The National Institute of Neurological Disorders and Stroke (NINDS) awarded a $431,750 R21 project grant (CFDA 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders) to Rutgers, The State University of New Jersey to study the role of the RIPK3 protein in protecting neurons from excitotoxicity during Zika virus infection. The two-year project will use a combination of pharmacogenetics, imaging, molecular biology, and electrophysiology to investigate how RIPK3...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID), under the Allergy and Infectious Diseases Research program (CFDA 93.855), supports research to define the impact of maternal viral infections and inflammation on immune programming within the fetal brain and lymphoid organs in a non-human primate model. The $3,305,720 award, granted on July 12, 2024, with a completion date of May 31, 2029, will be used to: 1) Determine innate immune pathways...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) supports the development of a novel T cell-based vaccine to prevent dengue and Zika virus infections. The $781,718 award to Loyola University of Chicago will fund research to design a vaccine that targets the non-structural protein 3 (NS3) of Zika and dengue viruses, using a strategy to enhance its degradation in the proteasome...
This federal Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID), under the Allergy and Infectious Diseases Research program (CFDA 93.855), is focused on advancing CRISPR-based genome editing strategies to manage Aedes aegypti mosquito populations and reduce the public health burden of mosquito-borne diseases like yellow fever, Zika, chikungunya, and dengue. The $441,502 award aims to address key limitations of existing CRISPR-based approaches, such as...
This $769,115 Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) will support research at The Washington University in St. Louis aimed at advancing the mechanistic understanding of how meningeal structures function in regulating and responding to neurotropic virus infections. The key research objectives are to: 1) Define the role of arachnoid cuff exit (ACE) points in enabling...
This federal Project Grant award from the National Institute of Child Health and Human Development (CFDA 93.865 - Child Health and Human Development Extramural Research) provides $2,474,368 to evaluate the long-term medical, developmental, and mental health impacts of Congenital Zika Syndrome (CZS) on a cohort of 187 children. The award will fund a collaborative research effort led by RTI International, in partnership with the Altino Ventura Foundation in Brazil and researchers from the...
This $2,065,600.00 Project Grant award from the National Institute of Allergy and Infectious Diseases (CFDA 93.855 - Allergy and Infectious Diseases Research) will fund research to investigate the complex relationships between pre-existing immunity to different flaviviruses and subsequent infection outcomes. The award will integrate studies in non-human primate models and human cohorts to evaluate the impact of flavivirus exposure on antibody repertoire diversity, neutralization, and Fc effector...
This Project Grant award of $699,339.00 from the National Institute of Allergy and Infectious Diseases (CFDA 93.855 - Allergy and Infectious Diseases Research) supports research to characterize the transmission dynamics of dengue and Zika viruses at multiple geographic scales in northwestern coastal Ecuador. The research, led by the Regents of the University of Michigan, aims to understand how environmental, social, and biological factors influence virus transmission across diverse...
This Project Grant award, provided by the National Eye Institute (NEI) under the Vision Research program (CFDA 93.867), supports research to investigate how Zika virus (ZIKV) infection disrupts the blood-retinal barrier and causes ocular complications. The $121,090 award, covering the period from September 30, 2024 to August 31, 2026, will allow the principal investigator at Wayne State University to: 1) examine the role of the Ang/Tie-2 and S1P signaling pathways in ZIKV-induced blood-retinal...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID), under the Allergy and Infectious Diseases Research program (CFDA 93.855), provides $284,331 to the University of Massachusetts Medical School (UMass Medical) to conduct research on the stability of gene therapy vectors based on adeno-associated virus (AAV) when challenged by natural viral infections. The key objectives are to: 1) Track changes in AAV vector genome abundance and episomal...
HUMAN GENETIC VARIATION REGULATING CELLULAR SUSCEPTIBILITY TO ZIKA VIRUS - PROJECT SUMMARY/ABSTRACT ZIKA VIRUS, A SMALL POSITIVE-STRANDED RNA VIRUS, CAUSES A REMARKABLE SPECTRUM OF INFECTION OUTCOMES, RANGING FROM ASYMPTOMATIC INFECTION IN UP TO 80% OF INDIVIDUALS TO MICROCEPHALY IN CONGENITAL ZIKA SYNDROME. THIS VARIATION IN HUMAN SUSCEPTIBILITY WAS HIGHLIGHTED DURING THE 2015-2016 EPIDEMIC OF THE AMERICAS THAT RESULTED IN OVER A MILLION INFECTIONS AND 3,500 CASES OF MICROCEPHALY IN BRAZIL ALONE. THESE DIFFERENCES IN OUTCOME ARISE FROM THE COMPLEX INTERPLAY OF EXPOSURE, ENVIRONMENT, AGE, ZIKA VIRUS GENETICS, AND HUMAN GENETICS. THE OVERALL GOAL OF MY LAB IS TO UNDERSTAND HOW HUMAN GENETIC DIVERSITY REGULATES SUSCEPTIBILITY AND SEVERITY OF INFECTIONS. FAMOUS EXAMPLES OF GENETIC DIFFERENCES THAT PROFOUNDLY IMPACT SUSCEPTIBILITY INCLUDE SICKLE CELL ALLELE PROTECTION AGAINST MALARIA AND CCR5 DELETION PROTECTION AGAINST HIV. SUCH GENETIC DIFFERENCES CAN LEAD TO INSIGHTS ON PATHOGENESIS, DRUG TARGETS (E.G. CCR5 INHIBITORS), AND MORE PERSONALIZED CARE. WHILE GENOME-WIDE ASSOCIATION STUDIES (GWAS) ARE A POWERFUL APPROACH TO DISCOVER COMMON GENETIC DIFFERENCES THAT CONFER DISEASE RESISTANCE, THERE ARE NO PUBLISHED GWAS OF HUMAN ZIKA VIRUS INFECTION. HOWEVER, STUDIES OF DIZYGOTIC TWINS WITH DISCORDANT OUTCOMES HAVE DEMONSTRATED THAT CELLS FROM THE TWIN EXHIBITING CONGENITAL ZIKA SYNDROME ARE MORE SUSCEPTIBLE TO INFECTION IN VITRO. THEREFORE, WE HYPOTHESIZE THAT HUMAN GENETIC DIFFERENCES THAT REGULATE ZIKA INFECTION CAN BE IDENTIFIED THROUGH MEASURING INTER-INDIVIDUAL VARIATION IN CELLULAR INFECTION PHENOTYPES. TO FACILITATE IDENTIFICATION OF GENETIC VARIANTS THAT AFFECT CELLULAR INFECTION PHENOTYPES, WE DEVELOPED A RAPID SINGLE- CELL GWAS APPROACH CALLED SCHI-HOST (SINGLE-CELL HIGH-THROUGHPUT HUMAN IN VITRO SUSCEPTIBILITY TESTING). SCHI- HOST FACILITATES ASSIGNMENT OF EACH CELL TO A GENOTYPED INDIVIDUAL, PHENOTYPING OF EACH CELL FOR VIRAL ENTRY AND BURDEN, AND MEASUREMENT OF HOST TRANSCRIPTOMIC RESPONSE, ALL FROM A SINGLE SCRNA-SEQ EXPERIMENT. WE PROPOSE THAT COUPLING CELL-BASED HUMAN GENETICS AND FUNCTIONAL VALIDATION WILL FACILITATE DISCOVERY OF NOVEL PATHWAYS AND GENETIC DETERMINANTS OF SUSCEPTIBILITY. SPECIFICALLY, WE WILL 1) IDENTIFY HUMAN GENETIC VARIANTS THAT CONFER SUSCEPTIBILITY/RESISTANCE TO CELLULAR ZIKA VIRUS INFECTION FOR STRAINS REPRESENTING THE MAJOR ZIKA VIRUS LINEAGES, AND 2) EXPERIMENTALLY VALIDATE GENETIC VARIANTS AND CAUSAL GENES ASSOCIATED WITH CELLULAR SUSCEPTIBILITY TO ZIKA VIRUS USING CRISPR-BASED APPROACHES IN DIVERSE CELL TYPES. THUS, THIS PROJECT WILL GENERATE AN EXPERIMENTALLY VALIDATED, HIGH-RESOLUTION ANALYSIS OF HOW HUMAN GENETIC VARIANTS IMPACT CELLULAR INFECTION PHENOTYPES DURING ZIKA VIRUS INFECTION. THIS WILL SERVE AS A SPRINGBOARD FOR CHARACTERIZING IDENTIFIED VARIANTS MORE DEEPLY THROUGH FUTURE MECHANISTIC STUDIES AND EXAMINING CLINICAL RELEVANCE IN HUMAN STUDIES. UNDERSTANDING THESE DIFFERENCES COULD LEAD TO NEW DIAGNOSTIC APPROACHES IN IDENTIFYING AT-RISK INDIVIDUALS AND NOVEL THERAPEUTIC STRATEGIES FOR TREATMENT.