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Principal Investigator: Jalene Velazquez
Organization: WASHINGTON STATE UNIVERSITY
Fiscal Year: 2024
Award: $45,214
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <(IFN) α><(IFN)-α><(IFN)α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Aching muscles><Acute><Alferon><Antibodies><Antibody Response><Antigen-Antibody Complex><Antigens><Arthralgia><Assay><Autoantibodies><Autoantigens><Autoimmune><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Autologous Antigens><Binding><Bioassay><Biological Assay><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Serum><Blood monocyte><Body Tissues><COVID-19 infection><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><Cell Body><Cells><Chaperonin 60><Chemotactic Cytokines><Clinical><CoV-2><CoV2><Cognition><Collaborations><Complement><Complement Proteins><Cytotoxic cell><Data><Deposit><Deposition><Development><Disease><Disease Outbreaks><Disorder><Double-Stranded DNA><EBOV><Ebola><Ebola Hemorrhagic Fever><Ebola Virus Disease><Ebola disease><Ebola virus><Ebola-like Viruses><Epidemic><Eye><Eyeball><Fc Receptor><Fc domain><Filoviridae><Filovirus><Glycans><Glycoproteins><Goals><Grippe><Heat-Shock Proteins 60><Histones><Homologous Chemotactic Cytokines><Household><Human><Humoral Immunities><IFN Alpha><IFN α><IFN-α><IFNa><IFNα><IgG1><Immune><Immune Cell Activation><Immune Complex><Immunes><Immunodominant Antigens><Immunology><Incubated><Individual><Infection><Inflammatory><Influenza><Intercrines><Interferon Alfa-n3><Interferon alpha><Interferon-α><Joint Pain><K lymphocyte><Leukocyte Interferon><Life><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Lymphoblast Interferon><Lymphoblastoid Interferon><Marrow Neutrophil><Marrow monocyte><Measures><Mediating><Mentors><Modern Man><Molecular Interaction><Muscle discomfort><Muscle pain><Muscle pain/fibrositis><Muscle sorenesss><Musculoskeletal><Myalgia><Myalgic><Myodynia><Myoneuralgia><Myosalgia><NK Cell Activation><NK Cells><Natural Killer Cell Activation><Natural Killer Cells><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological Manifestations><Neurological Signs and Symptoms><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Outbreaks><Pathogenesis><Pathogenicity><Pathologic><Pathology><Patients><Phagocytosis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Polysaccharides><Predisposition><Prevention><Property><Proteins><QOL><Quality of life><Recombinants><Recovery><Reporting><Research><Resolution><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Scientist><Self-Antigens><Semen><Seminal fluid><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Severities><Shapes><Sierra Leone><Site><Specificity><Structure><Survivors><Susceptibility><Symptoms><Syndrome><Time><Tissues><Training><Universities><Viral><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><antibody receptor><antibody-based immunity><autoimmune antibody><autoimmune condition><autoimmune disorder><autoimmune inflammation><autoimmunity disease><autoreactive antibody><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><cell type><chemoattractant cytokine><chemokine><chronic COVID><chronic COVID-19><chronic novel coronavirus disease 2019><cohort><complementation><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19 virus><cpn 060><cpn60><cytokine><developmental><ds-DNA><dsDNA><effective therapy><effective treatment><experience><experiment><experimental research><experimental study><experiments><extracellular><falls><hCoV19><hsp60 Family><hsp60 Protein><immune activation><immunogen><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><long-term sequelae><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><mRNA Expression><monocyte><nCoV2><nano-string><nanostring><neural manifestation><neutrophil><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><patient mobility><persistent COVID-19><post COVID syndrome><post COVID-19 syndrome><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-acute phases of COVID-19><programs><prolonged COVID-19 symptoms><recruit><resolutions><self reactive antibody><seropositive><skills><social role><therapeutic target><therapeutic vaccine><treatment vaccines><vaccine for the treatment><vaccine for treatment><viral RNA><viral infection><virology><virus RNA><virus infection><virus-induced disease>