Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome

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PROJECT SUMMARY Survivors of Ebola virus disease (EVD) have reported a wide range of symptoms following recovery from infection. These long-term sequelae are severe enough to interfere with their daily lives and are now collectively referred to as post-Ebola syndrome (PES). Although post-viral symptoms have posed a serious problem in the Ebola outbreaks of 1995 and 2013-2016, little is known about the underlying mechanism of PES pathogenesis. Ebola virus (EBOV) RNA has been found in immune-privileged sites, such as the eye and semen, so it is suggested that the virus may persist in tissues to cause continued antigenic stimulation over time. However, not all cases of PES can be attributed to viral persistence. Most of the symptoms that survivors experience are autoimmune-like, the most common being arthralgias and myalgias. Autoantibodies against common human proteins have also been found in survivor serum, alluding to virus-induced autoimmunity. We hypothesize that both virus-specific and autoimmune antibody responses play a role in the development of PES. Through a collaboration with Dr. John Schieffelin at Tulane University, we propose to analyze an existing cohort of EVD survivors and their household contacts from Sierra Leone that have been clinically characterized for development of PES. Our preliminary findings revealed that antibodies against the immunodominant antigen, the Ebola glycoprotein (EBOV GP), in asymptomatic EVD survivors were qualitatively different from survivors experiencing musculoskeletal manifestations of PES. Specifically, antibodies from asymptomatic individuals induced higher levels of antibody-dependent complement deposition and monocyte-mediated phagocytosis, but not neutrophil- mediated phagocytosis, and differed in NK cell activation profiles compared with individuals with PES. In addition, our data has also revealed that IgG1 levels against dsDNA, HSP-60, citrullinated histone, and IFNα are elevated in EVD survivors and GP-seropositive household contacts (HHC) compared to GP-seronegative HHC, indicating a correlation between autoantibodies and EBOV infection. Thus, the purpose of this proposal is to further investigate the role of both virus-specific and autoimmune antibody-mediated innate immune cell activation in PES, and whether this role is protective or pathologic. To do so, we propose to analyze antibodies for induction of innate effector function against EBOV-specific proteins in Aim 1 and Aim 2 will focus on the identification of potential autoimmune antibody responses that are elevated in individuals with PES. Together, these aims will address the role of qualitatively different antibodies with varying specificities in shaping susceptibility to/protection from the development of PES and may help to identify potential therapeutic targets to provide proper and effective treatment to EVD survivors suffering from PES. In addition to providing expertise in immunology, virology, and Ebola virus disease, my sponsor and co-sponsors, Drs. Bronwyn Gunn, John Schieffelin, and Anthony Nicola have developed a comprehensive training plan aimed at providing me with the necessary skills needed for me to succeed in this proposal and as a research scientist.