Immune Evasion by Parasites Causing 
Tropical Diseases 
John E. Donelson, Ph.D. — Investigator 
Dr. Donelson is also Distinguished Professor in the Department of Biochemistry at the University of Iowa, 
Iowa City. He obtained his bachelor's degree in biophysics from Iowa State University, served as a Peace 
Corps volunteer for two years in Ghana, West Africa, and then completed a Ph.D. degree in biochemistry 
at Cornell University. His postdoctoral research was conducted at the MRC laboratory of Molecular 
Biology in Cambridge, England, and at Stanford University. He has received the Iowa Governor's 
Science Medal and the Burroughs Wellcome Award in Molecular Parasitology. 
THE risk of acquiring parasitic infections is a 
part of the daily lives of more than 3 billion 
people living in the developing countries of the 
tropics. The various protozoan and helminthic 
parasites that are responsible for these infectious 
diseases possess a variety of mechanisms for evad- 
ing the immune response of their hosts. Our labo- 
ratory studies the interactions between several of 
these parasites and the immune system, in antici- 
pation that a more detailed understanding of 
these immune evasion mechanisms will suggest 
better ways to combat or prevent the infections. 
The parasites that cause three of these tropical 
diseases are described here. 
Trypanosomiasis 
African trypanosomes are protozoan parasites 
that cause sleeping sickness or trypanosomiasis 
throughout equatorial Africa. They are transmit- 
ted from tsetse flies to the mammalian blood- 
stream, where they continually confront the hu- 
moral and cellular immune systems. Each 
trypanosome in the bloodstream is covered by 
about 10 million copies of a single protein, the 
variant surface glycoprotein (VSG). The trypano- 
some population survives the continuous 
immune assault because individual parasites 
occasionally switch spontaneously from the ex- 
pression of one VSG to another — a process called 
antigenic variation. A new immune response 
must be mounted against the VSG of the switched 
parasite and its descendants, enabling the trypan- 
osome population as a whole to stay "one step 
ahead" of the host immune defenses. We are ex- 
amining the events at the DNA and RNA level that 
are responsible for this antigenic variation. 
We know that the trypanosome genome con- 
tains about 1,000 different genes encoding anti- 
genically distinct VSGs. Usually one, and only 
one, of these VSG genes is expressed at a time. 
Rearrangements and duplications of these genes 
are partly responsible for the selection of which 
VSG gene is to be transcribed and for the switch 
event itself. 
The rearrangements maneuver specific VSG 
genes into and out of special chromosomal loca- 
tions, called expression sites, where transcrip- 
tion occurs. These expression sites are always lo- 
cated near the ends of the chromosomes, i.e., 
near the chromosomal telomeres, for reasons that 
are not well understood. The expression process 
is complicated by the fact that several, and per- 
haps many, potential telomere-linked expression 
sites exist in the genome, yet only one is normally 
activated at any time. Our goal is to understand 
this activation mechanism at the molecular level. 
In one project we have identified a protein that 
specifically binds to a region upstream of a VSG 
gene in an expression site activated during the 
final developmental stage of the parasite in the 
tsetse fly, i.e., the metacyclic stage. We think that 
this protein may contribute to the developmental 
regulation of that VSG gene's transcription. In an- 
other project we have detected a high rate of mu- 
tation in the telomere-linked VSG genes, which 
may increase the effectiveness of antigenic varia- 
tion still further. A third project involves a charac- 
terization of a group of very small chromosomes 
that are unique to African trypanosomes and con- 
tain many of the VSG genes destined for sequen- 
tial expression. In still another project we have 
introduced into trypanosomes several plasmids 
containing combinations of sequences upstream 
of an expressed VSG gene and an easily detected 
luciferase gene in an effort to identify the se- 
quences that regulate the transcription of the 
VSG gene. 
Leishmaniasis 
Leishmania parasites are protozoan pathogens 
that cause a spectrum of diseases, including cuta- 
neous, mucocutaneous, and visceral leishmania- 
sis, in many tropical countries. During their life 
cycle these parasites reside in both the sandfly 
vector and a mammalian host. Within sandflies 
they exist as uniflagellar promastigotes that de- 
velop from a less-infectious form to the final 
highly infectious form. This developmental pro- 
cess can be mimicked during cultivation of pro- 
mastigotes in liquid medium. After transmission 
from the sandfly to the mammalian host blood- 
stream, the promastigotes penetrate host macro- 
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