Complement C4 Prevents Viral Infection through Capsid Inactivation.

Cell host & microbe (2019-03-31)
Maria Bottermann, Stian Foss, Sarah L Caddy, Dean Clift, Laurens M van Tienen, Marina Vaysburd, James Cruickshank, Kevin O'Connell, Jessica Clark, Keith Mayes, Katie Higginson, Heidrun E Lode, Martin B McAdam, Inger Sandlie, Jan Terje Andersen, Leo C James
ABSTRACT

The complement system is vital for anti-microbial defense. In the classical pathway, pathogen-bound antibody recruits the C1 complex (C1qC1r2C1s2) that initiates a cleavage cascade involving C2, C3, C4, and C5 and triggering microbial clearance. We demonstrate a C4-dependent antiviral mechanism that is independent of downstream complement components. C4 inhibits human adenovirus infection by directly inactivating the virus capsid. Rapid C4 activation and capsid deposition of cleaved C4b are catalyzed by antibodies via the classical pathway. Capsid-deposited C4b neutralizes infection independent of C2 and C3 but requires C1q antibody engagement. C4b inhibits capsid disassembly, preventing endosomal escape and cytosolic access. C4-deficient mice exhibit heightened viral burdens. Additionally, complement synergizes with the Fc receptor TRIM21 to block transduction by an adenovirus gene therapy vector but is partially restored by Fab virus shielding. These results suggest that the complement system could be altered to prevent virus infection and enhance virus gene therapy efficacy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Rabbit IgG (whole molecule)–Peroxidase antibody produced in goat, affinity isolated antibody
Sigma-Aldrich
Anti-Mouse IgG (whole molecule)–Peroxidase antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
Anti-Human IgG (Fab specific) antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-Human IgG (Fc specific)−Alkaline Phosphatase antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-Human IgG (Fab specific)−FITC antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-Adenovirus Antibody, Chemicon®, from goat

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