Malaria remains one of the most devastating infectious diseases. It kills around a million people every year while causing immense suffering and economic losses worldwide. The two main weapons to fight the disease - insecticides that kill the mosquito vector and drugs that kill the parasites in infected individuals - significantly contribute to contain the disease. However, it is imperative that additional measures, such as vaccines, be developed for the elimination and eventual eradication of the disease. Human infection is initiated when during a bite by an infected mosquito, sporozoites are deposited in the skin of the bitten person. Next, sporozoites enter the circulation and must leave it in the liver t continue their cycle. Liver vessels are lined by two cell types - endothelial cells and Kupffer cels - and sporozoites exit the vessels by preferentially traversing Kupffer cells. Using a phage peptide display library we have identified three peptides - P39, P61 and P52 - that bind specifically to Kupffer cells and by doing so, inhibit sporozoite traversal both in vitro (Kupffer ell cultures) and in vivo (live mice). Further work determined that the peptides bind to the CD68 Kupffer cell surface receptor protein. Moreover, the peptides structurally mimic domains of Plasmodium berghei glyceraldehyde 3-phosphate dehydrogenase (PbGAPDH), a protein present on the surface of sporozoites. In addition, we have shown that the CD68 and PbGAPDH proteins interact directly. This project aims at identifying domains of the PbGAPDH protein that mediate interactions with the CD68 receptor. These protein domains will be used as antigens to immunize mice. It is expected that the antibodies of immune mice will interfere with sporozoite traversal of Kupffer cells and in this way, thwart liver infection. The antigens identified in this study may conceivably be used to enhance the effectiveness of the RTS,S pre-erythrocytic vaccine, which in phase III trials has proven to be partially effective.
Malaria infection is initiated when sporozoites delivered by a mosquito bite exit the blood vessels in the liver by preferentially traversing Kupffer cells. This project seeks to identify vaccine antigens that interfere with Kupffer cell traversal. Such vaccine would protect people from malaria infection.
|Cha, Sung-Jae; McLean, Kyle Jarrod; Jacobs-Lorena, Marcelo (2018) Identification of Plasmodium GAPDH epitopes for generation of antibodies that inhibit malaria infection. Life Sci Alliance 1:e201800111|