Biochemical characterization of Plasmodium complement factors binding protein for its role in immune modulation.

Abstract

Complement system is the first line of human defence against intruding pathogens and is recognized as a potentially useful therapeutic target. Human malaria parasite Plasmodium employs a series of intricate mechanisms that enables it to evade different arms of immune system, including the complement system. Here, we show the expression of a multi-domain Plasmodium Complement Control Protein 1, PfCCp1 at asexual blood stages and its binding affinity with C3b as well as C4b proteins of human complement cascade. Using a biochemical assay, we demonstrate that PfCCp1 binds with complement factors and inhibits complement activation. Active immunization of mice with PfCCp1 followed by challenge with Plasmodium berghei resulted in the loss of biphasic growth of parasites and early death in comparison to the control group. The study also showed a role of PfCCp1 in modulating Toll-like receptor (TLR)-mediated signalling and effector responses on antigen-presenting cells. PfCCp1 binds with dendritic cells that down-regulates the expression of signalling molecules and pro-inflammatory cytokines, thereby dampening the TLR2-mediated signalling; hence acting as a potent immuno-modulator. In summary, PfCCp1 appears to be an important component of malaria parasite directed immuno-modulating strategies that promote the adaptive fitness of pathogens in the host.

• Authors: Shweta Sharma, Gautam Kumar, Mohit Vashishta, Rajan Pandey, Sumit Rathore, Bishwanath K Chourasia, Jhalak Singhal, Arunaditya Deshmukh, Md Kalamuddin, Gourab Paul, Ashutosh Panda, Shreyansh Tatiya, Khushboo Rawat, Dinesh Gupta, Asif Mohmmed, Krishnamurthy Natarajan, Pawan Malhotra
• Journal: The Biochemical journal (Biochem J) Vol. 475 Issue 17 Pg. 2877-2891 (09 14 2018) ISSN: 1470-8728 [Electronic] England
• PMID: 30049893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Immunologic Factors
• Protozoan Proteins
• Tlr2 protein, mouse
• Toll-Like Receptor 2

Topics

• Animals
• Dendritic Cells (immunology)
• Humans
• Immunization
• Immunologic Factors (immunology)
• Mice
• Mice, Inbred BALB C
• Plasmodium berghei (immunology)
• Plasmodium falciparum (immunology)
• Protozoan Proteins (immunology)
• Signal Transduction (immunology)
• Toll-Like Receptor 2 (immunology)