Document text
Principal Investigator: Alexander Bukreyev
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2021
Award: $215,591
Funding agency: National Institute of Allergy and Infectious Diseases
BSL-4 CORE (Core B): PROJECT SUMMARY/ABSTRACT
The pathogenesis of Ebola virus (EBOV) disease is characterized by a dysregulated immune response
that includes the suppression of the innate immune system leading to “immune paralysis” and
paradoxically activation of inflammatory pathways characteristic of a “cytokine storm”. The goal of this
Program Project is to investigate the molecular mechanisms of the dysregulated immune response to
EBOV infections. EBOV infections must be performed under Biosafety Level 4/Animal Biosafety level
4 (BSL-4/ABSL-4) containment in accordance with government and institutional biosafety, biosecurity
and select agent regulations; therefore, this Program Project requires a BSL-4 Core (Core B). Core B
will use the BSL-4 and ABSL-4 facilities of the Galveston National Laboratory (GNL), which is part of
the University of Texas Medical Branch (UTMB). Interactions between Core B and the Research
Projects (RPs) will be coordinated by the Administrative Core (Core A).
Fundamental to the efforts included in the Program Project will be performing infections of primary
immune and nonimmune cells from deidentified human subjects with EBOV and a mutant with a
disabled interferon-inhibiting domain. Next, cells and tissues will be taken from rhesus macaques
infected with the same viruses, which will be used to complement in vitro data. The infected cells will
be used for investigation of transcriptional (Research Project [RP]1), posttranscriptional (RP2), and
posttranslational mechanisms (RP3) that lead to the dysregulated immune response to EBOV. The
initial steps of the experimental procedures, which involve infectious materials, for all RPs and targeting
of critical nodes leading to dysregulated responses at gene expression levels in vitro will be performed
in GNL BSL-4 facilities. The in vivo validation of the targeting will be performed in mice and rhesus
macaques will be performed in GNL ABSL-4 facilities.
The procedures that will be performed in Core B are critical for achieving the major goals of the
proposed studies, including: (a) detailed knowledge of transcriptional mechanisms leading to the
dysregulated immune response to EBOV, (b) elucidation of the role of posttranscriptional mechanisms
in the dysregulated immune response to EBOV, (c) elucidation of the role of posttranslational
mechanisms in the dysregulated immune response to EBOV, and (d) building and experimental
validation of a comprehensive model for the pathogenesis of EBOV infection and other severe viral
infections, such as Marburg, Lassa fever, dengue, and COVID-19. Completion of Core B Specific Aims
will provide critical support for RP1, RP2, and RP3 to identify the role of transcriptional,
posttranscriptional, and posttranslational mechanisms in the dysregulated immune response to EBOV.
Terms: <Animal Model><Animal Models and Related Studies><Animals><BSL-4 facility><BSL4 facility><Blood donor><Body Tissues><COVID-19><COVID19><CV-19><CV19><Cell Body><Cells><Characteristics><Complement><Complement Proteins><Containment><Data><Dengue><Disabled Persons><Disabled Population><Doctor of Philosophy><EBOV><Ebola Hemorrhagic Fever><Ebola Virus Disease><Ebola disease><Ebola virus><Ebola-like Viruses><Emerging Communicable Diseases><Emerging Infectious Diseases><Frankfurt-Marburg Syndrome Virus><Funding><Gene Expression><Gene Transcription><Genetic Transcription><Goals><Government><Handicapped><Human><IFN><Immune><Immune Tolerance><Immune response><Immunes><Immunity><Immunologic Tolerance><Immunological response><In Vitro><Infection><Inflammatory><Infrastructure><Innate Immune System><Institutes><Interferons><International><Investigation><Knowledge><Laboratories><Lassa Fever><Lassa disease><Lead><M mulatta><M. mulatta><Macaca mulatta><Marburg><Marburg virus><Marburg-like Viruses><Marburgvirus><Medical><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><Organ><Pathogenesis><Pathway interactions><Pb element><People with Disabilities><Persons with Disabilities><Ph.D.><PhD><Primary Infection><Procedures><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Expression><Regulation><Research><Research Grants><Research Project Grants><Research Projects><Research Resources><Resources><Rhesus Macaque><Rhesus Monkey><Role><Sampling><Science><Sea><Senior Scientist><Texas><Tissues><Training><Transcription><United States National Institutes of Health><Universities><Vaccines><Validation><Viral><Viral Diseases><Virus><Virus Diseases><Work><biodefense><biosafety level 4 facility><biosecurity><career><corona virus disease 2019><coronavirus disease 2019><cytokine release syndrome><cytokine storm><depository><disabled><disabled individual><disabled people><ebolavirus><experience><experiment><experimental research><experimental study><heavy metal Pb><heavy metal lead><host response><human subject><immune system response><immune system tolerance><immune unresponsiveness><immunological paralysis><immunoresponse><in vivo><individuals with disabilities><member><model of animal><model organism><mutant><pathway><professor><programs><proteogenomics><repository><response><social role><viral infection><virus infection><virus-induced disease>