Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria

• Published in: Nature (London) Vol. 582; no. 7810; pp. 104 - 108
• Main Authors: Raj, Dipak K., Das Mohapatra, Alok, Jnawali, Anup, Zuromski, Jenna, Jha, Ambrish, Cham-Kpu, Gerald, Sherman, Brett, Rudlaff, Rachel M., Nixon, Christina E., Hilton, Nicholas, Oleinikov, Andrew V., Chesnokov, Olga, Merritt, Jordan, Pond-Tor, Sunthorn, Burns, Lauren, Jolly, Grant, Ben Mamoun, Choukri, Kabyemela, Edward, Muehlenbachs, Atis, Lambert, Lynn, Orr-Gonzalez, Sachy, Gnädig, Nina F., Fidock, David A., Park, Sangshin, Dvorin, Jeffrey D., Pardi, Norbert, Weissman, Drew, Mui, Barbara L., Tam, Ying K., Friedman, Jennifer F., Fried, Michal, Duffy, Patrick E., Kurtis, Jonathan D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2020; Nature Publishing Group
• Subjects: 13; 13/106; 13/2; 13/31; 13/56; 14/19; 14/28; 631/326/417/1716; 631/326/417/2546; 631/326/590/2294; 692/699/255/1629; 82; 82/1; 82/80; Adolescent; Adolescents; Adult; Amino acids; Animals; Antibodies; Antibodies, Protozoan - immunology; Antigens; Antigens, Protozoan - chemistry; Antigens, Protozoan - immunology; Aotidae - immunology; Aotidae - parasitology; Apoptosis; Apoptosis - immunology; Care and treatment; Caspases - metabolism; Causes of; Cell culture; Cell death; Child; Children; Cloning; Cohort Studies; DNA, Protozoan - chemistry; DNA, Protozoan - metabolism; Egress; Enzyme Activation; Erythrocytes; Erythrocytes - parasitology; Female; Food; Health aspects; Hepatocytes; Humanities and Social Sciences; Humans; Immunization; Intercellular Signaling Peptides and Proteins - chemistry; Intercellular Signaling Peptides and Proteins - immunology; Kenya; Malaria; Malaria Vaccines - immunology; Malaria, Falciparum - immunology; Malaria, Falciparum - parasitology; Malaria, Falciparum - prevention & control; Male; Mice; multidisciplinary; Parasites; Parasites - cytology; Parasites - growth & development; Parasites - immunology; Physiological aspects; Plasma; Plasmodium falciparum - cytology; Plasmodium falciparum - growth & development; Plasmodium falciparum - immunology; Primates; Proteins; Proteomes; Protozoan Proteins - chemistry; Protozoan Proteins - immunology; Science; Science (multidisciplinary); Synergism; Tanzania; Transmission electron microscopy; Trophozoites - cytology; Trophozoites - growth & development; Trophozoites - immunology; Vaccines; Vacuoles - immunology; Vector-borne diseases; Viral antibodies; Kenya; Tanzania
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-2220-1

Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children 1 , yet the promise of an effective vaccine has not been fulfilled. Here, using our previously described differential screening method to analyse the proteome of blood-stage P. falciparum parasites 2 , we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant—but not those who are susceptible—to malaria caused by P. falciparum . PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum . Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes. Antibodies against Plasmodium falciparum glutamic-acid-rich protein (PfGARP), an antigen expressed on the surface of infected red blood cells, kill P. falciparum parasites by inducing programmed cell death and reduce the risk of severe malaria.