Knobs, knob proteins and cytoadherence in falciparum malaria.

1. The sequestration of trophozoite and schizont infected erythrocytes (IRBC) in post-capillary venules of host internal organs causes most of the morbidity and mortality in falciparum malaria. It is a knob mediated cytoadherence phenomenon where knobs act as the focal junction between IRBC and host endothelial cell. Knobless (K-) parasites, isolated from cultures (not yet isolated from in vivo), do not cause virulent infections. Knobs thus play an important role in pathophysiology of falciparum malaria. 2. The chemical composition of knobs is partly explored, several proteins (Known as knob proteins) have been identified. According to their function they can be classified as (a) knob-inducing protein, "KAHRP" (b) knob-associated cytoadherent proteins, e.g. PFEMP-1, modified band 3 and an antigen recognized by monoclonal 33G2 and (c) knob-associated structural protein, e.g. PFEMP-2/MESA/PP-300. Most of them show size polymorphism among different isolates. Only KAHRP and MESA/PFEMP-2 have been studied at molecular level. Their chromosomal locations have been identified such as KAHRP on chromosome 2 and MESA/PFEMP-2 on chromosomes 5 and 6. 3. The receptor molecules on endothelial cells for knob ligands have been identified and partially characterized. 4. Knob ligands and their receptor molecules can play an important role in developing the immunotherapeutic reagents. 5. Based on the available data a tentative hypothesis has been proposed about the loss of knobs in vitro. Nevertheless, this needs further support from other experimental evidence. 6. Future work should be directed towards the structure and function of knob proteins and their interactions with each other as well as with host proteins. Regulation of expression of knobs and knob protein(s), evaluation of knob antigens for immunotherapy of severe falciparum malaria and for a malaria vaccine also require further investigations.