Further evidence of the importance of secreted cytokines in protecting the host is the
detection of raised circulation levels of IFN-γand TNF-αin humans infected mainly with
P. vivaxand P. falciparum. The fever suffered by patients with malaria may be due to the
presence of elevated levels of the pyrogenic compound TNF-α. The increased body
temperature may be inhibitory to the growth of the parasites.n 10.5 CEREBRAL MALARIA
Cerebral malaria is caused by P. falciparumand about 1% of P. falciparuminfections cause
childhood deaths. Erythrocytes containing maturing trophozoites become sequestered
in the capillaries of brain, spleen, skeletal muscles, placenta and other internal organs.
In the cerebral blood vessels the sequestration can be very dense. The exact mechanism
causing the sequestration is still not clear and it is also not clear as to why only some chil-
dren develop this condition. Patients suffering from cerebral malaria often relapse into
a coma and what causes this condition is also not entirely understood.
The coma may be due to the cerebral blood vessels becoming blocked with infected
erythrocytes attached or sequestered to the inner walls of the cerebral blood vessels. It
was found that in some of the human clinical cases of cerebral malaria the sequestered
cells in the cerebral blood vessels were exclusively parasitised erythrocytes, whereas in
the mouse model the sequestered cells were found to be leukocytes.
Children with cerebral malaria were found to have significantly higher levels of cir-
culating tumour necrosis factor alpha (TNF-α) than children infected with non-cerebral
malaria.
In mouse cerebral malaria it was demonstrated that TNF-αcan upregulate the inter-
cellular adhesion (ICAM-1) molecules responsible for the adhesion of white blood cells
to the walls of the blood vessels. An increase in the concentration of ICAM-1 molecules
was detected in mice suffering from the mouse equivalent of cerebral malaria. In
humans susceptibility to cerebral malaria may be due to whether or not TNF-αis
activated.
It is not known why a child with cerebral malaria may be deeply comatosed one
day and walking about the next. When parasitised erythrocytes in the cerebral blood
vessels are sequestered, TNF-αis released locally and this stimulates the endothelium
to release nitric oxide (NO). Nitric oxide is known to react with cells of nervous
systems and disrupts transmission of stimuli between nerve cells. Some or all of the NO
diffuses into the surrounding brain tissue and this could be the cause of the comatose
condition.
Those patients who survive being infected with P. falciparummust have developed an
immune response to the parasite to be able to control the infection. A prominent aspect
of this response is the control of asexual multiplication of the merozoites, the stage that
invades the eythrocytes. The monocytes, activated by toxins released by the parasite, secrete
the pyrogenic compound TNF-α, ie this stimulates fever. The increase in body temper-
ature may inhibit most of the growth of the parasites. The activated monoyctes and
macrophages release cytokines that activate the T cells, both T helper and T cytotoxic
cells. The Th 1 helper cells secrete IFN-γwhich, together with TNF-αalready released
by activated macrophages, stimulates both the macrophages and neutrophils to attack the
parasites.
In addition, the activated Th 2 helper cells act on the B cells which in turn produce
antibody-secreting plasma cells. The antibodies are specific to P. falciparumantigen and
may help to control the infection. The question that arises is: why is the infection not
completely eliminated?PARASITOLOGY