with subsequent localization to the CNS. Histopathologic findings in the brain are consistent with meningoencephalitis, with lymphocytic infiltration and perivascular cuffing of the membranes. The appearance of morula cells of Mott (large, strawberry-like cells, supposedly derived from plasma cells) is a characteristic finding in chronic disease.
Mechanisms underlying virulence in HAT are still incompletely understood but seem to be mediated by a complex interplay of trypanosomal, human, and Glossina factors. T. brucei gambiense secretes a specific glycoprotein, TgsGP, while T. brucei rhodesiense expresses a protein known as serum resistance–associated protein (SRA), which counteracts trypanolytic apolipoprotein L-1 (ApoL1) in human serum. Trypanosomes also secrete a host of biologically active molecules that can dampen immune responses. For example, T. brucei adenylate cyclase (TbAdC) is hyperproduced when a trypanosome is phagocytosed by responding macrophages, causing a spike in cyclic adenosine monophosphate (cAMP), which then activates the macrophage's protein kinase and shuts down TNF-α production, acting as a Trojan horse and downregulating the immune response. Another molecule, T. brucei –derived kinesin heavy chain (TbKHC1), downregulates host nitrogen oxide production, dampening the proinflammatory response and causing an increase in production of host polyamines, which are essential nutrients for the parasite. Other parasite-derived molecules are involved in modulating B cell and macrophage responses, especially in chronic infection, resulting in an immune-tolerant condition that allows parasite proliferation without killing the host. Although antigenic variation of variant surface glycoprotein (VSG) on the trypanosome surface has long been recognized as a major factor in evading acquired immunity during infection, VSG also inhibits complement activation and antibody-mediated aggregation, facilitating establishment and maintenance of infection. Soluble VSG is hypersecreted, especially at the peak of parasitemia, and may serve as a decoy for antibodies and complement factor, diverting immune responses away from trypanosomes.
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