trans

90 ANTIGENIC VARIATION
scientific recognition so far. In contrast, variant
antigens on the surface of the malaria-infected
erythocyte appear to have more complex functions.
These differences probably reflect the
major differences in the life of these two protozoal
pathogens: the African trypanosomes are
extracellular throughout their occupation of
the mammalian host whereas multiplication of
malaria parasites occurs intracellularly, initially
in the liver but predominantly in erythrocytes.
Although generally referred to as ‘bloodstream
forms’, trypanosomes generally populate the
interstitial spaces, lymphatics and capillary
beds at higher concentrations than they are
found in the major blood vessels. As infection
progresses, trypanosomes migrate to the central
nervous system, leading to coma and inevitable
death. Because of the state of knowledge about
antigenic variation in trypanosomes, which is
largely attributable to the relative ease with
which they can be studied in the laboratory,
this chapter will focus on trypanosomes. Investigations
of the molecular genetics of antigenic
variation in malaria have lagged behind those of
trypanosomes, but are rapidly gaining ground.
During the 1990s, trypanosomes and malaria
parasites have become more amenable to cultivation
and genetic manipulation. When these
advances are coupled to the output of genomic
sequencing projects, the prospects of understanding
the ways in which these parasites
evade the immune responses of their hosts look
brighter than ever. Meanwhile, antigenic variation
remains a major obstacle to immunization
against malaria and sleeping sickness.
AFRICAN TRYPANOSOMES
Trypanosomes are members of the order
Kinetoplastida, which comprises unicellular
parasitic protozoa distinguished by a single flagellum
and a kinetoplast, an ancient misnomer
for the mitochondrial DNA (kinetoplast DNA
or kDNA: see Chapter 12) that is neither a
discrete organelle – although located in a specific
region of the single mitochondrion – nor
involved in motility of the organism, despite
its juxtaposition with the basal body of the flagellum.
Trypanosomes are ubiquitous parasites
of invertebrate and vertebrate hosts throughout
the world. They represent an evolutionary
branch that diverged 500 MYA. African trypanosomiasis
is a zoonosis. About a dozen
Trypanosoma species and subspecies populate
the African mammalian fauna, from small
antelopes to large carnivores. Although many
animals and indigenous cattle harbor the same
trypanosome species that are fatal to humans
and to imported livestock, most of the fauna
appear to tolerate trypanosome infections
without overt pathology, presumably due to
natural selection during millions of years of
co-evolution. Some animals, including humans,
have innate immunity to the majority of trypanosome
species and clones. I will return to
this interesting topic in a later section. African
trypanosomes are a more constant factor in
animal husbandry (cattle, goats, sheep, pigs,
horses, and dogs are constantly challenged)
than for humans, but, in many locations, human
sleeping sickness remains a serious threat,
almost to the same extent as in the early part of
the twentieth century. The separate evolution
and primary geographic restriction of trypanosomes
that cause so-called African trypanosomiasis
appears to be largely dependent
on the range of their specific insect vector
Glossina, commonly known as the tsetse.
Notwithstanding the several developmental
stages that trypanosomes obligatorily undergo
in the tsetse, transmission can occur in the
absence of this vector. This is exemplified by
the presence of T. vivax and T. evansi in South
America and Asia, where they are transmitted
by biting flies and vampire bats. T. equiperdum
MOLECULAR BIOLOGY