Adenovirus E1B 19-Kilodalton Protein Modulates Innate Immunity through Apoptotic Mimicry

Abstract

Cells that undergo apoptosis in response to innate immune inflammation during accumulation of virally infected cells at sites of infection and suggest that E1B 19K-deleted, replicating adenoviral vectors might induce greater inflammatory responses to virally infected cells than E1B 19K-positive vectors, because of the net effect of their loss-of-function mutation. IMPORTANCE We observed that cells dying a nonapoptotic cell death induced by adenovirus infection repressed macrophage proinflammatory responses while cells dying by apoptosis induced by infection with an E1B 19K deletion mutant virus did not repress macro-

Exploiting death: apoptotic immunity in microbial pathogenesis

“…65 That is, apoptotic-like cells, dying as a result of infection with an E1B 19 K-deficient adenovirus, were not immunosuppressive, and non-apoptotic cells, dying as a result of wild-type adenoviral infection, were immunosuppressive. This 'reversed' behavior was attributable genetically to E1B 19 K. That authentic Bcl-2 could substitute for E1B 19 K, but that it does not program such a reversed behavior in the context of Figure 3 Glycosomal localization of glycolytic enzymes.…”

“…65 The complete genetic basis of adenoviral cell death reprogramming and its mechanism remain to be elucidated. Similarly, whether other viruses direct cell death reprogramming remains unexplored.…”

Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis

“…We reported that Ad5 E1B 19K function is required for Ad-infected, dying cells (CPE corpses) to repress stimulus-induced, NF-B-dependent transcription and related cytokine production by responder macrophages, an E1B 19K function termed apoptotic mimicry (7). As observed with wt Ad5 infection, wt Ad14-infected human A549 (lung epithelial cell) CPE corpses repressed PMA-induced NF-B-dependent transcription in reporter cells, whereas CPE corpses infected with either Ad14p1 clinical isolate failed to repress this response, in a pattern similar to that of infection with the 19K-deleted Ad mutant, H5 dl337 (Fig.…”

“…We have previously reported that cells dying as a result of wt Ad5 infection repress the host inflammatory response to the virus (7). Expression of the Ad E1B 19-kilodalton (19K) protein is required for this anti-inflammatory activity since cells infected with an Ad mutant that lacks expression of 19K fail to exhibit anti-inflammatory activity.…”

“…We postulated that emergent Ad strains that induce ARDS might either lack sufficient expression of 19/20K or express a mutated 19/20K, resulting in an enhanced host proinflammatory response to Ad infection. Adenoviruses that express either reduced levels or a mutant form of 19/20K have a large-plaque (lp) phenotype and increased cytopathic effect (CPE) in cell culture (the so-called cyt phenotype) and generate CPE corpses that either fail to repress or induce increased proinflammatory responses of activated macrophages (7).…”