Advancing complement inhibition for the treatment of malarial anemia: a translational roadmap

Severe anemia is responsible for hundreds of thousands of deaths in children with malaria. For every Plasmodium -infected erythrocyte that is lysed, considerably more than 10 uninfected erythrocytes are cleared by extravascular hemolysis, thus leading to anemia. Compelling evidence indicates that breakdown products released from infected erythrocytes in the bloodstream activate complement and promote “innocent bystander” deposition of C3 activation fragments on the uninfected erythrocytes, thereby sensitizing them for elimination. We propose a series of in vitro experiments with blood cultures of malaria parasites to test the hypothesis that use of inhibitors that block complement at the C3 activation step can preserve and protect uninfected erythrocytes from C3 deposition. Successful demonstration of in vitro protection will set the stage for clinical trials based on the limited and focused use of complement inhibitors to prevent severe anemia in malaria.

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Publication Details

Journal
Malaria Journal
Published
2026-08-25
DOI
https://doi.org/10.1186/s12936-026-06120-7
Primary Topic
Malaria Research and Control
Type
article
Field-Weighted Citation Impact
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article

Advancing complement inhibition for the treatment of malarial anemia: a translational roadmap

Alexander Pichugin, Ronald P. Taylor, José A. Stoute, John D. Lambris et al.
Malaria Journal
Malaria Research and Control
article

Advancing complement inhibition for the treatment of malarial anemia: a translational roadmap

Alexander Pichugin, Ronald P. Taylor, José A. Stoute, John D. Lambris, Margaret A. Lindorfer, Dimitrios C. Mastellos, Christoph Q. Schmidt, D. Gray Heppner, Richard J.H. Smith, Rosario Notaro, Antonio M. Risitano, Yuzhou Zhang, John N. Waitumbi
article en

Abstract

Severe anemia is responsible for hundreds of thousands of deaths in children with malaria. For every Plasmodium -infected erythrocyte that is lysed, considerably more than 10 uninfected erythrocytes are cleared by extravascular hemolysis, thus leading to anemia. Compelling evidence indicates that breakdown products released from infected erythrocytes in the bloodstream activate complement and promote “innocent bystander” deposition of C3 activation fragments on the uninfected erythrocytes, thereby sensitizing them for elimination. We propose a series of in vitro experiments with blood cultures of malaria parasites to test the hypothesis that use of inhibitors that block complement at the C3 activation step can preserve and protect uninfected erythrocytes from C3 deposition. Successful demonstration of in vitro protection will set the stage for clinical trials based on the limited and focused use of complement inhibitors to prevent severe anemia in malaria.

Malaria Journal
University of Iowa (US), Universität Ulm (DE), National Centre of Scientific Research "Demokritos" (GR), United States Army Medical Research Directorate - Africa (KE), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), Istituto per lo Studio e la Prevenzione Oncologica (IT), ClearMotion (United States) (US), Azienda Ospedaliera S.Giuseppe Moscati (IT), University of Virginia (US), University of Pennsylvania (US), Walter Reed Army Institute of Research (US)
Openalex Percentile: Top 8%
Malaria Research and Control
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