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PLoS Pathogens. Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus
[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]
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Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus
Gopi S. Mohan<SUP>1</SUP>, Wenfang Li<SUP>1</SUP><SUP>,</SUP><SUP>2</SUP>, Ling Ye<SUP>1</SUP>, Richard W. Compans<SUP>1</SUP><SUP>*</SUP>, Chinglai Yang<SUP>1</SUP><SUP>*</SUP>
<SUP></SUP>
1 Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, United States of America, 2 Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
Abstract
In addition to its surface glycoprotein (GP<SUB>1,2</SUB>), Ebola virus (EBOV) directs the production of large quantities of a truncated glycoprotein isoform (sGP) that is secreted into the extracellular space. The generation of secreted antigens has been studied in several viruses and suggested as a mechanism of host immune evasion through absorption of antibodies and interference with antibody-mediated clearance. However such a role has not been conclusively determined for the Ebola virus sGP. In this study, we immunized mice with DNA constructs expressing GP<SUB>1,2</SUB> and/or sGP, and demonstrate that sGP can efficiently compete for anti-GP<SUB>12</SUB> antibodies, but only from mice that have been immunized by sGP. We term this phenomenon ?antigenic subversion?, and propose a model whereby sGP redirects the host antibody response to focus on epitopes which it shares with membrane-bound GP<SUB>1,2</SUB>, thereby allowing it to absorb anti-GP<SUB>1,2</SUB> antibodies. Unexpectedly, we found that sGP can also subvert a previously immunized host's anti-GP<SUB>1,2</SUB> response resulting in strong cross-reactivity with sGP. This finding is particularly relevant to EBOV vaccinology since it underscores the importance of eliciting robust immunity that is sufficient to rapidly clear an infection before antigenic subversion can occur. Antigenic subversion represents a novel virus escape strategy that likely helps EBOV evade host immunity, and may represent an important obstacle to EBOV vaccine design.
Author Summary
The function of the Ebola virus (EBOV) secreted glycoprotein (sGP) has been long debated, and the fact that sGP production is conserved among all known EBOV species strongly indicates an important role in the viral life cycle. Furthermore, the recent finding that EBOV mutates to a predominantly non-sGP-forming phenotype in cell culture, while the mutant virus reverts to an sGP-forming phenotype in vivo, suggests that sGP is critical for EBOV to survive in its infected host. Here we demonstrate that sGP can function to absorb anti-GP antibodies. More importantly, instead of simply passively absorbing host antibodies, sGP actively subverts the host immune response to induce cross-reactivity with epitopes it shares with membrane-bound GP<SUB>1,2</SUB>. Immune subversion by sGP represents a distinct mechanism from the use of secreted antigens as antibody decoys, an immune evasion tactic previously proposed for other viruses, and should be an important consideration for future EBOV vaccine design efforts since vaccines may need to be specifically tailored to avoid subversion.
Citation: Mohan GS, Li W, Ye L, Compans RW, Yang C (2012) Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus. PLoS Pathog 8(12): e1003065. doi:10.1371/journal.ppat.1003065
Editor: Christopher F. Basler, Mount Sinai School of Medicine, United States of America
Received: May 9, 2012; Accepted: October 10, 2012; Published: December 13, 2012
Copyright: ? 2012 Mohan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study is supported by Public Health Service grants 1R01AI093406 and 1R01AI069148 from the National Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: rcompan@emory.edu (RWC); chyang@emory.edu (CY)
-Gopi S. Mohan<SUP>1</SUP>, Wenfang Li<SUP>1</SUP><SUP>,</SUP><SUP>2</SUP>, Ling Ye<SUP>1</SUP>, Richard W. Compans<SUP>1</SUP><SUP>*</SUP>, Chinglai Yang<SUP>1</SUP><SUP>*</SUP>
<SUP></SUP>
1 Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, United States of America, 2 Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
Abstract
In addition to its surface glycoprotein (GP<SUB>1,2</SUB>), Ebola virus (EBOV) directs the production of large quantities of a truncated glycoprotein isoform (sGP) that is secreted into the extracellular space. The generation of secreted antigens has been studied in several viruses and suggested as a mechanism of host immune evasion through absorption of antibodies and interference with antibody-mediated clearance. However such a role has not been conclusively determined for the Ebola virus sGP. In this study, we immunized mice with DNA constructs expressing GP<SUB>1,2</SUB> and/or sGP, and demonstrate that sGP can efficiently compete for anti-GP<SUB>12</SUB> antibodies, but only from mice that have been immunized by sGP. We term this phenomenon ?antigenic subversion?, and propose a model whereby sGP redirects the host antibody response to focus on epitopes which it shares with membrane-bound GP<SUB>1,2</SUB>, thereby allowing it to absorb anti-GP<SUB>1,2</SUB> antibodies. Unexpectedly, we found that sGP can also subvert a previously immunized host's anti-GP<SUB>1,2</SUB> response resulting in strong cross-reactivity with sGP. This finding is particularly relevant to EBOV vaccinology since it underscores the importance of eliciting robust immunity that is sufficient to rapidly clear an infection before antigenic subversion can occur. Antigenic subversion represents a novel virus escape strategy that likely helps EBOV evade host immunity, and may represent an important obstacle to EBOV vaccine design.
Author Summary
The function of the Ebola virus (EBOV) secreted glycoprotein (sGP) has been long debated, and the fact that sGP production is conserved among all known EBOV species strongly indicates an important role in the viral life cycle. Furthermore, the recent finding that EBOV mutates to a predominantly non-sGP-forming phenotype in cell culture, while the mutant virus reverts to an sGP-forming phenotype in vivo, suggests that sGP is critical for EBOV to survive in its infected host. Here we demonstrate that sGP can function to absorb anti-GP antibodies. More importantly, instead of simply passively absorbing host antibodies, sGP actively subverts the host immune response to induce cross-reactivity with epitopes it shares with membrane-bound GP<SUB>1,2</SUB>. Immune subversion by sGP represents a distinct mechanism from the use of secreted antigens as antibody decoys, an immune evasion tactic previously proposed for other viruses, and should be an important consideration for future EBOV vaccine design efforts since vaccines may need to be specifically tailored to avoid subversion.
Citation: Mohan GS, Li W, Ye L, Compans RW, Yang C (2012) Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus. PLoS Pathog 8(12): e1003065. doi:10.1371/journal.ppat.1003065
Editor: Christopher F. Basler, Mount Sinai School of Medicine, United States of America
Received: May 9, 2012; Accepted: October 10, 2012; Published: December 13, 2012
Copyright: ? 2012 Mohan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study is supported by Public Health Service grants 1R01AI093406 and 1R01AI069148 from the National Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: rcompan@emory.edu (RWC); chyang@emory.edu (CY)
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