Interference of the Zika Virus E-Protein With the Membrane Attack Complex of the Complement System

Abstract

The complement system has developed different strategies to clear infections by several effector mechanisms, such as opsonization, which supports phagocytosis, attracting immune cells by C3 and C5 cleavage products, or direct killing of pathogens by the formation of the membrane attack complex (MAC). As the Zika virus (ZIKV) activates the classical complement pathway and thus has to avoid clearance by the complement system, we analyzed putative viral escape mechanisms, which limit virolysis. We identified binding of the recombinant viral envelope E protein to components of the terminal pathway complement (C5b6, C7, C8, and C9) by ELISA. Western blot analyses revealed that ZIKV E protein interfered with the polymerization of C9, induced on cellular surfaces, either by purified terminal complement proteins or by normal human serum (NHS) as a source of the complement. Further, the hemolytic activity of NHS was significantly reduced in the presence of the recombinant E protein or entire viral particles. This data indicates that ZIKV reduces MAC formation and complement-mediated lysis by binding terminal complement proteins to the viral E protein.

New Insights into the Role of the Complement System in Human Viral Diseases

“…However, in some cases, ZIKV infection can lead to severe thrombocytopenia and profuse bleeding and nervous system damage [ 211 ]. The classical complement system pathway has been identified as a major factor for the complement system activation in ZIKV infection [ 212 , 213 ]. It results in the neutralization and reduction of virus titers in the body during infection.…”

Functional Identification of Complement Factor D and Analysis of Its Expression during GCRV Infection in Grass Carp (Ctenopharyngodon idella)

“…Df catalyzes the hydrolysis of the single Arg–Lys bond of Bf—the only known natural substrate of Df in the AP—into Ba and Bb fragments and forms a complex with Bb and C3b that is an alternative C3 convertase [ 25 , 26 , 71 , 72 , 73 ]. Subsequently, activity of this C3 convertase leads to the cleavage of C3 and the activation of terminal complement components and to the formation of a membrane attack complex that eliminates invading microbes or host cells infected with viruses [ 10 , 74 ]. In addition, Df is a component absolutely required for the AP, since it is the only enzyme in mammalian blood able to catalyze C3bBb formation [ 61 , 62 , 75 ].…”

Virus-Encoded Complement Regulators: Current Status

“…Examination of the mechanism that restricts viral lysis showed that the E protein inhibits the MAC formation. Direct interaction studies showed that E protein binds to C5b-6, C8, and C9, and as a result, blocks polymerization of C9 [48]. HCV encodes six non-structural proteins: NS2, NS3, NS4A, NS4B, NS5A, and NS5B.…”