CSIC researchers uncover how the complement system and immune cells collaborate to eliminate pathogens

The research groups of M. Cristina Vega and Santiago Rodríguez de Córdoba from the CIB Margarita Salas have collaborated to determine the structure of the complex between the iC3b opsonin and the ɑI extracellular domain of the CR3 integrin. This work, soon to be published in Nature Communications, explains at the molecular level how macrophages and other immune cells recognize the key molecule with which the complement system tags pathogens for their elimination via phagocytosis.

The complement system comprises more than 30 plasma proteins besides various receptors and regulators present on the membrane of many cells. It is a fundamental component of innate immunity and the first line of defense against pathogens and other foreign particles. When a pathogen enters our organism, it activates the complement system component C3 and the massive deposition of C3 activated molecules (C3b, iC3b, C3dg) on the pathogen’s surface. This process, known as opsonization, takes place in minutes and is crucial for our organism to fight infections. On the other hand, complement receptor 3 (CR3) is a sensor of pathogen-associated molecular patterns located on the surface of many effector cells of the immune system. Recognition by CR3 on macrophage and neutrophil membranes of iC3b attached to the pathogen’s surface initiates a complex series of molecular and cellular processes culminating in the adhesion to and phagocytosis of the pathogen.

The determination by X-ray crystallography of the atomic structure of iC3b in complex with the extracellular ɑI domain of the CR3 receptor has revealed how macrophages and neutrophils can specifically recognize the presence of massive amounts of iC3b molecules on the pathogen’s surface. In this manner, the simultaneous interaction of thousands of CR3 and iC3b molecules across densely populated areas of the immune cell and the pathogen favors adhesion and phagocytosis of the pathogen.

The Vega and Rodríguez de Córdoba groups belong to the CSIC Global Health Platform (Plataforma Salud Global del CSIC). They collaborate in studies to develop treatments for the most severe symptoms of COVID-19 through strategies centered in the complement system. The two groups have previously described immune evasion mechanisms in Streptococcus pyogenes and other pathogenic bacteria that interfere with the complement protein C5a, thus reducing neutrophil recruitment to sites of infection. The work they publish now will facilitate the development of strategies to modulate CR3 activity in autoimmune and inflammatory diseases.

Reference: The crystal structure of iC3b-CR3 αI reveals a modular recognition of the main opsonin iC3b by the CR3 integrin receptor. Fernández FJ*, Santos-López J, Martínez-Barricarte R, Querol-García J, Martín-Merinero H, Navas-Yuste S, Savko M, Shepard WE, Rodríguez de Córdoba S, & Vega MC*. Nature Communications 13, 1955 (2022). https://www.nature.com/articles/s41467-022-29580-2

More information:

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CSIC Press release (in Spanish): link.

SOLEIL synchrotron Press release: link.