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C-reactive protein is a broad-spectrum capsule-binding receptor for hepatic capture of blood-borne bacteria

Danyu Chen,Jiao Hu,Mengran Zhu,Yufeng Xie,Hantian Yao,Haoran An,Y. Meng,Juanjuan Wang,Xueting Huang,Yanni Liu,Zhujun Shao,Ye Xiang,Jianxun Qi,G. Gao,Jing-Ren Zhang

Published 2025 in EMBO Journal

ABSTRACT

Plasma C-reactive protein (CRP) is widely used as a biomarker for bacterial infections due to its massive induction during infections. However, the biological function of CRP remains largely undefined. Here we show that CRP enables liver resident macrophages (Kupffer cells) to capture and eliminate a wide range of invasive bacteria from the bloodstream of mice, and thereby provides rapid and sterilizing immunity. Mechanistically, CRP binds to at least 20 capsule types of Gram-positive and -negative pathogens, and shuffles the encapsulated bacteria to Kupffer cells embedded in the lining of the liver sinusoidal vasculatures by the complement-dependent and -independent pathways. The complement-dependent mode involves the activation of complement C3 at the bacterial surface, and the capture of the C3-opsonized bacteria by the CRIg and CR3 complement receptors on Kupffer cells. Cryo-electron microscopy analysis revealed a flexible structural framework for CRP’s recognition of structurally diverse capsular polysaccharides. Because human CRP also possesses the broad capsule-binding activities, our findings provide a biological reason for the massive rise of plasma CRP during bacterial infections. Plasma C-reactive protein (CRP) is widely used as a biomarker for bacterial infection, but its biological function remains obscure. This study identifies CRP as a potent bacterial capsule receptor that enables liver-resident macrophages (i.e., Kupffer cells) to capture and eliminate a wide range of invasive bacteria from the mouse bloodstream. CRP recognizes many bacterial capsule types via a flexible structural platform. CRP-bound bacteria are rapidly captured by Kupffer cells via complement-dependent and -independent mechanisms. Activation of complement C3 is involved in the complement-dependent pathway. Kupffer cells capture C3-opsonized bacteria using their CRIg and CR3 complement receptors. CRP recognizes many bacterial capsule types via a flexible structural platform. CRP-bound bacteria are rapidly captured by Kupffer cells via complement-dependent and -independent mechanisms. Activation of complement C3 is involved in the complement-dependent pathway. Kupffer cells capture C3-opsonized bacteria using their CRIg and CR3 complement receptors. CRP binds to a wide variety of bacterial capsule types to facilitate bacterial capture by liver-resident macrophages.

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