Overexpression of Cytochromecby a Recombinant Rabies Virus Attenuates Pathogenicity and Enhances Antiviral Immunity

Abstract

The pathogenicity of individual rabies virus strains appears to correlate inversely with the extent of apoptotic cell death they induce and with the expression of rabies virus glycoprotein, a major inducer of an antiviral immune response. To determine whether the induction of apoptosis by rabies virus contributes to a decreased pathogenicity by stimulating antiviral immunity, we have analyzed these parameters in tissue cultures and in mice infected with a recombinant rabies virus construct that expresses the proapoptotic protein cytochrome c.

Overexpression of the Rabies Virus Glycoprotein Results in Enhancement of Apoptosis and Antiviral Immune Response

“…However, besides the structural features of RV G, a variety of other factors, in particular host cell factors, such as cytokines, contribute significantly to the development of immunity against rabies (11). Several events that are involved in the pathogenesis of rabies may also play a pivotal role in induction of antiviral immunity (20), a notion supported by the observations that the pathogenicity of a particular RV variant appears to correlate inversely with RV G expression levels and that increased G accumulation correlates with the induction of apoptosis (10,17). These findings, together with the well-known fact that nonpathogenic RV strains, not pathogenic RV strains, induce a strong antiviral immune response (29), suggest an association between RV G expression, apoptosis, RV pathogenicity, and antiviral immunity.…”

Oral Efficacy of an Attenuated Rabies Virus Vaccine in Skunks and Raccoons

“…It is unclear if the lack of detectable neutralizing antibodies and yet protection from rabies virus challenge following oral vaccination with SAG-2 is a phenomenon unique to this avirulent mutant or if this is a more generalized phenomenon perhaps characteristic of highly attenuated modified live rabies virus vaccines. Attenuated mutants may enhance apoptosis, as observed with recombinant rabies viruses (Pulmanausahakul et al, 2001). This may in turn result in a different presentation and composition of viral antigens than just glycoprotein expressed on the cell surface of intact neurons as may predominate with attenuated fixed and street rabies virus infections.…”

Respiratory Syncytial Virus Infection Sensitizes Cells to Apoptosis Mediated by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

“…For example, loading of dendritic cells with human immunodeficiency virus-infected apoptotic, but not necrotic, cells induced proliferation of human immunodeficiency virus-specific CD4 ϩ and CD8 ϩ cells (79). In the context of virus infection in vivo, a recombinant rabies virus that was engineered to express cytochrome c, an effective apoptosis-inducing protein, was associated with attenuated pathogenicity and an increased induction of virus-neutralizing antibodies (51). The concept that apoptosis can play a significant role in pathogenesis and the host immune response is of direct relevance for vaccine development.…”