Malaria Pathophysiology: Genetic Factors

There seems to be several genetic factors that influence the final clinical outcome of an infection. Persons with a gain-of-function mutation in the promoter-region of “inducible nitric oxide synthase” (NOS2), the enzyme which synthetizes NO, have a 75-85% lower risk of severe malaria. NO is a strong vasodilator. High NO levels may be protective against P. falciparum infection by inhibiting cytoadherence. This suggests that the therapeutic potential of NO in the treatment of severe falciparum malaria should be evaluated. Preliminary data suggest that certain TNF-alpha alleles and certain promoters (DNA regios) confer protection against severe malaria. The mean number of complement receptor 1 (CR1, syn. CD35) molecules on erythrocytes in normal individuals is 100-1000 molecules per cell. There seems to be a direct interaction between PfEMP1 on infected cells and a functional site of CR1 on uninfected erythrocytes. This 'stickiness' between PfEMP1 and CR1 contributes to rosetting, and rosetting probably relates to obstruction of blood vessels. Complement-receptor polymorphism probably influences this interaction and therefore the severity of a malaria attack. Certain blood group antigens (e.g. Knops) are located on CR1. The relationship between malaria severity and Knops blood groups (cfr McCoy, Swain-Langley) is being studied at present. A large case-control study of malaria in West African children showed that a human leukocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as sickle-cell trait. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes as well as other genes has evolved primarily through natural selection by infectious pathogens.

Category: Medicine Notes