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. 
He obtained his bachelor's degree in biophysics from Iowa State University, served as a Peace Corps vol- 
unteer 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, California. He has received the Iowa Governor's Science 
Medal and the Burroughs-Wellcome Award in Molecular Parasitology. 
MORE than a billion people in tropical areas 
of the world endure parasitic infections 
during most of their life. The various protozoan 
and helminthic parasites that cause these in- 
fectious diseases have evolved a variety of mecha- 
nisms for evading the immune response of their 
hosts. Our laboratory studies the interactions be- 
tween several of these parasites and the immune 
system, in anticipation that a more detailed un- 
derstanding of these immune evasion mecha- 
nisms will suggest ways in which to combat or 
prevent the infections. The parasites that cause 
three of these tropical diseases are described 
here. 
Leishmaniasis 
Leishmania parasites are protozoan pathogens 
found in many tropical countries, where they 
cause a spectrum of diseases that include cutane- 
ous, mucocutaneous, and visceral leishmaniasis. 
The parasites have a two-stage life cycle that oc- 
curs in the sandfly vector and a mammalian host. 
Within sandflies they exist as uniflagellar pro- 
mastigotes and develop from a less infectious 
form to the final highly infectious form. This de- 
velopmental process can be mimicked during 
cultivation of promastigotes in liquid medium. 
After transmission from the sandfly to the mam- 
malian host, promastigotes are phagocytosed by 
host macrophages, where they reside as spherical 
amastigotes in acidic phagolysosomes. Thus the 
parasites evade the immune response by "hid- 
ing" inside macrophages — one of several cell 
types of the immune system that normally help to 
destroy foreign pathogens and substances. When 
a sandfly ingests amastigote-laden macrophages 
during a blood meal, the life cycle is completed. 
We are studying how these organisms are able to 
survive in hostile environments as diverse as a 
sandfly midgut and an acidic macrophage 
phagolysosome . 
A major glycoprotein on the surface of both 
promastigotes and amastigotes is a metallopro- 
tease of about 63 kDa (gp63) This enzyme proba- 
bly participates in the uptake of the promasti- 
gotes by macrophages and contributes to the 
survival of the amastigotes within them. The 
amount of gp63 on the surface of promastigotes 
increases about 10-fold as the parasites develop 
into the highly infectious, virulent form during 
growth in culture. We have recently discovered 
that three different RNA species encoding gp63 
occur during cultured promastigote growth. One 
RNA species is present in the organisms only dur- 
ing the early, less infectious stages of cultured 
growth, when little gp63 is on the promastigote 
surface. This gp63 RNA disappears and another 
gp63 RNA species appears as the promastigotes 
become more infectious. The amount of this sec- 
ond RNA correlates with the increased amount of 
gp63 protein. The third gp63 RNA species is con- 
tinuously present at a low level throughout cul- 
tured growth. The three RNAs encode similar 
gp63 proteins and difl'er primarily in the nucleo- 
tide sequences of their 3'-untranslated regions. 
They are derived from diff'erent genes, and we are 
determining the molecular mechanisms that regu- 
late their differential expression. In addition, we 
are introducing recombinant DNAs into leish- 
mania to amplify, alter, or delete individual gp63 
genes so that we may determine the functions of 
each of the three gp63 proteases during the pro- 
mastigote and amastigote stages. 
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 try- 
panosome population survives the continuous 
immune assault because individual parasites oc- 
casionally switch spontaneously from the expres- 
sion of one VSG to another — a process called an- 
tigenic variation. A new immune response must 
be mounted against the VSG of the switched para- 
site and its descendants, enabling the trypano- 
some population as a whole to stay "one step 
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