Complement Activation Is Required for Induction of a Protective Antibody Response against West Nile Virus Infection

Abstract

Infection with West Nile virus (WNV) causes a severe infection of the central nervous system (CNS) with higher levels of morbidity and mortality in the elderly and the immunocompromised. Experiments with mice have begun to define how the innate and adaptive immune responses function to limit infection. Here, we demonstrate that the complement system, a major component of innate immunity, controls WNV infection in vitro primarily in an antibody-dependent manner by neutralizing virus particles in solution and lysing WNV-infected cells. More decisively, mice that genetically lack the third component of complement or complement receptor 1 (CR1) and CR2 developed increased CNS virus burdens and were vulnerable to lethal infection at a low dose of WNV. Both C3-deficient and CR1-and CR2-deficient mice also had significant deficits in their humoral responses after infection with markedly reduced levels of specific anti-WNV immunoglobulin M (IgM) and IgG. Overall, these results suggest that complement controls WNV infection, in part through its ability to induce a protective antibody response.

Field Investigation of Innate Immunity in Passerine Birds in Suburban Chicago, Illinois, Usa

“…Complement activation plays a critical role in antiviral immunity as well (Avirutnan et al, 2008). In murine models, mice lacking individual components of the three pathways of complement activation had marked increases in WNV susceptibility, for example (Mehlhop et al, 2005;Mehlhop and Diamond, 2006). Our observation of a lower E. coli 8739 microbicidal capacity in American Robins compared to Gray Catbirds is consistent with the observations that these two hosts show different competence for WNV and Borrelia infection (Mather et al, 1989;Richter et al, 2000;Ginsberg et al, 2005;Kilpatrick et al, 2007).…”

Anti-inflammatory activity of intravenous immunoglobulins protects against West Nile virus encephalitis

“…IVIG has a broad repertoire of neutralizing antibodies for various pathogens and neutralization is commonly assumed to be the mechanism of protection against viral infection. However, we have shown in the HSV1 model that IVIG devoid of neutralizing antibodies is as effective as IVIG in protection against encephalitis (Ramakrishna et al, 2011) and the reports that non-neutralizing antibodies can protect against WNV infection are consistent with this (Chung et al, 2006;Mehlhop et al, 2005;Vogt et al, 2011). Studies investigating IVIG protection from WNV infection have based dosing on its neutralizing activity and have thus used IVIG at suboptimal doses (0.1-0.6 g kg 21 ) to elicit antiinflammatory responses.…”

“…Studies in murine models using low doses of IVIG preparations that contained high titres of WNV neutralizing antibodies confirmed robust protection from WNV encephalitis (Ben-Nathan et al, 2003. Passive transfer of WNV-specific monoclonal or murine polyclonal antibodies aborted or limited WNV infections in rodent models in a dose-, time-and complementdependent manner (Agrawal & Petersen, 2003;Mehlhop et al, 2005;Morrey et al, 2006). Our earlier investigation of the protective mechanisms of IVIG in a model of herpes simplex virus type 1 (HSV1) encephalitis demonstrated that IVIG's potent anti-inflammatory and immunomodulatory activities, rather than its neutralizing activity, were essential for protection.…”

The Vaccinia Virus Complement Control Protein Modulates Adaptive Immune Responses during Infection

“…Ab responses are important for clearance of primary VACV infection (1,60). Further, complement activation is important for the development of optimal IgM and IgG antibody responses to several viruses (7,38,44). Therefore, we examined the effect of VCP expression on the development of anti-VACV IgM and IgG Ab responses by using a VACVspecific ELISA to measure levels of anti-VACV Abs following infection of B6 mice with vv-VCPwt and vv-VCPko.…”

“…Complement activation can also contribute to defense against viral infection by enhancing adaptive antibody (Ab) and T cell responses. Complement has been shown to enhance Ab responses to several viruses, including herpes simplex virus (HSV) (7,14,15,55,56), vesicular stomatitis virus (VSV) (44), and West Nile virus (WNV) (37,38). Recently, it has become clear that complement is also important for eliciting optimal T cell responses to several viral pathogens (10,24,37,50).…”