The Interactions of the Complement System with Human Cytomegalovirus

Abstract

The complement system is an evolutionarily ancient component of innate immunity that serves as an important first line of defense against pathogens, including viruses. In response to infection, the complement system can be activated by three distinct yet converging pathways (classical, lectin, and alternative) capable of engaging multiple antiviral host responses to confront acute, chronic, and recurrent viral infections. Complement can exert profound antiviral effects via multiple mechanisms including the induction of inflammation and chemotaxis to sites of infection, neutralization/opsonization of viruses and virally infected cells, and it can even shape adaptive immune responses. With millions of years of co-evolution and the ability to establish life-long infections, herpesviruses have evolved unique mechanisms to counter complement-mediated antiviral defenses, thus enabling their survival and replication within humans. This review aims to comprehensively summarize how human herpesviruses engage with the complement system and highlight our understanding of the role of complement in human cytomegalovirus (HCMV) infection, immunity, and viral replication. Herein we describe the novel and unorthodox roles of complement proteins beyond their roles in innate immunity and discuss gaps in knowledge and future directions of complement and HCMV research.

Keywords: complement; cytomegalovirus; herpesvirus; innate immunity.

Figure 1

Overview of the human complement system. The complement system comprises three distinct, yet converging pathways: the classical, the lectin, and the alternative. The activation of each complement pathway generally requires unique molecular cues (initiator molecules) for initiation and depends on several host proteases for continuation to subsequent steps in the complement cascade. The proteolytic cleavage of complement proteins yields biproducts that assemble into multimolecular complexes with enzymatic activity known as C3 and C5 convertases, both of which contribute to amplification and the terminal stage of the complement cascade referred to as the membrane attack complex (MAC). The MAC induces a membrane pore with potent lytic activity capable of neutralizing diverse microorganisms. To prevent self-damage, the complement system is tightly regulated in all three pathways at multiple levels by soluble and membrane-bound host complement inhibitors (red), and to a lesser degree, host complement enhancers (green). Original figure designed with the assistance of Biorender software (www.biorender.com). See references [5,6,7].

Figure 2

Mechanisms of complement evasion by viruses. General overview of complement evasion strategies of viruses. ① Inhibition of complement pattern recognition molecules, ② virally encoded complement inhibiting proteins, ③ inhibiting cleavage of complement proteins, ④ suppression of anaphylatoxin biproducts, ⑤ altering of complement protein synthesis during infection, and ⑥ incorporation of host complement proteins into the viral membrane. For specific examples of viruses and virally encoded proteins mediating these complement evasion strategies, see references [19,20,21,22,23,24,25,26,27,28].