Reduced risk of placental parasitemia associated with complement fixation on Plasmodium falciparum by antibodies among pregnant women

BMC Medicine

Alistair R. D. McLean¹  Linda Reiling¹  D. Herbert Opi²  Jo-Anne Chan²  James G. Beeson³  Freya J. I. Fowkes⁴  Michelle J. Boyle⁵  Stephen J. Rogerson⁶  Alice Ura⁷  Danielle I. Stanisic⁸  Ivo Mueller⁹ 

[1] Burnet Institute, 85 Commercial Road, 3004, Melbourne, Victoria, Australia;Burnet Institute, 85 Commercial Road, 3004, Melbourne, Victoria, Australia;Department of Immunology, Monash University, Melbourne, Australia;Department of Medicine at the Doherty Institute, University of Melbourne, Melbourne, Australia;Burnet Institute, 85 Commercial Road, 3004, Melbourne, Victoria, Australia;Department of Immunology, Monash University, Melbourne, Australia;Department of Medicine at the Doherty Institute, University of Melbourne, Melbourne, Australia;Department of Microbiology, Monash University, Clayton, Australia;Burnet Institute, 85 Commercial Road, 3004, Melbourne, Victoria, Australia;Department of Infectious Diseases, Monash University, Melbourne, Australia;Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Australia;Department of Epidemiology and Preventative Medicine, Monash University, Melbourne, Australia;Burnet Institute, 85 Commercial Road, 3004, Melbourne, Victoria, Australia;Human Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia;Department of Medicine at the Doherty Institute, University of Melbourne, Melbourne, Australia;Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea;Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea;Institute for Glycomics, Griffith University, Southport, Queensland, Australia;Walter and Eliza Hall Institute of Medical Research, Parkville, Australia;Department of Medical Biology, University of Melbourne, Melbourne, Australia;Institute Pasteur, Paris, France;

关键词: Malaria;    Pregnancy;    Complement;    Antibodies;    VAR2CSA;   

DOI  :  10.1186/s12916-021-02061-x

来源: Springer

【 摘 要 】

BackgroundThe pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells (pRBCs) in the placenta, contributing to poor pregnancy outcomes. Parasite accumulation is primarily mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). Magnitude of IgG to pRBCs has been associated with reduced risk of MiP in some studies, but associations have been inconsistent. Further, antibody effector mechanisms are poorly understood, and the role of antibody complement interactions is unknown.MethodsStudying a longitudinal cohort of pregnant women (n=302) from a malaria-endemic province in Papua New Guinea (PNG), we measured the ability of antibodies to fix and activate complement using placental binding pRBCs and PfEMP1 recombinant domains. We determined antibody-mediated complement inhibition of pRBC binding to the placental receptor, chondroitin sulfate A (CSA), and associations with protection against placental parasitemia.ResultsSome women acquired antibodies that effectively promoted complement fixation on placental-binding pRBCs. Complement fixation correlated with IgG1 and IgG3 antibodies, which dominated the response. There was, however, limited evidence for membrane attack complex activity or pRBC lysis or killing. Importantly, a higher magnitude of complement fixing antibodies was prospectively associated with reduced odds of placental infection at delivery. Using genetically modified P. falciparum and recombinant PfEMP1 domains, we found that complement-fixing antibodies primarily targeted a specific variant of PfEMP1 (known as VAR2CSA). Furthermore, complement enhanced the ability of antibodies to inhibit pRBC binding to CSA, which was primarily mediated by complement C1q protein.ConclusionsThese findings provide new insights into mechanisms mediating immunity to MiP and reveal potential new strategies for developing malaria vaccines that harness antibody-complement interactions.

【 授权许可】

CC BY