USMLE – Malaria
Malaria caused by the intracellular protozoan parasite Plasmodium falciparum is a worldwide infection that affects 100 million and kills 1 to 1.5 million persons per year and so is the major parasitic cause of death. P. falciparum and the three other malaria parasites that infect humans (P. vivax, P. ovale, P. malariae) are transmitted by more than a dozen species of Anopheles mosquitoes widely distributed throughout Africa, Asia, and Latin America. The wide geographic distribution of malaria is due to the failure of a massive campaign from the 1950s to 1980s to eradicate malaria. This campaign produced mosquitoes that are resistant to DDT and malathion and P. falciparum parasites resistant to chloroquine and pyrimethamine. Some of the molecular mechanisms for parasite resistance to these drugs have recently been determined.
P. vivax and P. malariae cause mild anemia and, in rare instances, splenic rupture and nephrotic syndrome. Acute P. falciparum infections produce high parasitemias, severe anemia, cerebral symptoms, renal failure, pulmonary edema, and death. Therefore, the focus of the discussion that follows is on the pathologic process caused by P. falciparum.
Malaria sporozoites, the stage transmitted by mosquito bites, have a single antigen on their surface that is an important vaccine candidate. Sporozoites are released into the blood and within minutes attach to and invade liver cells by binding to the hepatocyte receptor for the serum proteins thrombospondin and properdin, located on the basolateral surface of hepatocytes. The binding is accomplished because of the presence of sporozoite surface proteins that contain a domain homologous to the binding domain of thrombospondin. Within liver cells, malaria parasites multiply rapidly, so as many as 30,000 merozoites (asexual, haploid blood forms) are released when the hepatocyte ruptures. The HLA-B53-associated resistance to P. falciparum infections exhibited by many Africans appears to be caused by the ability of HLA-B53 to present liver stage-specific malaria antigens to cytotoxic T cells, which then kill malaria-infected hepatocytes.
Once released, P. falciparum merozoites bind by a parasite lectin-like molecule to sialic residues on glycophorin molecules on the surface of red blood cells. (P. vivax merozoites bind by a homologous lectin to the Duffy antigens on red blood cells, so many Africans who are Duffy negative are resistant to this parasite.) The merozoites release multiple proteases from a special organelle called the rhoptry, also found, as we have seen, in Toxoplasma, Cryptosporidium, and Babesia parasites. Within the red blood cells, the parasites multiply in a membrane-bound digestive vacuole, hydrolyzing hemoglobin through secreted enzymes that include an aspartate protease homologous to that of HIV, which is the target of new anti-AIDS drugs. Individuals with the sickle cell trait are resistant to malaria because their red blood cells sickle when parasitized and so are removed by the spleen. Although most malaria parasites within the red blood cells develop into merozoites, rupture the cell, and then infect new red blood cells, some parasites develop into sexual forms called gametocytes that infect the mosquito when it takes its blood meal.
As the malaria parasites mature within red blood cells, they change morphologic appearance from ring to schizont form and secrete proteins that form 100-nm bumps on the red blood cell surface, called knobs. Malaria proteins on the surface of the knobs, called sequestrins, are encoded by var genes, so called because they exhibit antigenic variation. Sequestrins bind to endothelial cells by ICAM-1, the thrombospondin receptor, and the glycophorin CD46 and so cause malaria-infected red blood cells to be removed from circulation. In this way, red blood cells containing immature ring forms of the parasite, which are flexible and can pass through the spleen, circulate in the blood, whereas red blood cells containing mature schizonts, which are more rigid, avoid sequestration in the spleen. In addition, sequestrin causes red blood cells to bind to and form rosettes with uninfected red blood cells.
Cerebral involvement by P. falciparum, which causes as many as 80% of deaths in children, is due to adhesion of the P. falciparum parasites to endothelial cells within the brain. Patients with cerebral malaria have increased amounts of ICAM-1, thrombospondin receptor, and CD46 on their cerebral endothelial cells (perhaps activated by cytokines such as TNF) to which the malaria-infected red blood cells bind.
P. falciparum infection initially causes congestion and enlargement of the spleen, which may eventually exceed 1000 gm in weight. Parasites are present within red blood cells, and there is increased phagocytic activity of the reticuloendothelial cells. In chronic malaria infection, the spleen becomes increasingly fibrotic and brittle, with a thick capsule and fibrous trabeculae. The parenchyma is gray or black because of phagocytotic cells containing granular, brown-black, faintly birefringent hemozoin pigment. In addition, macrophages with engulfed parasites, red blood cells, and debris are numerous.
The liver becomes progressively enlarged and pigmented with progression of malaria. Kupffer cells are heavily laden with malarial pigment, parasites, and cellular debris, while some pigment is also present in the parenchymal cells. Pigmented phagocytic cells may be found dispersed throughout the bone marrow, lymph nodes, subcutaneous tissues, and lungs. The kidneys are often enlarged and congested with a dusting of pigment in the glomeruli and hemoglobin casts in the tubules.
In malignant cerebral malaria caused by P. falciparum, brain vessels are plugged with parasitized red cells, each cell containing dots of hemozoin pigment. About the vessels, there are ring hemorrhages that are probably related to local hypoxia incident to the vascular stasis and small focal inflammatory reactions (called malarial or Durck granulomas). With more severe hypoxia, there is degeneration of neurons, focal ischemic softening, and occasionally scant inflammatory infiltrates in the meninges.
Nonspecific focal hypoxic lesions in the heart may be induced by the progressive anemia and circulatory stasis in chronically infected patients. In some, the myocardium shows focal interstitial infiltrates. Finally, in the nonimmune patient. pulmonary edema or shock with DIC may cause death, sometimes in the absence of other characteristic lesions.