The life-and-death struggle between the complement system and pathogens: Mechanisms of elimination, evasion tactics, and translational potential

Abstract

The complement system, along with its intricate network, constitutes a vital component of the innate immune response, playing a pivotal role in defending the host against invading pathogens. While it is essential for maintaining immune homeostasis, dysregulation of this system can lead to significant pathological consequences: deficiencies in complement components increase susceptibility to infections, whereas excessive activation causes inflammatory tissue damage. Through its diverse functions and regulatory mechanisms, including but not limited to cytolytic effects, opsonophagocytosis, induction of inflammatory responses, and facilitation of antigen presentation, the complement system can independently or synergistically eliminate pathogens with high specificity and efficiency. In response to this robust immune defense strategy, pathogens have evolved a range of sophisticated evasion and resistance mechanisms to counteract the lethal effects of complements. In-depth research into these complement-pathogen interactions enhances our understanding of disease pathogenesis and progression, providing vital theoretical foundations and potential targets for novel therapeutics.

Keywords: Complement system; complosome; infection and anti-infection; interactions; vaccine strategies.

Figure 1.

Immune defense mechanisms of the complement system. (A) cytolysis mediated by the membrane attack complex (MAC). Sequential assembly of C5b-9 leads to pore formation on the pathogen surface, resulting in cell lysis. (B) opsonophagocytosis enhances pathogen clearance. Complement opsonins (e.g. C3b) facilitate pathogen recognition and phagocytosis by macrophages and neutrophils through their interaction with complement receptors (CRs) and fc receptors (FcRs). (C) induction of inflammation via complement signaling. C3a and C5a interact with their respective receptors (C3aR, C5aR) to activate inflammatory pathways, including the NLRP3 inflammasome, leading to cytokine production and enhanced immune responses. (D) connecting innate and adaptive immunity. Complement components regulate B cell activation through CR2 (CD21) and enhance antigen presentation and phagocytosis via dendritic cells (DCs). CRs on T cells promote chemotaxis and activation, thereby linking innate and adaptive immune response.

Figure 2.

Microbial strategies for evasion of complement and mechanisms of complement-mediated immune defense. This schematic illustrates the intricate interplay between microbial strategies for evading complement-mediated immune responses and the host’s complement system. On the left, four major microbial strategies are shown: (A) the expression of enzymatically active proteins that degrade complement components (e.g. LIC13322 from Leptospira, which degrades C9 to prevent MAC assembly), (B) the expression of complement-interacting proteins that inhibit complement activation (e.g. SIC from streptococcus pneumoniae blocking C5b-9/MAC formation), (C) the secretion of proteins that mimic complement ligands to competitively bind host complement receptors (e.g. Plasmodium proteins Rh4 and PvEBP binding to complement receptor 1 (CR1)), and (D) the recruitment of host negative regulators of complement to suppress activation (e.g. bordetella pertussis Vag8 interacting with C1 inhibitor (C1INH) to inhibit both classical (CP) and lectin (LP) pathways). On the right, the activation cascades of the canonical complement pathways are illustrated: classical pathway (CP), lectin pathway (LP), and alternative pathway (AP). This depiction highlights key activation complexes (e.g. C3 and C5 convertases) and regulatory factors (e.g. soluble regulators like factor H (CFH), membrane inhibitors such as CD59, and membrane cofactor proteins like CD46 (MCP)). Complement activation leads to various effector functions, including opsonophagocytosis, inflammation, cytolysis via membrane attack complex (MAC) formation, and bridging innate and adaptive immunity. This figure underscores the evolutionary arms race between pathogens and host immunity through specific modulation of complement pathways.