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INNATE RESISTANCE, HUMAN SUSCEPTIBILITY AND SEX 105
geographic separation closely follows the
western edge of the African rift valley. The virulent
East African T. rhodesiense causes acute
disease that leads to death in a matter of
weeks. The typical West African T. gambiense is
less virulent, causing a chronic infection that
can take a year or more to death. The issue of
genetic exchange is raised here because it is
relevant to the origins and population stability
of human-infective lines. Genetic exchange
can occur between lines of T. brucei under laboratory
conditions and probably occurs infrequently
in natural infections, where it is less
easy to observe. Sex is not an obligatory stage
in the trypanosome life cycle and its mechanism
is unclear. Some form of ‘mating’ takes
place in the tsetse, possibly in the epimastigote
stage in the salivary gland, but no haploid
stage has been identified. A still debatable but
reasonable hypothesis is that T. gambiense
and T. rhodesiense are human-infective clones
of T. brucei that are substantially or completely
genetically isolated. There is evidence that
typical T. gambiense isolates are clonal and
have a more limited and homogeneous VSG
repertoire. Typing of T. rhodesiense from different
epidemics, using various molecular markers,
suggests that new and old outbreaks are
caused by very similar clones.
Human resistance to infection by T. b. brucei
has been attributed to two sub-fractions of
serum high-density lipoprotein, operationally
known as trypanosome (T. b. brucei) lytic
factor (TLF). The presence of one unique component,
haptoglobin-related protein (Hpr),
distinguishes highly purified TLF from other
HDL fractions, but the mechanism by which
TLF causes lysis is unknown, beyond the fact
that the difference between TLF-sensitive and
resistant trypanosomes apparently depends
on whether TLF is endocytosed (sensitive) or not
(resistant). The genetics of Hpr itself are interesting
and suggestive of ancient evolutionary
selection for resistance to trypanosomiasis.
Human primate ancestors may have evolved
resistance to T. b. brucei when Hpr arose by triplication
of the haptoglobin locus in Old World
primates, subsequently reduced to a duplication
in humans. Chimpanzees, which are susceptible
to T. b. brucei, have a frameshift
mutation in their Hpr gene. Intriguingly, the
Hpr gene is amplified in a significant proportion
of African Americans.
Although incompletely understood, we
know more about the human infectivity of
T. rhodesiense than of T. gambiense. Although
it may not be the only gene that can confer
human infectivity, one gene has been identified
that certainly can. This so-called ‘serumresistance-associated’
(SRA) gene encodes an
intriguing and probably GPI-anchored cellsurface
protein that seems to be a mosaic of
a truncated VSG-like amino-terminal domain
fused to a typical VSG carboxy-terminal domain
(Figure 5.3). SRA is present in one ES, which
explained previous conflicting results suggesting
that human resistance was sometimes
linked to VSG switching, but not necessarily
so. Its presence in one ES, which is also atypical
in its structure (it contains only ESAGs 5, 6
and 7), could also explain why serum resistance
would be more readily lost than gained,
and may be part of the explanation of why
T. rhodesiense epidemics arise sporadically yet
seem to be relatively clonal in nature. We do
not know why and how SRA expression allows
trypanosomes to evade the innate TLF-based
resistance mechanism. Once we understand
the structure, origin and action of the SRA protein,
we may be able to better understand and
even predict the chances that human-infective
clones of T. brucei will arise from within the populations
circulating in the tsetse. T. gambiense
does not have a direct homolog of the SRA
gene, and the mechanism that enables it to
survive the presence of TLF is unknown.
MOLECULAR BIOLOGY