Biomedical Engineering Reference
In-Depth Information
11.2 Malaria
Worldwide, malaria accounts for 2-3 million deaths each year, including many
children in Africa. In addition,
300 million clinical cases are reported each
year. As the symptoms caused by infection with the malaria parasite are
debilitating, there can be major effects on commerce, education, and other
functions of a growing nation. Nearly half of the world's population lives in
regions where malaria is endemic. These facts have led the World Health
Organization to issue a call for new drug development. This effort is especially
important, as resistance against the current therapeutics is increasing.
The life cycle of the malaria parasite in man begins with the injection of
sporozoites into the bloodstream through the bite of an infected female ano-
pheline mosquito while it is taking a blood meal. The sporozoites travel
through the bloodstream to the liver, where they invade liver parenchymal cells.
There, they transform into an exoerythrocytic stage parasite that divides by
schizogony until the liver cell ruptures, releasing thousands of merozoites into
the bloodstream. The merozoites invade red blood cells, initiating the blood-
stage infection. Each merozoite develops inside the erythrocyte and divides by
schizogony until the red cell ruptures, releasing 16-32 daughter merozoites,
which invade new red blood cells.
During the intraerythrocytic stage, the parasite degrades hemoglobin
through a semi-ordered pathway involving aspartic, cysteine, and metallo-
peptidases.
3,4
The parasite engulfs hemoglobin via the cytostome, a specialized
organelle of the parasite, and the hemoglobin is transported to the food vacuole
in endosomal vesicles. During this process, digestive enzymes of the aspartic
peptidase class
5
, which are resident in the cytostome membranes, are also
released into the food vacuole and converted from the inactive proenzyme form
to the mature and catalytically active form. Subsequently, hemoglobin is
degraded by initial cleavage of the Phe-Leu peptide bond between residues 33
and 34 of the a-chain. Additional cleavages lead to the production of peptide
fragments, which can be processed by aminopeptidases in the cytosol of the
erythrocyte.
It was originally believed that degradation of hemoglobin was essential to
provide nutrient amino acids for energy metabolism and new protein synthesis
to the developing parasite. However, in addition to the nutritional needs of the
parasite, our current thinking is that it is essential to create space for the growth
of the parasite and provide osmotic stability in the red blood cell as the parasite
develops. The parasite can digest up to 75% of the hemoglobin of an infected
erythrocyte before rupture of the cell and release of new merozoites. The
merozoites, in addition to invading new erythrocytes, can develop into sexual
stages (gametocytes and microgametocytes) in the next stage of infection.
During rupture of the erythrocyte, the products of hemoglobin digestion,
which include hemozoin, a black-pigmented material composed of crystallized
hemin groups, are released, leading to an inflammatory response, which gives
the high fevers and chills that are characteristic of malaria. The bite of another
mosquito leads to uptake of some of the gametocytes and microgametocytes,
B
