Proposed mechanism for antigenic subversion.
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Abstract
<p>Regions of GP<sub>1,2</sub> that are shared with sGP are in red, while unshared epitopes are in green. B-cells are colored according to the regions of GP<sub>1,2</sub> and sGP against which they react. (A) A naïve animal begins with B-cells that can potentially recognize epitopes distributed throughout GP<sub>1,2</sub> and sGP. When sGP is expressed at much higher levels than GP<sub>1,2</sub>, as occurs during infection, those B-cells that recognize sGP epitopes, many of which are shared with GP<sub>1,2</sub> (red regions of sGP and GP<sub>1,2</sub>) are preferentially activated and expanded compared to B-cells that recognize unshared epitopes of GP<sub>1,2</sub> (green regions of GP<sub>1,2</sub>). Thus, sGP-reactive antibodies dominate the immune response. (B) Prior immunization by sGP. Because sGP shares over 90% of its linear sequence with GP<sub>1,2</sub>, animals primed with sGP generate anti-sGP antibodies, many of which are directed against epitopes shared with GP<sub>1,2</sub>. When these animals (or individuals who have previously been infected and recovered from EBOV infection) are boosted with GP<sub>1,2</sub>, sGP cross-reactive memory cells outnumber and express higher affinity receptors than naïve GP<sub>1,2</sub> specific B-cells, resulting in preferential expansion of these sGP-cross-reactive B-cells and a predominantly sGP-reactive immune response. (C) Prior immunization by GP<sub>1,2</sub>. Priming naïve animals with GP<sub>1,2</sub> results in antibodies largely against GP<sub>1,2</sub> epitopes not shared with sGP, presumably due to the immunodominance and high accessibility of the GP<sub>1,2</sub> mucin domain and shielding of shared epitopes. When these animals are boosted with sGP, or if they are infected with EBOV and do not have sufficiently high titers of anti-GP<sub>1,2</sub> antibodies to clear the infection rapidly, memory B-cells that recognize shared epitopes encounter their cognate antigen and expand, while non-cross-reactive GP<sub>1,2</sub>-specific B-cells are not boosted, resulting in subversion of the host immune response towards sGP cross-reactivity. (D) Successful clearance of EBOV infection. In order to avoid sGP-mediated antigenic subversion, high enough titers of non-crossreactive anti-GP<sub>1,2</sub> antibodies must be maintained to rapidly clear EBOV infection before subversion can occur.</p
