Clinical presentation and immune response of Human African

Global Advanced Research Journal of Medicine and Medical Science (ISSN: 2315-5159) Vol. 4(4) pp. 159-167, April, 2015
Available online http://garj.org/garjmms/index.htm
Copyright © 2015 Global Advanced Research Journals
Review
Clinical presentation and immune response of Human
African Trypanosomiasis – a review
D. Musa*, A. O Fajinmi, R.O Kalejaiye and T. Tese
Nigerian Institute for Trypanosomiasis and Onchocerciais Research (NITR) Kaduna, Nigeria
Accepted 26 March, 2015
Human African trypanosomiasis or sleeping sickness is caused by infection with two subspecies of the
tsetse-fly-vectored haemoflagellate parasite Trypanosomabrucei. Historically, epidemic sleeping
sickness has caused massive loss of life, and related animal diseases have had a crucial impact on
development in sub-Saharan Africa. After a period of moderately successful control during the mid-part
of the 20th century, sleeping sickness incidence is currently rising, and control is hampered by a
combination of factors, including civil unrest and the possible development of drug resistance by the
parasites. The prevailing view is that the disease is invariably fatal without anti-trypanosomal drug
treatment. However, there have also been intriguing reports of wide variations in disease severity as
well as evidence of asymptomatic carriers of trypanosomes. These differences in the presentation of the
disease will be discussed in the context of our knowledge of the immunology of trypanosomiasis. The
impact of dysregulated inflammatory responses in both systemic and CNS pathology will be examined
and the potential for host genotype variation in disease severity and control will be discussed.
Keywords: Trypanosomiasis, tsetse-fly
INTRODUCTION
Human African trypanosomiasis or sleeping sickness is
caused by infection with the tsetse-fly-transmitted
protozoan
haemoflagellates
Trypanosomabrucei
rhodesiense (in East and Southern Africa) and
T. b. gambiense (in West and Central Africa). This
disease is presently re-emergent and infection is
currently estimated at over 30 000 with about 55 million
people at risk of infection (WHO, 1998). These parasites,
along
with
the
non-human-infective
Trypanosomabruceibrucei are zoonoses, and disease
control is impeded by substantial wild and domestic
*Corresponding
Author
E-mail: [email protected]
animal reservoirs of infection. The taxonomic
relationships of the three T. brucei subspecies have been
defined using molecular markers. T. b. rhodesiense and
T. b. brucei are closely related host-range variants.
Human infectivity in T. b. rhodesiense is conferred by the
SRA (Xong et al., 1998) gene product which renders the
parasites resistant to lytic activity in normal human
serum. On the other hand T. b. gambiense is distinct,
with marked genetic and biochemical differences
(Gibson, 2002). T. b. gambiense does not possess the
SRA gene and the mechanism of human serum
resistance is not known (Gibson, 2002). African
trypanosomes may be adapted to growth in experimental
mouse models, and much of our knowledge of the
biology of these parasites comes from such studies.
160
Glo. Adv. Res. J. Med. Med. Sci.
Figure 1.
LIFE CYCLE AND DISEASE PROGRESSION
The infection is initiated by the injection of metacyclic
trypanosomes in the saliva of the tsetse fly (Figure 1).
After the bite of a trypanosome-infected tsetse fly, the
metacyclic forms establish in the skin, differentiate to the
bloodstream stage and spread via the local draining
lymph node into the vascular system. In some but not all
infections, a local skin reaction or chancre occurs at the
site of inoculation, which is caused by a local
inflammatory response to the parasites, and subsides
after 4 weeks (Fairbairn and Godfrey, 1957; Naessens et
al., 2003). The early (or haemolymphatic stage)
commences 1–3 weeks after an infective fly bite and
presents with periods of fever lasting 1–7 days and
generalized lymphadenopathy. During this period the
parasites proliferate within the blood and lymphatic
system. Symptoms include general malaise, anaemia,
headache, pyrexia, weight loss and weakness. Immuneactivation is evident from lymph node enlargement,
hepatomegaly
and
splenomagaly.
The
late
(meningoencephalitic) stage of infection coincides with
the invasion of the CNS by parasites and is associated
with psychiatric, motor and sensory disorders, along with
sleep abnormalities. If untreated, late-stage patients
progress to a final stage involving seizures, somnolence,
coma and death (Kennedy, 2004). Both T. b. rhodesiense
and T. b. gambiense infections follow this sequence of
infection stages, but with a marked difference rate of
progression. T. b. gambiense presents as a chronic
infection, in which progression to late stage may take
several months or longer, and late-stage CNS infection
may last several years (Barrett et al., 2003). On the other
hand, T. b. rhodesiense is generally regarded as an
acute infection, with progression to late stage occurring in
a matter of weeks and the late-stage CNS infection
leading to death within 3 months, although this may not
always be the case, as will be discussed in this review.
Figure 1. Life cycle of African trypanosomes. Infectious
metacyclic trypanosomes are injected by a tsetse fly. In
some cases a chancre forms at the site of infection. The
parasites spread via the local draining lymph node to the
vascular system. Bloodstream trypanosomes take two
forms. The slender undergoes continuous asexual
proliferation. Some slender forms differentiate to stumpy
forms which do not proliferate but are pre-adapted for
rapid establishment in the tsetse fly.
IMMUNOLOGY OF INFECTION
Antigenic variation and antibody responses
African trypanosomes’ primary immune-evasion strategy
is antigenic variation (Pays et al., 2004; Vanhamme et al.,
8
2001). The parasites are covered with a coat of 10
variant surface glycoprotein (VSG) molecules attached to
the
trypanosome
cell
membrane
via
a
glycosylphosphatidyl-inositol (GPI) anchor (Magez et al.,
2002). VSG is an immunodominant antigen, capable of
Musa et al. 161
eliciting both T-cell dependent and independent B-cell
responses, depending on its conformation (Mansfield,
1994). Antibody opsonized trypanosomes are effectively
cleared by the host lymphoreticular system (Macaskill et
al., 1981). The parasite, however, undergoes antigenic
variation and has a repertoire of more than 1000
transcriptionally inactive VSG genes and a single active
transcription site. The genetics of this process have been
reviewed elsewhere (Pays et al., 2004) and the result is a
continuous stochastic switching of VSG genes at a rate of
−3
−4
between 10 and 10 per cell division (Turner and Barry,
1989). This enables the parasite to maintain a state of
chronic infection in the host, and the importance of the
process is testified to by the fact that VSG genes occupy
10% of the trypanosome genome (Donelson, 2003). The
VSG molecule therefore plays a pivotal role in host
responses to African trypanosomes. The humoral
response to VSG also has immunopathologicalsequelae.
VSG elicits polyclonal B-cell activation, and in human
infection this manifests in the generation of autoantibodies (Kazyumba et al., 1986) and immune complex
disease (Lambert et al., 1981). Furthermore, in the
meningoencephalitic
stage
of
infection
both
trypanosome-specific IgG and IgM and polyclonal IgM
responses have been detected in the cerebrospinal fluid
(CSF) (Lejon et al., 1998). These may derive from
modified plasma cells known as Mott or morular cells in
the white matter and also plasma cells which form
perivascular infiltrates in the brain (Kennedy, 2004).
Cellular immune activation
Most studies of the cellular response to African
trypanosome infection have involved the use of
experimental mouse models. In early (7–21 days)
infection in mice, macrophage activation results in the
release of nitric oxide, and pro-inflammatory mediators
such as TNF-α and IL-1. Several mechanisms have been
proposed to drive macrophage activation in African
trypanosome infection. One of these involves a direct
interaction with VSG and VSG-GPI anchor components.
It has been estimated that with the clearance of each
parastaemic peak, some 200 µg of VSG molecules are
shed (Magez et al., 2002). Soluble VSG carrying the GPI
anchor glycosylinositol phosphate (GIP-sVSG) core and
the residual dimyristoylglycerol glycerol (DMG) anchor
moiety are potent macrophage-activating factors (Magez
et al., 1998) which appear to have different modes of
action. The GIP moiety directly induces macrophage
activation (Coller et al., 2003) and TNF-α induction
(Coller et al., 2003) in macrophages after IFN-γ
stimulation, whereas the DMG component of the VSG
anchor does not itself induce TNF-α but is involved in
macrophage priming. This may account for earlier
observations of a synergy between parasite-soluble
factors and IFN-γ in the in vitro activation of nitric oxide
synthesis in macrophages (Sternberg and Mabbott,
1996). Interestingly, the timing of IFN-γ stimulation seems
to be important, and it has been observed that if
macrophages are exposed to GIP-sVSG before IFN-γ,
there is a dose-dependent inhibition of macrophage IFNγ-dependent STAT1 phosphorylation and activation
(Coller et al., 2003). It has been long known that IFN-γ is
produced in murine trypanosomiais (Bancroft et al.,
1983), and recently this has been confirmed in plasma
samples from clinical cases (MacLean et al., 2001).
+
Considerable experimental evidence supports CD4 Tcells responding to VSG and other parasite antigens as
the main cellular source of IFN-γ production in murine
trypanosomiasis (Schleifer et al., 1993; Hertz et al., 1998;
Schopf et al., 1998). Other putative sources of IFN-γ are
+
CD8 T-cells (Donelson et al., 1998) and activated NK
cells (Sternberg, 1998). In mouse models, activated
macrophages mediate suppression of both B- and T-cell
proliferative responses (Sternberg, 1998; Schleifer and
Mansfield,
1993)
and
contribute
to
the
immunosuppression
which
is
associated
with
trypanosomiasis (Askonas, 1985) via nitric oxide,
prostaglandin and TNF-α release (Magez et al., 1999).
The significance of immunosuppression in the pathology
of human trypanosomiasis is unclear, but the proinflammatory cytokine TNF-α has multiple pathological
targets which are consistent with the pathology observed
in both HAT and experimental infections, including tissue
necrosis, anaemia (Magez et al., 2004) and cachexia
(Cerami and Beutler, 1988). TNF-α mediated
inflammatory responses have also been proposed to be
necessary for the penetration of parasites through the
blood–brain barrier endothelia (Enanga et al., 2002).
Experiments using genetically attenuated parasites have
indicated that in subtolerant hosts which exhibit survival
times of longer than 200 days there is a transition to a
type II cellular response profile, with the production of
counter-inflammatory cytokines including IL-10 and the
development of alternatively activated macrophages
(Namangala et al., 2001; De Baetselier et al., 2001). The
association of this immune response profile with a
relatively benign infection indicates that maintenance of a
counter-inflammatory cytokine milieu may be important in
allowing survival with a chronic trypanosome infection.
Such a view is confirmed by the restoration of a virulent
disease profile in attenuated parasites when inoculated in
IL-10 knockout mice (De Baetselier et al., 2001). While
such data suggest that the pro-inflammatory response
triggered by the parasites is detrimental to the host, there
have also been reports that TNF-α is lytic to African
trypanosomes (Magez et al., 1997) and may account for
the exacerbation of parasitaemia in TNF-α knockout
mice. Despite elevated parasitaemia, such mice showed
lower levels of histopathology and anaemia (Magez et al.,
1999). This indicates that parasitaemia control and
pathology are independent traits (Magez et al., 2004),
and it is important when extrapolating from the mouse
model to the human disease to bear in mind that it is
162
Glo. Adv. Res. J. Med. Med. Sci.
pathology which is the clinically relevant trait. It should be
added that a direct trypanolytic role of TNF-α is subject to
some debate, and data has also been presented
indicating no effect on the parasite (Kitani et al., 2002). It
is possible to prevent African trypanosomes from
shedding VSG and GPI anchor components and thus
remove a macrophage pro-inflammatory stimulus from
the host using GPI-phospholipase-C (PLC) knockout
trypanosomes (Webb et al., 1997). PLC is responsible for
the cleavage of the GPI anchor of the VSG molecule, and
the release of GIP-sVSG and DMG from trypanosomes
(Magez et al., 1998). Such parasites were able to
maintain chronic infection in experimental mice over
periods longer than 100 days, and this was associated
with a switch from a type I inflammatory immune
response to a type II response characterized by IL-10
and IL-4 and macrophages with an alternative activation
phenotype (De Baetselier et al., 2001), although TNF-α
levels continued to be elevated. Thus it appears that
removal of a macrophage-activating stimulus allows
infection-associated inflammation to be controlled. A
PLC-knockout mutant has since been generated in
T. b. brucei 427, where animals are overwhelmed by
fulminating parasitaemia rather than infection-associated
pathology, and this mutant is no less virulent than its wildtype form (Leal et al., 2001), further supporting the role of
PLC-shed components in modulating inflammatory
pathology. In summary, experimental studies of T. brucei
infection in mice indicate that the balance of pro- and
counter-inflammatory activity determines the severity of
pathology and the survival time of animals.
Inflammatory and counter-inflammatory cytokines in
human African trypanosomiais
Studies of cytokine production in sleeping sickness
patients from Uganda and Congo have enabled
predictions from the mouse model to be tested. With one
exception, these studies have been of a before–after
design, in which plasma cytokine levels are measured in
a sample taken at the time of parasitological diagnosis
and a subsequent sample is taken at the end of
treatment. In a study of T. b. rhodesiense patients in
Uganda, both early and late-stage infections were
characterized by elevated levels of IFN-γ, TNF-α and IL10, although IFN-γ levels did diminish in the late-stage
cases (MacLean et al., 2001; MacLean et al., 1999). This
pattern of cytokine production is entirely consistent with
the mouse model of moderately chronic disease
progression obtained with subtolerant hosts (Magez et
al., 2004) or PLC knockout trypanosomes (De Baetselier
et al., 2001). The mouse model also predicts nitric oxide
production in the early stages of infection. This has not
been consistently observed (MacLean et al., 1999) in
human subjects, and may reflect the fact that most HAT
patients are diagnosed after a considerable period of
infection. Although it is straightforward to determine the
stage of infection, information obtained from patients on
the duration of illness is often unreliable. In
T. b. gambiense patients, one study demonstrated
increased plasma IL-10, IL-6 and IL-8, but no detectable
IFN-γ or TNF-α (Lejon et al., 2002). However, two other
studies detected elevated TNF-α levels (Rhind et al.,
1997; Okomo-Assoumou et al., 1995) in T. b. gambiense
patients, and in one of these TNF-α concentration was
significantly correlated to the severity of disease (OkomoAssoumou et al., 1995). Thus, whereas the cytokine
response profile in T. b. gambiense sleeping sickness
requires clarification, in rhodesiense sleeping sickness it
may be interpreted as representing a balance between
inflammatory mediators (TNF-α, IFN-γ) and a
counterbalancing IL-10 counter-inflammatory response
(Moore et al., 2001). The cellular source of these
cytokines remains to be determined. Macrophages are
clearly important sources of TNF-α, and in an in vitro
study it was demonstrated that T. b. gambiense activated
a human macrophage cell line to release TNF-α
(Daulouede et al., 2001). Also TNF-α and IFN-γ
transcripts have been detected by RT-PCR analysis of
RNA isolated from HAT patient peripheral blood
mononuclear cells (Sternberg JM and MacLean L,
unpublished data).
Inflammatory responses and late-stage progression
in HAT
The most serious and ultimately fatal consequences of
the disease manifest after the invasion of the CNS by
parasites in the late or meningoencephalitic stage
(Kennedy, 1999). Post-mortem (Adams et al., 1986) and
mouse histopathological studies (Kennedy, 1999) have
indicated that the late stage of disease is characterized
by inflammatory processes (Kennedy, 1999). In
particular, non-specific perivascular inflammatory cell
infiltrates occur in the leptomeninges and white matter,
and there is a pronounced activation of microglia and
astrocytes (Hunter et al., 1992). In mouse models of the
late stage, the onset of these histopathological changes
coincides with the up-regulation of pro-inflammatory
cytokines (Hunter and Kennedy, 1992; Hunter et al.,
1991). The resulting inflammatory response is most
pronounced
in
the
post-treatment
reactive
encephalopathy (PTRE) which occurs in 5–10% of
patients after treatment with arsenical drugs (Atouguia
and Costa, 1999) and which can be ameliorated in a
model system by administration of anti-inflammatory
agents (Hunter et al., 1992). The trypanostatic drug
DFMO
reduces
astrocyte
activation
and
neuroinflammatory responses, and this may be a key
factor in its efficacy (Jennings et al., 1997). Thus, the
mouse model predicts that the pathological sequelae of
late-stage sleeping sickness are mediated by proinflammatory cytokines in the brain, released by activated
astrocytes or microglia. This scenario is consistent with
Musa et al. 163
Figure 2.
inflammatory pathology caused by other infectious
diseases in the CNS, such as tuberculous meningitis
(Tsenova et al., 1999).
The above prediction was not immediately borne out
when the first analysis of cytokines in the CSF of sleeping
sickness
patients
was
undertaken.
In
both
T. b. rhodesiense and T. b. gambiense patient CSFs, the
late stage was associated with increased IL-10 and IL-6
but not TNF-α or IFN-γ (Lejon et al., 2002; MacLean et
al., 2005). Moreover, at least in the case of
T. b. rhodesiense infection, IL-10 and IL-6 were
synthesized in the CNS (MacLean et al., 2005). In no
cases was TNF-α or IL-1 detected. Can this result be
reconciled with post-mortem histological evidence of
inflammatory pathology and the results from the mouse
models? One possibility is that the published mouse
infection studies and the sleeping sickness studies are
examining different stages of the development of latestage pathogenesis. Almost all neuropathological data
from human subjects involves post-mortem studies of
PTRE cases, and much of the published mouse infection
data involves advanced CNS infection or PTRE models.
Thus, pro-inflammatory cytokines and resultant cellular
responses may be important in the ‘final stage’ of
meningoencephalitic sleeping sickness, but before this is
reached IL-10 down regulates the production of TNF-α
and other pro-inflammatory cytokines by astrocytes and
microglia, despite continued immune stimulation by the
parasites. IL-10 has been demonstrated to have similar
counter-inflammatory regulatory activity in cerebral
toxoplasmosis (Sarciron and Gherardi, 2000) and
experimental autoimmune encephalitis (Cua et al., 2001).
Initial data on the temporal progression of IL-10 and TNFα levels in the brains of mice during trypanosome
invasion support this hypothesis (Figure 2).
Figure 2. Brain IL-10 and TNF-α levels during the
development of CNS infection. Adult female CD1 mice
4
were infected with 4 × 10 T. b. brucei GVR35/CL6. In this
model, parasites first enter the brain between day 7 and
14, and increasing histopathology is evident from day 21.
This coincides with increased TNF-α levels and reduced
IL-10 levels. *significantly increased over control,
P < 0·01. Source: Sternberg JM, MacLean L, Rodgers J
and Kennedy PGE, unpublished data.
164
Glo. Adv. Res. J. Med. Med. Sci.
TOWARDS AN IMMUNOEPIDEMIOLOGY OF HUMAN
AFRICAN TRYPANOSOMIASIS?
Given the central role of inflammatory immune responses
in sleeping sickness pathogenesis, it is possible that
immunogenetic variation in host populations may
influence disease progression and outcome. This is an
area of investigation which has received scanty attention,
partly
because
substantive
field
studies
of
trypanosomiasis immunology have only recently started,
and partly because of the widely held view that infection
invariably leads to death if untreated. In fact this
statement is not correct, and not only is there evidence
that individuals can be asymptomatic carriers, but also
there are tremendous variations in the severity and speed
of progression of the disease. In T. b. gambiense
infection, apparently healthy carriers have been reported
during large-scale population surveys (Wery and Burke,
1972; Jamonneau et al., 2004). Indeed, one widely used
experimental isolate of T. b. gambiense was derived from
a subject who had been asymptomatic for 20 years, and
was only diagnosed while living in Europe (Lapierre and
Coste, 1963).
With T. b. rhodesiense infection in man there have also
been reports of both asymptomatic carriers and mild
infections which progress with a chronic disease
evolution in the southern areas of East and Central Africa
(Ormerod, 1967; Buyst, 1977), and more recently a
systematic
study
has
confirmed
that
subacuteT. b. rhodesiense sleeping sickness exists in
Malawi (MacLean et al., 2004). These differences in
disease severity do not necessarily imply variation in host
resistance, as they could equally reflect genetic variation
in parasite virulence. Indeed innate variation in parasite
virulence is certainly manifest is experimental infections,
where subclones of differing but stable virulence
phenotype can be generated from a single parental clone
(Inverso et al., 1988), and such variation is clearly evident
in human infection in the difference in disease
progression
between
T. b. rhodesiense
and
T. b. gambiense. However, experimental models also
demonstrate that host genotype influences the
progression of trypanosome infection. Inbred mouse
models range from highly susceptible to subtolerant to
trypanosome infection. Subtolerance is not related to H-2
(Clayton, 1978) and is under polygenic control (Murray et
al., 1984). The genetics of the control of
susceptibility/subtolerance to trypanosome infection has
been studied in detail using the cattle parasite,
Trypanosomacongolense in mouse infection models.
Three quantitative trait loci (QTLs) have been identified,
designated Tir1, Tir2, Tir3 (Kemp et al., 1997). Fine
mapping (Iraqi et al., 2000) has recently led to the
resolution of three QTLs within Tir3. One of these (Tir3b)
maps close to the chromosomal location of both the IL-10
gene and a key regulatory gene for IL-10 synthesis on
chromosome 1 (Tabel et al., 2000), although it must be
emphasized that the resolution of these QTLs is still
limited, with a 95% CI for Tir3b of 10 cm. Similar studies
are being made to understand the genetic basis of
trypanotolerance in cattle (Kemp et al., 1997). While it is
important to bear in mind that there are fundamental
differences in pathogenesis between T. congolense and
T. brucei spp. (Taylor and Mertens, 1999), it is
reasonable to ask if it is possible that a similar
immunogenetic control of disease severity may be found
in HAT? At present there is no definitive answer to this
question, but there are some intriguing clues in a
comparative study of clinical presentation, disease
progression and plasma cytokine responses of
T. b. rhodesiense-infected patients in Malawi and Uganda
(MacLean et al., 2004). Disease in Ugandan patients was
acute, with rapid progression to late stage. In contrast, in
Malawi the disease was mild, no patients had chancres,
and progression to late stage was slow, with some
individuals remaining in early stage for several months or
longer. In both localities the parasites were clearly
T. b. rhodesiense, because they carried the SRA gene.
When the plasma cytokine levels of the two groups were
compared, dramatic differences in inflammatory/counterinflammatory responses were observed. Whereas IFN-γ
and IL-10 were elevated in all cases, TNF-α was elevated
only in the acute disease group from Uganda.
Conversely, in the mild disease group from Malawi, TNFα levels remained normal but TGF-β levels were
elevated. TGF-β has multiple functions depending on its
environment and concentration, but at high concentration
it suppresses TNF-α production by macrophages
(Espevik et al., 1987) and NK cells (Bellone et al., 1995).
If TNF-α does indeed mediate the onset of pathology and
disease progression, the capacity to maintain a TGF-βmediated counter-inflammatory response may be critical
to the mild presentation of T. b. rhodesiense infection and
for the slow progression to CNS infection in Malawian
HAT cases. TGF-β seems to have a similar role in
regulating disease severity in other infectious diseases,
including malaria (Omer et al., 2000). Of course, an
association of cytokine responses with disease severity
does not demonstrate causality, and it may yet be that
the potent pro-inflammatory response observed in
Ugandan patients is simply a reflection of an innately
more aggressive parasite. However, there are other clues
that host genotype may be involved in determining
disease severity, and thus polymorphisms in immune
response regulation may be significant. In a study of
sleeping sickness in Zimbabwe, where the mild
presentation of T. b. rhodesiense infection occurs, it was
found that while all European patients developed
chancres at the site of the infective tsetse fly bite and
subsequent severe pyrexial illness, African patients did
not develop chancre and limited data suggested a
reduced severity of pyrexia (Ashworth and Goldsmid,
1975). This is consistent with the presentation of sleeping
sickness in Malawi, but not in Uganda. It has been
Musa et al. 165
proposed that populations of Bantu ancestry may have a
degree of innate resistance to T. b. rhodesiense sleeping
sickness (Buyst, 1977), and this is consistent with
modern populations in the southern foci largely being of
Bantu ancestry, whereas in the northern foci there are
significant populations of Nilo-Hamitic descent who
migrated to the lake Victoria basin from a tsetse-free area
to the north.
CONCLUDING REMARKS
Although immunological study of African trypanosomiasis
in humans is still in its infancy, dysregulated inflammatory
responses appear to play a role disease progression and
pathology consistent with that described in experimental
mouse models, with the outcome of infection being
determined by a balance between pro-inflammatory
triggering by parasite components, such as GPI, and
counter-inflammatory regulatory mechanisms involving
IL-10 and TGF-β. An understanding of the immunological
component of this disease offers new opportunities for
therapeutic intervention, and already preliminary data on
vaccination with GPI in mice indicates that TNFassociated immunopathology is reduced in subsequently
infected mice (Magez et al., 2002). Furthermore, as the
first systematic studies of trypanosomiasis patients with
varying severity of disease begin (MacLean et al., 2004),
it should be possible to determine if there is indeed an
immunogenetic component to HAT.
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