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Human Host and Malaria

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Pathophysiology of Malaria | Genetic Factors That Influence Malaria | Immune Responses to Malaria

Pathophysiology of Malaria

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.

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.