Human Astrovirus Coat Protein Inhibits Serum Complement Activation via C1, the First Component of the Classical Pathway

Abstract

Human astroviruses (HAstVs) belong to a family of nonenveloped, icosahedral RNA viruses that cause noninflammatory gastroenteritis, predominantly in infants. Eight HAstV serotypes have been identified, with a worldwide distribution. While the HAstVs represent a significant public health concern, very little is known about the pathogenesis of and host immune response to these viruses. Here we demonstrate that HAstV type 1 (HAstV-1) virions, specifically the viral coat protein (CP), suppress the complement system, a fundamental component of the innate immune response in vertebrates. HAstV-1 virions and purified CP both suppress hemolytic complement activity. Hemolytic assays utilizing sera depleted of individual complement factors as well as adding back purified factors demonstrated that HAstV CP suppresses classical pathway activation at the first component, C1. HAstV-1 CP bound the A chain of C1q and inhibited serum complement activation, resulting in decreased C4b, iC3b, and terminal C5b-9 formation. Inhibition of complement activation was also demonstrated for HAstV serotypes 2 to 4, suggesting that this phenomenon is a general feature of these human pathogens. Since complement is a major contributor to the initiation and amplification of inflammation, the observed CP-mediated inhibition of complement activity may contribute to the lack of inflammation associated with astrovirus-induced gastroenteritis. Although diverse mechanisms of inhibition of complement activation have been described for many enveloped animal viruses, this is the first report of a nonenveloped icosahedral virus CP inhibiting classical pathway activation at C1.

Microarray analysis of microRNA expression in LPS induced inflammation of human middle ear epithelial cells (HMEECs)

“…Several genes were commonly predicted including C1QC, C1S, C2, C8B and C8G. C1q is associated with the production of C1, the first component of the serum complement system and mediates the activation of C1 in response to antibody present in immune complexes [28]. C1s and C2 are the parts of the classical pathway of the complement system C8B and C8G comprises the component 8 which participates in the formation of membrane attack complex that results in the cell lysis [29].…”

Clinical hypothermia temperatures increase complement activation and cell destruction via the classical pathway

“…Heat-aggregated IgG was generated from purified human IgG (Gammagard, Baxter) as described elsewhere [23]. The reaction was stopped with EDTA-GVBS - - and the samples were measured by C5a ELISA (R&D Systems).…”

Human Astroviruses

“…Indeed, evidence in this regard comes from published in vitro data on human viruses (132)(133)(134)(135)(136), as well as from in vivo studies with infected young turkeys (122,137) and immunodeficient mice (100). Unpublished studies in our laboratory have also explored the interplay between HAstV replication and the interferon (IFN) response in cultured cells, observing that infection of CaCo-2 cells induces little type I IFN (IFN-I) response and that this occurs at late stages of infection.…”