Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

Abstract

The complement system is a key component of innate immunity which readily responds to invading microorganisms. Activation of the complement system typically occurs via three main pathways and can induce various antimicrobial effects, including: neutralization of pathogens, regulation of inflammatory responses, promotion of chemotaxis, and enhancement of the adaptive immune response. These can be vital host responses to protect against acute, chronic, and recurrent viral infections. Consequently, many viruses (including dengue virus, West Nile virus and Nipah virus) have evolved mechanisms for evasion or dysregulation of the complement system to enhance viral infectivity and even exacerbate disease symptoms. The complement system has multifaceted roles in both innate and adaptive immunity, with both intracellular and extracellular functions, that can be relevant to all stages of viral infection. A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. This review will discuss the antiviral effects of the complement system against numerous viruses, the mechanisms employed by these viruses to then evade or manipulate this system, and how these interactions have informed vaccine/therapeutic development. Where relevant, conflicting findings and current research gaps are highlighted to aid future developments in virology and immunology, with potential applications to the current COVID-19 pandemic.

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

“…C5b recruits and binds complement proteins C6, C7, C8, and multiple units of C9 to form the membrane attack complex (MAC), a pore that inserts into lipid bilayer membranes of certain bacteria, parasites, enveloped viruses (29,30), infected host cells, or, pathogenically, endogenous cells such as erythrocytes, to induce lysis (1,19,28). C5a, together with C3a, are potent anaphylatoxins modulating a plethora of cell types expressing G-protein coupled C5a or C3a receptors (C5aR1 and C3aR, respectively).…”

Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus

“…These proposed modification strategies would require experimental testing and verification. It is of interest to note that the vast majority of HAdV species have very short penton base RGD loops that may point to an evolutionary complement attack evasion mechanism [ 48 , 53 ]. Whether or not HAdV species with short penton base RGD loops are more resistant to C4 complement-mediated neutralization, compared to HAdv species C, also requires experimental verification.…”

Impact of cytokine storm and systemic inflammation on liver impairment patients infected by SARS-CoV-2: Prospective therapeutic challenges

“…Viral infection has been reported to stimulate the complement cascade and consequently, initiate specific inflammatory responses[ 100 ]. Among these complements, complement factor 5a (C5a) is the most potent inflammatory peptide in the complement cascade, which increases the production of pro-inflammatory cytokines such as IL-6, IL-1, and TNF-α from macrophages under the effect of TLR-2, TLR-4, and TLR-9[ 101 , 102 ].…”