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Research Article

CRIg plays an essential role in intravascular clearance of bloodborne parasites by interacting with complement

Gongguan Liu, Yong Fu, Mohammed Yosri, Yanli Chen, Peng Sun, Jinjun Xu, Mingshun Zhang, Donglei Sun, Ashley B. Strickland, Zachary B. Mackey, and Meiqing Shi
PNAS November 26, 2019 116 (48) 24214-24220; first published November 13, 2019 https://doi.org/10.1073/pnas.1913443116
Gongguan Liu
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
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Yong Fu
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
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Mohammed Yosri
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
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Yanli Chen
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
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Peng Sun
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
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Jinjun Xu
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
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Mingshun Zhang
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
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Donglei Sun
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
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Ashley B. Strickland
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;
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Zachary B. Mackey
bDepartment of Biochemistry and Fralin Life Science Institute, Vector-Borne Disease Division, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061;
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Meiqing Shi
aDivision of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742;cMaryland Pathogen Research Institute, University of Maryland, College Park, MD 20742
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  • For correspondence: mshi@umd.edu
  1. Edited by Peter Hotez, Baylor College of Medicine, Houston, TX, and accepted by Editorial Board Member Carl F. Nathan October 24, 2019 (received for review August 3, 2019)

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Significance

Bloodborne parasites develop very sophisticated mechanisms to survive in the bloodstream, causing serious diseases. The mechanisms involved in intravascular clearance of bloodborne parasites are largely unknown. Understanding the underlying mechanisms is fundamental for developing strategies to treat the diseases. In the current study, we reveal that CRIg, a macrophage receptor previously shown to bind C3b/iC3b in vitro, plays an essential role in intravascular clearance of the bloodborne parasites African trypanosomes. More importantly, we demonstrate that CRIg, through interactions with complement deposited on the parasites in vivo, rather than parasites themselves, captures parasites under flow conditions. Thus, CRIg functions as a complement receptor in vivo to capture bloodborne pathogens and may represent a target for treatment.

Abstract

Although CRIg was originally identified as a macrophage receptor for binding complement C3b/iC3b in vitro, recent studies reveal that CRIg functions as a pattern recognition receptor in vivo for Kupffer cells (KCs) to directly bind bacterial pathogens in a complement-independent manner. This raises the critical question of whether CRIg captures circulating pathogens through interactions with complement in vivo under flow conditions. Furthermore, the role of CRIg during parasitic infection is unknown. Taking advantage of intravital microscopy and using African trypanosomes as a model, we studied the role of CRIg in intravascular clearance of bloodborne parasites. Complement C3 is required for intravascular clearance of African trypanosomes by KCs, preventing the early mortality of infected mice. Moreover, antibodies are essential for complement-mediated capture of circulating parasites by KCs. Interestingly, reduced antibody production was observed in the absence of complement C3 during infection. We further demonstrate that CRIg but not CR3 is critically involved in KC-mediated capture of circulating parasites, accounting for parasitemia control and host survival. Of note, CRIg cannot directly catch circulating parasites and antibody-induced complement activation is indispensable for CRIg-mediated parasite capture. Thus, we provide evidence that CRIg, by interacting with complement in vivo, plays an essential role in intravascular clearance of bloodborne parasites. Targeting CRIg may be considered as a therapeutic strategy.

  • CRIg
  • complement
  • intravital imaging
  • bloodborne parasites
  • African trypanosomes

Footnotes

  • ↵1Present address: Department of Veterinary Medicine, Academy of Animal Science and Veterinary Medicine, State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, 810016 Xining, China.

  • ↵2Present address: The Regional Center for Mycology and Biotechnology, Al-Azhar University, 11787 Cairo, Egypt.

  • ↵3Present address: Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, 225009 Yangzhou, China.

  • ↵4Present address: Department of Immunology, Nanjing Medical University, 211166 Nanjing, China.

  • ↵5To whom correspondence may be addressed. Email: mshi{at}umd.edu.
  • Author contributions: G.L. and M.S. designed research; G.L., Y.F., M.Y., Y.C., P.S., J.X., M.Z., D.S., and A.B.S. performed research; Z.B.M. contributed new reagents/analytic tools; G.L. and M.S. analyzed data; and G.L., A.B.S., Z.B.M., and M.S. wrote the paper.

  • The authors declare no competing interest.

  • This article is a PNAS Direct Submission. P.H. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1913443116/-/DCSupplemental.

Published under the PNAS license.

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CRIg plays an essential role in intravascular clearance of bloodborne parasites by interacting with complement
Gongguan Liu, Yong Fu, Mohammed Yosri, Yanli Chen, Peng Sun, Jinjun Xu, Mingshun Zhang, Donglei Sun, Ashley B. Strickland, Zachary B. Mackey, Meiqing Shi
Proceedings of the National Academy of Sciences Nov 2019, 116 (48) 24214-24220; DOI: 10.1073/pnas.1913443116

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CRIg plays an essential role in intravascular clearance of bloodborne parasites by interacting with complement
Gongguan Liu, Yong Fu, Mohammed Yosri, Yanli Chen, Peng Sun, Jinjun Xu, Mingshun Zhang, Donglei Sun, Ashley B. Strickland, Zachary B. Mackey, Meiqing Shi
Proceedings of the National Academy of Sciences Nov 2019, 116 (48) 24214-24220; DOI: 10.1073/pnas.1913443116
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