Research Project
10296983
SUMMARY Ebolaviruses (EBOV) are among the deadliest pathogens known to man, with a case fatality rate of 25?90% depending on the outbreak. For the first time, monoclonal antibodies Zmapp, Mab114, REGN-EB3 and Remdesivir (inhibitor of viral RNA synthesis) were used, improving survival rates in Ebola treatment units (ETU) during the ongoing outbreak of Ebola virus disease (EVD) in Congo-Kinshasa. Despite treatments, 34% of EVD survivors experienced eye complications. In addition, they had lower [mean (SD)] minimental test examination (MMSE) scores i.e. [25 (5.5)] relative to controls [29.9 (0.6)] (p < 0.01); and women perform poorly [24.8 (5.90] relative to men [28.4 (3.2)](p < 0.01). The odds of depression were higher in EVD survivors [OR: 14.9 (95%CI: 4.4 ? 50.1)], mostly in women [OR: 4.4. (95%CI: 2.1 ? 9.6)] and, intriguingly, MMSE deficit in women was associated with higher initial EBOV viral load [OR: 0.84 (95%CI: 0.73 ? 0.98, p = 0.03, for one-unit increase in ctXptNP; lower ctXpt = higher viral load] after adjustment for age and depression status. EBOV persisted in breastmilk, wet preps, and semen for several months after acute EVD. We propose to test the hypothesis that occurrence of neuroophthalmologic sequalae is dictated by initial and/or persistence of EBOV viral load with discernable IgG responses, and/or a persistent inflammatory state driven by elevated cytokines and immune cell activation; by addressing the following specific aims: Aim 1. To contrast neuro- ophthalmologic deficits (spectrum & extent) found in confirmed EVD survivors to relevant profiles seen in their IgG+ but EVD-free close contacts, and IgG- controls (N = 90 per group). In Aim 1A, study participants will have longitudinal (0, 6, 12, 24, 36, and 48 month-time-points) assessments of neurocognition using the computerized Test of Variables of Attention (auditory and visual), the Test of Attentional Performance, and CogState for nonverbal cognitive skills. In Aim 1B, they will undergo psychophysical tests for visual acuity, contrast sensitivity, color vision, and visual field; as well as spectral domain-optical coherence tomography to elucidate structural biomarkers of disease within visual pathways. Aim differences levels overabundance 2 will determine whether group- on neuroophthalmologic outcomes found in Aim 1 are mediated by EBOV viral load or persistence, of anti-EBOV IgG, alterations in levels or activation status of circulating immune cells, and/or of proinflammatory cytokines. Aim 3 will enhance capacity in neurocognitive assessments, ophthalmologic evaluations and EVD immunoprofiling and molecular biology (RT-PCR). Gaps of knowledge to be filled include lack of understanding of (1) EBOV persistence, (2) long-lasting immune dysregulation, (3) IgG positivity with no overt EVD symptoms, all in contexts of post-EVD treatment. The overall goal of the proposed work aligns with the global health mission of the NIH while integrating the institute-specific missions of FIC, NEI, NIAID, NINDS, and the Office of Disease Prevention.
