DEFINING THE PROTECTIVE OR PATHOLOGIC ROLE OF ANTIBODIES IN POST-EBOLA SYNDROME

Jalene V. Velazquez

doi:10.7273/000007850

The 2014-2016 Ebola virus (EBOV) outbreak in West Africa was the largest in history, with over 28,000 cases and a 40% case fatality rate. A subset of survivors of Ebola virus disease (EVD) have reported a wide variety of long-term symptoms years after recovery from acute infection, collectively called Post-Ebola Syndrome (PES). Although post-viral symptoms have posed a serious problem in the Ebola outbreaks of 1995 and 2014-2016, the underlying basis for why some survivors develop PES while others do not is unclear. As antibodies have been shown to play a vital role during acute infection, the purpose of this project is to investigate the role of anti-EBOV antibodies in the development of PES. We aim to identify differences in antibody profiles between EVD survivors with or without long-term sequelae by measuring both quantity and functional quality of EBOV-specific antibodies. To do this, we used a systems serology approach to profile sera from 354 Sierra Leonean EVD survivors and 186 household contacts (HHC) obtained 2.5 years after resolution of acute infection, where 68% of EVD survivors were asymptomatic and 32% reported a range of PES symptoms. We observed that survivors without PES had elevated levels of EBOV-specific IgG1 and IgG3 compared to survivors with PES, which also corresponded to elevated levels of EBOV glycoprotein (GP)-specific activation of Fc-mediated innate immune effector functions in survivors without PES, such as complement deposition, monocyte-mediated phagocytosis, and NK cell activation. However, we observed that while GP-specific IgG1 correlated with effector functions in survivors with and without PES, GP-specific IgG3 was also correlated with effector function in survivors with PES, linked to an increased ratio of IgG3 to IgG1 in the context of PES. To determine if distinct pathways within innate immune cells were differentially activated by antibodies from survivors with and without PES, we profiled mRNA expression in NK cells and monocytes following activation by EBOV GP-specific antibodies. We found that there were differentially expressed genes between cells activated by asymptomatic survivor antibodies and those activated by symptomatic survivor antibodies, suggesting that antibody-mediated activation profiles of innate immune cells are distinct between survivors with and without PES. We also screened survivors and HHC for autoantigen-specific antibodies, as some PES symptoms resemble those of autoimmune disease, and found that asymptomatic survivors had higher autoantigenic IgG and IgA compared to survivors with PES. Additionally, HHC who were seropositive for anti-EBOV GP IgG had elevated autoantibody levels compared to HHC who were GP-seronegative. Although survivors report that these long-term sequelae are severe enough to interfere with their daily lives, there remain to be major knowledge gaps in what is known about how these symptoms develop. This study contributes to existing literature on how antibody properties correlate with protection from severe disease and highlights the importance of these properties not only in acute infection, but in long-term outcome as well. Together, these data suggest that the development of qualitatively different antibodies may shape susceptibility to/protection from the development of PES, thereby identifying antibody features that can potentially be used to leverage the innate immune system during acute infection as a prevention strategy against long-term sequelae.

DEFINING THE PROTECTIVE OR PATHOLOGIC ROLE OF ANTIBODIES IN POST-EBOLA SYNDROME

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