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Pathophysiology of Malaria | Genetic
Factors That Influence Malaria | Immune
Responses to Malaria
Pathophysiology
of Malaria
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This woman, seen at a clinic in Thailand near the Myanmar border, had microscopically confirmed Plasmodium falciparum malaria. Image contributed by Shoklo Malaria Research Unit, Mae Sot, Thailand.
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All
the typical clinical symptomology and severe disease pathology associated
with malaria is caused by the asexual erythrocytic or blood stage parasites.
When
the parasite develops in the erythrocyte numerous known and unknown waste
substances such as hemozoin pigment and other toxic factors accumulate
in the infected red blood cell. These are dumped into the bloodstream
when the infected cells lyse and release invasive merozoites. The hemozoin
and other toxic factors such as glucose phosphate isomerase (GPI) stimulate
macrophages and other cells to produce cytokines and other soluble
factors which act to produce fever, rigors and probably influence other
severe pathophysiology associated with malaria.
Plasmodium falciparum-infected erythrocytes, particularly those
with mature trophozoites, adhere to the vascular endothelium of venular
blood vessel walls and do not freely circulate in the blood. When this
sequestration of infected erythrocytes occurs in the vessels of the
brain it is believed to be a factor in causing the severe disease syndrome
known as cerebral malaria, which is associated with high mortality.
Anemia
is also associated with malaria infections and is frequently severe in
children and pregnant women infected with P. falciparum. Severe
anemia can also be seen with P. vivax infections. Macrophages not
only clear infected erythrocytes but also phagocytize and destroy uninfected
red blood cells during malaria infections. Active malaria infections also
through unknown mechanisms induce bone marrow dyscrasias and suppress
normal development. Intravascular hemolysis does not appear to be a major
contributor to malarial anemia except in the pathological state known
as blackwater fever.
Genetic
Factors That Influence Malaria
Innate
factors are those specific characteristics of a host that are present
from birth. Several innate influence malaria infection. For example,
persons who carry the sickle cell trait (heterozygotes
for the abnormal hemoglobin gene HbS) will be relatively protected
against severe disease and death caused by Plasmodium falciparum malaria.
In general, the prevalence of hemoglobin-related disorders and other
blood cell dyscrasias, such as Hemoglobin C, the thalassemias and
G6PD deficiency, are more prevalent in malaria endemic areas and are
thought to provide protection from malarial disease. Another example
of a genetic factor involves persons who do not have the Duffy blood
on their erythrocytes. These Duffy negative individuals have red blood
cells that are refractory to infection by P.
vivax. Most of the people in West Africa and much of East Africa
do not have this receptor and they are protected from P. vivax infection.
Immune
Responses to Malaria
Acquired
factors are not present at birth but are those characteristics which people
can adaptively develop later, such as the development of acquired immunity.
People residing in malaria-endemic regions acquire immunity to malaria
through natural exposure to malaria parasites. This naturally acquired
malarial immunity that is protective against parasites and clinical disease
results only after continued exposure from multiple infections with malaria
parasites over time. Clinical immunity generally provides protection against
severe effects of malaria but fails to provide strong protection against
infection with malaria parasites, and generally develops first. After
several years of continued exposure people develop immunity that limits
high-density parasitemia; however it does not lead to sterile protection.
The
transmission intensity influences the course of development of both clinical
and parasitic immunity. Where malaria transmission is intense, young children
bear the brunt of the disease, but as they grow older, they build up an
acquired immunity and are relatively protected against disease and blood
stage parasites. In areas of low malaria endemicity both children and
adults suffer disease and high parasitemia since exposure is less.
Two
other characteristics of the immunity acquired against malaria is that
the maintenance of this non-sterile state of immune protection requires
continued exposure to malaria infection and a functioning spleen. Splenectomy
makes an otherwise immune protected animal or human fully susceptible
again to infection and disease. Likewise, when immune individuals leave
a malaria endemic area and reside for several years in a malaria-free
area often become susceptible to infection and clinical symptoms if they
return to a malarious area.
Malaria
parasites infect different targets such as liver and erythrocytes and
therefore different immune responses are elicited by infection with malaria
parasites. These immune responses include antibodies, lymphocytes, monocytes,
macrophages, natural killer (NK) cells, and neutrophils. Experimental
studies have shown that both antibodies, cells and cellular factors can
mediate protection in malaria as well as disease.
Antibodies
can mediate their protective effect by multiple mechanisms. Antibodies
developed against parasites can neutralize the parasites, retard parasite
development and prevent them from entering target cells and help macrophages
to efficiently engulf the parasites and infected cells. Antibodies developed
against gametocytes (sexual stage parasites) can prevent development of
sexual stage parasites in mosquitoes when taken up along with the blood
meal. This type of immune protection is often referred to as transmission-blocking
immunity.
Some
of the research conducted
by CDC scientists focuses on how humans acquire protective antibodies
after natural exposure to malaria parasites and how it helps them to
control malaria parasites and prevent disease. NK cells and neutrophils
are first line defenses against malaria and they can attack malaria parasites
in several ways. Macrophages are responsible for eventual clearance of
parasites from the blood. These cells engulf malaria parasites and parasitized
erythrocytes and kill them. Cellular immunity involving cytotoxic T
cells are particularly effective in attacking malaria parasites during
the liver stage development. Cytokines (cellular factors) released from
lymphocytes enhance this process. Cytokines secreted by different leukocyte
populations may also play a direct role in protection. For example,
interferon-gamma has been shown to work against liver stage parasite
development and activate macrophages to attack blood stage parasites.
Cytokines
are also responsible for the severity of disease. A cytokine known as
tumor necrosis factor (TNF)-alpha is one factor responsible for inducing
high fever observed in malaria patients. The severity of disease may
vary depending upon the level and the type of cytokines produced after
malaria parasite infection. CDC scientists conduct research to know
more about these cytokines that influence disease manifestation one
way or the other. Such studies will help in developing further improvements
for treating severe malaria disease. For example, only about 2/3 of
the patients who develop the clinical syndrome known as cerebral malaria
survive after curative and supportive treatment. It is not known, though,
why still about 20 to 30% of patients die despite treatment. Understanding
the host immune pathways may help to improve treatments for cerebral
malaria. Similar studies will also help in understanding maternal and
neonatal complications associated with malaria
during pregnancy. This includes understanding why some women deliver
prematurely after malaria and why some women deliver low birth weight
babies.
Each
of the developmental forms (liver stages, asexual blood stages, gametocytes,
sporozoites) of the malaria parasites presents a different group of targets
(antigens) to the immune system of the infected host. In addition to this
diversity of targets, malaria parasites mutate rapidly generating different
variant forms such that individual antigens may differ within the same
species of parasite. This ability to generate different forms and a diversity
of polymorphism within the antigenic targets of the host's immune system
help the parasites to evade malarial immunity. Characterization of parasite
diversity is critical for developing suitable targets for vaccine development.
Date: April 23, 2004
Content source: National Center for Infectious Diseases, Division of Parasitic Diseases
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