Plasmodium falciparum has evolved multiple mechanisms to hijack human immunoglobulin M
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Plasmodium falciparum causes the most severe malaria in humans. Immunoglobulin M (IgM) serves as the first line of humoral defense against infection and potently activates the complement pathway to facilitate P. falciparum clearance. A number of P. falciparum proteins hijack IgM, leading to immune evasion and severe disease. However, the underlying molecular mechanisms remain unknown. Here, using high-resolution cryo-electron microscopy, we delineate how P. falciparum proteins VAR2CSA, TM284VAR1, DBLMSP, and DBLMSP2 target IgM. Each protein binds IgM in a different manner, and together they present a variety of Duffy-binding-like domain-IgM interaction modes. We further show that these proteins interfere directly with IgM-mediated complement activation, with VAR2CSA exhibiting the most potent inhibitory effect. Structural analyses suggest that VAR2CSA occludes the congregation of the complement C1 complex on IgM. These results underscore the importance of IgM for the adaptation of P. falciparum to humans, and provide critical insights into the immune evasion mechanism of P. falciparum .
Authors 7
-
Peking University · State Key Laboratory of Protein and Plant Gene Research
Affiliation as printed
School of Life Sciences, Peking University, Beijing, China
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing, China
-
Peking University · State Key Laboratory of Protein and Plant Gene Research
Affiliation as printed
School of Life Sciences, Peking University, Beijing, China
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing, China
-
Peking University · State Key Laboratory of Protein and Plant Gene Research
Affiliation as printed
School of Life Sciences, Peking University, Beijing, China
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing, China
-
Peking University · State Key Laboratory of Protein and Plant Gene Research
Affiliation as printed
School of Life Sciences, Peking University, Beijing, China
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing, China
-
Affiliation as printed
Joint Graduate Program of Peking-Tsinghua-NIBS, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
-
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Section Electron Microscopy, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
-
Junyu Xiao corresponding
Peking University · Center for Life Sciences · State Key Laboratory of Protein and Plant Gene Research
Affiliation as printed
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
School of Life Sciences, Peking University, Beijing, China
State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing, China
Cited by 3 stored of 3
3 results
No patents citing this paper on Lens.org (checked 2026-10-11).