Complement System and Antimicrobial Peptides/AMPs

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Complement System and Antimicrobial Peptides/AMPs

In contrast to adaptive immunity, innate immune effectors, such as phagocytes, complement, chemokines, and antimicrobial peptides (AMPs), provide a rapid and nonspecific host response. AMPs, which were originally described in silk worms, are important in the initial clearance of bacteria at biological boundaries that are susceptible to infection. However, many AMPs, such as defensins and LL-37, also possess chemotactic activity against leukocytes, T cells, and mast cells. Conversely, chemokines, which attract and activate specific leukocyte populations during inflammation and infection, were recently shown to exert direct antimicrobial functions. Thus, it is becoming increasingly clear that various protein and peptide mediators bridge the innate and adaptive immune systems.

All vertebrate species are constantly challenged by infectious agents and pathogens. In order to fight these infectious agents the human host has developed a sophisticated and powerful immune defense. The complement system, which represents the first defense line of innate immunity is activated immediately, within seconds. The activated immune system recognizes and damages an invading microbe, coordinates the host immune response and further orchestrates the adaptive immune response. Activation of the complement system leads to a rapid and amplified response which includes the generation of small peptides like C3a and C4a that display antimicrobial, anti-fungal and anaphylactic activity. For example, C3a exerts multiple proinflammatory functions, involving histamine release from mast cells, smooth-muscle contraction, increased vascular permeability, and chemoattraction against mast cells. The biological effects of C3a are regulated by the plasma protease carboxypeptidase N, which cleaves off the C-terminal arginine to generate the inactive C3a-desArg peptide.

Antimicrobial Mechanisms of Complement System

The antimicrobial mechanism of the complement activation peptides C3a and C4a is based on a conformational change upon binding to the microbial surface. Circular dichroism spectroscopy revealed an induction of an α-helical conformation of C3a and C4a after LPS E. coli binding. E. coli LPS induced very similar structural changes in synthetic C3a peptides derived from C. rotundicauda and Homo sapiens. Thus suggesting interaction and destabilization of microbial membranes upon binding of C3a and/or C4a to LPS or peptidoglycans. These structural changes mediate an insertion into the membrane and likely result in direct bacterial killing.

The α-helical conformation as well as the amphipathic character are hallmarks for a group of antimicrobial peptides such as cathelicidin LL-37. Both features are also true for C3a and C4a. Therefore, it is likely that these antimicrobial complement peptides act in the same manner as the other a-helical antimicrobial peptides (AMPs). AMP cross the outer cell-wall by binding to LPS from Gram-negative or to peptidoglycans from Gram-positive bacteria. There the peptides interact with the lipid bilayer leading to stretched membranes.

Complement System and Antimicrobial Peptides/AMPs References

1. Zipfel P F, et al. (2009). Complement activation products C3a and C4a as endogenous antimicrobial peptides. International Journal of Peptide Research and Therapeutics, 15(2), 87-95.
2. Nordahl E A, et al. (2004). Activation of the complement system generates antibacterial peptides. Proceedings of the National Academy of Sciences of the United States of America, 101(48), 16879-16884.

Complement System
Complement System Overview
Complement System Component / Protein Regulator and Receptor
Complement Genetic Feature
Complement Activation Pathways
Complement System Role
Complement System and Direct Interactions+
- Mannose Binding Lectin/MBL
Complement System Function in Immune System+
- Complement System in Adaptive Immunity
- Complement System in Innate Immunity
Complement-Dependent Cytotoxicity/CDC+
- Complement-Dependent Cytotoxicity/CDC Crossmatch
Therapeutic Target of Complement System+
- Serine Protease Inhibitors as Therapeutic Target of Complement System
- Soluble Complement Regulators as Therapeutic Target of Complement System
- Complement Component Inhibitors as Therapeutic Target of Complement System
- Anaphylatoxin Receptor Antagonists as Therapeutic Target of Complement System
- Therapeutic Antibodies of Complement System
Complement System and Toll-like Receptors / TLRs
Complement System and Coagulation
Complement Cascade and Inhibitors
Complement Evasion of Pathogens
Complement System and Antimicrobial Peptides/AMPs
Complement System and Diseases
Complement System Deficiency Diseases
Complement System Structure
Complement System Effector Functions
Anti-Complement Antibody Products