Abstract
Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses. Among the major groups of viruses, RNA viruses contribute significantly to the global mortality and morbidity index associated with viral infection. Despite multiple routes of entry adopted by these viruses, facing complement is inevitable. The initial interaction with complement and the nature of this interaction play an important role in determining host resistance versus susceptibility to the viral infection. Many RNA viruses are potent activators of complement, often resulting in virus neutralization. Yet, another facet of virus-induced activation is the exacerbation in pathogenesis contributing to the overall morbidity. The severity in disease and death associated with RNA virus infections shows a tip in the scale favoring viruses. Growing evidence suggest that like their DNA counterparts, RNA viruses have co-evolved to master ingenious strategies to remarkably restrict complement. Modulation of host genes involved in antiviral responses contributed prominently to the adoption of unique strategies to keep complement at bay, which included either down regulation of activation components (C3, C4) or up regulation of complement regulatory proteins. All this hints at a possible “hijacking” of the cross-talk mechanism of the host immune system. Enveloped RNA viruses have a selective advantage of not only modulating the host responses but also recruiting membrane-associated regulators of complement activation (RCAs). This review aims to highlight the significant progress in the understanding of RNA virus–complement interactions.
Highlights
The complement system (CS) is evolutionarily ancient and is a prime component of the innate immunity arsenal, capable of targeting a wide range of pathogens [1]
The CS operates via three pathways, namely, the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP) [5], and functions like a cascade brought about by the sequential proteolytic cleavage of zymogens into their active fragments
Complement–RNA virus interactions are complex, with each remaining in the cross hairs of the other
Summary
The complement system (CS) is evolutionarily ancient and is a prime component of the innate immunity arsenal, capable of targeting a wide range of pathogens [1]. The CP is initiated by the binding of C1q to the Fc region of IgG or IgM in an antigen– antibody complex or directly to the pathogen This leads to the autocatalytic activation of C1r, which activates the serine protease C1s, which can sequentially cleave C4 into C4a and C4b and C2 into C2a and C2b [6]. Binding of mannose binding lectin (MBL) or ficolins to unique carbohydrate moieties rich in D-mannose or L-fucose [7] on the pathogen surface [pathogen-associated molecular patterns (PAMPs)] activates the LP This is facilitated by the activation of two MBL-associated serine proteases (MASP), MASP-1, and MASP-2 [8], leading to the cleavage of C4 and C2. C4 acts as the point where both the CP and LP merge, leading to the association of C4b and C2a, generating the C3 convertase (C4b2a; Figure 1)
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