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Monday 6 October 2003

malarial infections

Definition: Malaria, caused by the intracellular parasite Plasmodium, is a worldwide infection that affects 300 million and kills 1 million people each year.


- man recently returned from Africa. Liver failure 2 to Malaria. hepatic malaria

According to the World Health Organization, 90% of deaths from malaria occur in sub-Saharan Africa, where malaria is the leading cause of death in children younger than 5 years old.

Plasmodium falciparum, which causes severe malaria, and the three other malaria parasites that infect humans (Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae) are transmitted by female Anopheles mosquitoes that are widely distributed throughout Africa, Asia, and Latin America.

Nearly all of the approximately 1500 new cases of malaria each year in the United States occur in travelers or immigrants, although rare cases transmitted by Anopheles mosquitoes or blood transfusion do occur.

Worldwide public health efforts to control malaria in the 1950s through 1980s failed, leaving mosquitoes resistant to DDT and malathion and Plasmodium resistant to chloroquine and pyrimethamine.


- CD36 polymorphism is associated with protection from cerebral malaria (12506336)


Possible regulation of adaptive immunity to blood-stage malaria by cytokines produced by cells of the innate immune response.

In response to parasite ligands recognized by pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and CD36, or inflammatory cytokines, such as interferon-gamma (IFN-gamma), dendritic cells (DCs) mature and migrate to the spleen — the primary site of immune responses against blood-stage Plasmodium parasites.

Maturation of DCs is associated with the upregulation of expression of MHC class II molecules, CD40, CD80, CD86 and adhesion molecules and the production of cytokines including interleukin-12 (IL-12).

IL-12 activates natural killer (NK) cells to produce IFN-gamma and induces the differentiation of T helper 1 (TH1) cells. The production of cytokines, particularly IFN-gamma, by NK cells results in DC maturation and enhances the effect of parasite-derived maturation stimuli, facilitating the clonal expansion of antigen-specific naive CD4+ T cells.

IL-2 produced by antigen-specific TH1 cells further activates NK cells to produce IFN-, which induces DC maturation and activates macrophages, further amplifying the adaptive immune response.

Cytokines such as IL-10 and transforming growth factor-beta (TGF-beta or TGFB) negatively regulate both innate and adaptive responses.

Host Resistance to Plasmodium

There are two general mechanisms of host resistance to Plasmodium. First, inherited alterations in red blood cells make people resistant to Plasmodium. Second, repeated or prolonged exposure to Plasmodium species stimulates an immune response that reduces the severity of the illness caused by malaria.

Several common mutations in hemoglobin genes confer resistance to malaria. People who are heterozygous for the sickle cell trait (HbS) become infected with P. falciparum, but they are less likely to die from infection.

The HbS trait causes the parasites to grow poorly or die at low oxygen concentrations, perhaps because of low potassium levels caused by potassium efflux from red blood cells on hemoglobin sickling. The geographic distribution of the HbS trait is similar to that of P. falciparum, suggesting evolutionary selection of the HbS trait in people by the parasite.

HbC, another common hemoglobin mutation, also protects against severe malaria by reducing parasite proliferation. People can also be resistant to malaria due to the absence of proteins to which the parasites bind. P. vivax enters red blood cells by binding to the Duffy blood group antigen. Many Africans, including most Gambians, are not susceptible to infection by P. vivax because they do not have the Duffy antigen.

Individuals living where Plasmodium is endemic often gain partial immune-mediated resistance to malaria, evidenced by reduced illness despite infection. Antibodies and T lymphocytes specific for Plasmodium reduce disease manifestations, although the parasite has developed strategies to evade the host immune response. P. falciparum uses antigenic variation to escape from antibody responses to PfEMP1.

Each haploid P. falciparum genome has about 50 var genes, each encoding a different form of PfEMP1. The mechanism of var regulation is not known, but at least 2% of the parasites switch PfEMP1 genes each generation.

Cytotoxic T lymphocytes may also be important in resistance to P. falciparum. Individuals with the HLA allele B53 are resistant to P. falciparum, perhaps because HLA-B53 presents liver stage-specific malaria antigens to cytotoxic T lymphocytes, which then kill malaria-infected hepatocytes.142 The parasite has also evolved to evade this mechanism of the immune response: Plasmodia-infected red blood cells inhibit cytotoxic T-lymphocyte development by blocking maturation and antigen presentation by dendritic cells. Despite enormous efforts, there has been little success in developing a vaccine for malaria.


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 macrophages in the spleen. 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 phagocytic cells containing granular, brown-black, faintly birefringent hemozoin pigment. In addition, macrophages with engulfed parasites, red blood cells, and debris are numerous.

With progression of malaria, the liver becomes progressively enlarged and pigmented. 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 (Fig. 8-52). 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 Dürck 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.


- Haldar K, Murphy SC, Milner DA, Taylor TE. Malaria: Mechanisms of Erythrocytic Infection and Pathological Correlates of Severe Disease. Annu Rev Pathol. 2007 Feb 28;2:217-249. PMID: 18039099

- Kwiatkowski DP. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet. 2005 Aug;77(2):171-92. PMID: 16001361

- Silvie O, Franetich JF, Renia L, Mazier D. Malaria sporozoite: migrating for a living. Trends Mol Med. 2004 Mar;10(3):97-100. PMID: 15106591

- Fortin A, Stevenson MM, Gros P. Susceptibility to malaria as a complex trait: big pressure from a tiny creature. Hum Mol Genet. 2002 Oct 1;11(20):2469-78. PMID: 12351583