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

Dipak K. Raj, Alok Das Mohapatra, Anup Jnawali, Jenna Zuromski, Ambrish Jha, Gerald Cham-Kpu, Brett Sherman, Rachel M. Rudlaff, Christina E. Nixon, Nicholas Hilton, Andrew V. Oleinikov, Olga Chesnokov, Jordan Merritt, Sunthorn Pond-Tor, Lauren Burns, Grant Jolly, Choukri Mamoun, Edward Kabyemela, Atis Muehlenbachs, Lynn Lambert, Sachy Orr-Gonzalez, Nina F. Gnädig, David A. Fidock, Sangshin Park, Jeffrey D. Dvorin, Norbert Pardi, Drew Weissman, Barbara L. Mui, Ying K. Tam, Jennifer F. Friedman, Michal Fried, Patrick E. Duffy and Jonathan D. Kurtis ()
Additional contact information
Dipak K. Raj: Brown University Medical School
Alok Das Mohapatra: Brown University Medical School
Anup Jnawali: Brown University Medical School
Jenna Zuromski: Brown University Medical School
Ambrish Jha: Brown University Medical School
Gerald Cham-Kpu: Brown University Medical School
Brett Sherman: Brown University Medical School
Rachel M. Rudlaff: Boston Children’s Hospital
Christina E. Nixon: Brown University Medical School
Nicholas Hilton: Brown University Medical School
Andrew V. Oleinikov: Florida Atlantic University
Olga Chesnokov: Florida Atlantic University
Jordan Merritt: Florida Atlantic University
Sunthorn Pond-Tor: Brown University Medical School
Lauren Burns: Brown University Medical School
Grant Jolly: Brown University Medical School
Choukri Mamoun: Yale University
Edward Kabyemela: Seattle Biomedical Research Institute
Atis Muehlenbachs: Centers for Disease Control and Prevention
Lynn Lambert: National Institutes of Health
Sachy Orr-Gonzalez: National Institutes of Health
Nina F. Gnädig: Columbia University Irving Medical Center
David A. Fidock: Columbia University Irving Medical Center
Sangshin Park: Brown University Medical School
Jeffrey D. Dvorin: Boston Children’s Hospital
Norbert Pardi: University of Pennsylvania
Drew Weissman: University of Pennsylvania
Barbara L. Mui: Acuitas Therapeutics
Ying K. Tam: Acuitas Therapeutics
Jennifer F. Friedman: Brown University Medical School
Michal Fried: National Institutes of Health
Patrick E. Duffy: National Institutes of Health
Jonathan D. Kurtis: Brown University Medical School

Nature, 2020, vol. 582, issue 7810, 104-108

Abstract: Abstract Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children1, 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 parasites2, 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.

Date: 2020
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DOI: 10.1038/s41586-020-2220-1

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