학술논문
Ebola virus-induced eye sequelae: a murine model for evaluating glycoprotein-targeting therapeuticsResearch in context
Document Type
article
Author
Ha-Na Lee; Biying Xu; Aaron P. Lewkowicz; Kaliroi Engel; Logan Kelley-Baker; Ian L. McWilliams; Derek D.C. Ireland; Jennifer L. Kielczewski; Jinbo Li; Robert N. Fariss; Mercedes M. Campos; Alina Baum; Christos Kyratsous; Kristen Pascal; Chi-Chao Chan; Rachel R. Caspi; Mohanraj Manangeeswaran; Daniela Verthelyi
Source
EBioMedicine, Vol 104, Iss , Pp 105170- (2024)
Subject
Language
English
ISSN
2352-3964
Abstract
Summary: Background: Ebola virus disease (EVD) survivors experience ocular sequelae including retinal lesions, cataracts, and vision loss. While monoclonal antibodies targeting the Ebola virus glycoprotein (EBOV-GP) have shown promise in improving prognosis, their effectiveness in mitigating ocular sequelae remains uncertain. Methods: We developed and characterized a BSL-2-compatible immunocompetent mouse model to evaluate therapeutics targeting EBOV-GP by inoculating neonatal mice with vesicular stomatitis virus expressing EBOV-GP (VSV-EBOV). To examine the impact of anti-EBOV-GP antibody treatment on acute retinitis and ocular sequelae, VSV-EBOV-infected mice were treated with polyclonal antibodies or monoclonal antibody preparations with antibody-dependent cellular cytotoxicity (ADCC-mAb) or neutralizing activity (NEUT-mAb). Findings: Treatment with all anti-EBOV-GP antibodies tested dramatically reduced viremia and improved survival. Further, all treatments reduced the incidence of cataracts. However, NEUT-mAb alone or in combination with ADCC-mAb reduced viral load in the eyes, downregulated the ocular immune and inflammatory responses, and minimized retinal damage more effectively. Interpretation: Anti-EBOV-GP antibodies can improve survival among EVD patients, but improved therapeutics are needed to reduce life altering sequelae. This animal model offers a new platform to examine the acute and long-term effect of the virus in the eye and the relative impact of therapeutic candidates targeting EBOV-GP. Results indicate that even antibodies that improve systemic viral clearance and survival can differ in their capacity to reduce acute ocular inflammation, and long-term retinal pathology and corneal degeneration. Funding: This study was partly supported by Postgraduate Research Fellowship Awards from ORISE through an interagency agreement between the US DOE and the US FDA.