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Knobs, knob proteins and cytoadherence in falciparum malaria
1Department of Biotechnology, All India Institute of Medical Sciences, New Delhi.
Abstract:
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.
Insights
Knobs on infected red blood cells mediate cytoadherence, causing severe falciparum malaria. Understanding knob proteins and their interactions is crucial for developing new malaria treatments and vaccines.
Area of Science:
- Parasitology
- Molecular Biology
- Immunology
Background:
- Sequestration of infected erythrocytes (IRBC) in internal organs causes severe falciparum malaria morbidity and mortality.
- This cytoadherence is mediated by parasite-induced 'knobs' on the IRBC surface, acting as junctions with host endothelial cells.
- Knobless parasites do not cause virulent infections, highlighting the critical role of knobs in malaria pathophysiology.
Purpose of the Study:
- To explore the role of knobs in falciparum malaria pathophysiology.
- To identify and characterize knob proteins and their interactions with host endothelial receptors.
- To evaluate knob antigens as potential targets for immunotherapy and vaccine development.
Main Methods:
- Identification and classification of knob proteins (e.g., KAHRP, PFEMP-1, PFEMP-2/MESA/PP-300).
- Molecular-level studies on KAHRP and MESA/PFEMP-2, including chromosomal localization.
- Identification and partial characterization of endothelial receptor molecules for knob ligands.
Main Results:
- Several knob proteins have been identified, classified by function (knob-inducing, cytoadherent, structural).
- KAHRP is located on chromosome 2, and MESA/PFEMP-2 on chromosomes 5 and 6.
- Endothelial receptor molecules for knob ligands have been identified and partially characterized.
Conclusions:
- Knobs are critical for falciparum malaria virulence through cytoadherence.
- Knob proteins and their host receptors are potential targets for immunotherapeutic reagents.
- Further research on knob protein structure, function, interactions, and expression is needed for developing malaria treatments and vaccines.