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HUMAN AFRICAN TRYPANOSOMIASIS
Human African trypanosomiasis (HAT) is caused by two subspecies of Trypanosoma brucei: T.b. gambiense
that leads to the chronic form of HAT known as West African trypanosomiasis and T.b. rhodesiense that
leads to the acute form of HAT known as East African trypanosomiasis [168-170] . A third subspecies of T.
b. brucei infects cattle and very rarely infects the human host. HAT is transmitted to mammalian hosts
by the bite of infected tsetse flies. During a blood meal, the metacyclic trypomastigotes are injected
into the skin of the host, eventually entering the lymphatic and blood vessels. As parasites transform
into blood trypomastigotes, they are disseminated throughout the body. The life cycle is completed
when trypomastigotes infect feeding tsetse flies, wherein they transform and replicated into insect
stage parasites [168,171] . Unlike the other protozoan parasites, the entire life cycle of African trypanosomes
consists of extracellular stages, which alternately infect mammalian and insect hosts (CDC.gov, https://
www.cdc.gov/parasites/sleepingsickness/biology.html). Although T. brucei infection occurs through the
hemolymphatic stage in the initial systemic stage, the second phase is mainly characterized as a central
nervous system disease, due to parasite invasion of brain tissue, leading to the altered sensorium, seizures,
coma, and death. These symptoms are the reason that HAT is also referred to as African sleeping sickness.
Role of the VE in HAT
Bloodstream forms of T. brucei multiply to high density and eventually invade the central nervous system
through the penetration of the VE. Although the mechanism through which the T. brucei cross the BBB are
yet to be fully understood, it has been shown that T. brucei uses a multi-step process using the host derived
factors including the cytokines IFNa/β, IFNg, TNF, ICAM-1, and CXCL10 [97,172] . During infection, the VE
cells are activated by the translocation of NF-kB, due to action of parasite trans-sialidase, to the nucleus and
the induction pro-inflammatory cytokines such as TNF-a, IL-6, and IL-8. This process plus the induction
of other soluble factors such as the adhesion molecules (ICAM-1, E-selectin, and VCAM-1) [100] culminates
in leukocyte recruitment and transmigration of trypanosomes from the VE to the CNS [96,98] . Studies have
shown that T. brucei infection enhances the eNOS protein expression, and enhanced NO production leads
to elevated vasodilation and vascular permeability facilitating parasite invasion into the surrounding tissues
and the central nervous system [173] .
Parasite phospholipase C, protein kinase, and the parasite cysteine protease brucipain also participate
in transmigration of trypanosomes into the CNS [101,174] . Furthermore, it has been shown that T. brucei
[97]
crosses the VE of cerebral blood vessels of mice through interaction with laminin 8 of the ECs . The
transmigration of T. brucei through the vascular endothelium also depends on the calcium and the papain-
like cysteine proteases [101] . Collectively, this shows that interaction with the VE depends on various factors
that are essential to penetrate the BBB and infect the CNS.
Role of exosomes in HAT
The progression of HAT is modulated by several factors including macrophage hyper-activation,
uncontrolled production of TNF, and the transfer of virulence factors by exosomes [123,175] . Host-derived
exosomes play a major role in host defense and are targeted as vaccine candidates, whereas parasite-derived
exosomes transduce signal(s) to the host cells to establish infection [39,176,177] . A study has shown that a
spliced ladder RNA (SL RNA) is present in the exosomes of T. brucei that is essential in these parasites for
the formation of all mature mRNA. The cells secreting these SL RNA-containing exosomes affect the social
motility of these parasites [178] . The bloodstream form of the parasite is responsible for anemia and tissue
damage in the mammalian host [124,179] . This immunopathological outcome is due to several proteins released
from the exosomes that lead to sequential activation of the innate and acquired immune responses [180] . The
parasites secrete several molecules through exosomes to gain access to the host cells. Likewise, T. brucei
exosomes contain 156 proteins from diverse functional classes [123] . One study shows that T. brucei exosomes
fuse with mammalian erythrocytes and causes rapid clearance of erythrocytes and promotes anemia [123,124] .