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Principal Investigator: Mark T Heise
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2019
Award: $192,793
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Zika virus (ZIKV) is a mosquito borne flavivirus that recently emerged in the Americas. ZIKV infection is
associated with severe disease outcomes, including Guillain-Barré syndrome and microcephaly, a devastating
congenital disorder where fetal brain development is impaired. Despite ZIKV’s status as a significant emerging
disease threat, there are currently no approved vaccines or therapies for ZIKV infection. Thus a better
understanding of ZIKV replication is needed to guide both vaccine and therapy design. While relatively little is
known about ZIKV virulence determinants, a growing body of evidence suggests that RNA structural elements
in RNA viral genomes play a major role in virus replication and pathogenesis. The full complement of RNA
secondary structures within the ZIKV genome is not known, nor is it understood how these structures affect
replication. We therefore used selective 2′-hydroxyl acylation analyzed by primer extension and mutational
profiling (SHAPE-MaP) to define the RNA structural landscape of the entire ZIKV genome of a clinical isolate
from the ongoing ZIKV epidemic in the Americas. This analysis provided the first comprehensive view of RNA
structure in the ZIKV genome. We identified RNA secondary structures distributed throughout the genome,
including 19 regions with exceptionally high structural stability. These highly stable structures include known
structures within the ZIKV 5’ UTR and 3’ UTR, thus validating the use of SHAPE-MAP to identify ZIKV RNA
structures. The additional highly stable RNA structures are present across the coding region of the ZIKV genome
and have not been characterized. These results demonstrate that the ZIKV genome is highly structured, and
we hypothesize that the novel RNA structures may play important roles in multiple aspects of the ZIKV lifecycle.
The fact that known flavivirus RNA structures are highly conserved suggests that some of the novel ZIKV
structures are also conserved across flaviruses and may function as virulence determinants. Therefore, in Aim
1 we test whether novel, highly stable RNA structures in the ZIKV genome are important for ZIKV replication and
pathogenesis. To determine the level of RNA structural conservation between ZIKV and other flaviviruses, in
Aim 2 we use SHAPE-MaP to comprehensively define RNA structure in the entire genome of several other
medically important flaviviruses (Yellow Fever virus, West Nile virus, and Powassan virus). These studies will
significantly advance our understanding of how RNA structure impacts ZIKV biology, and provide new insights
into whether highly conserved RNA structures broadly contribute to flavivirus replication and pathogenesis.
Terms: <3' Untranslated Regions><3'UTR><5' Untranslated Regions><5'UTR><AIDP><Acute Autoimmune Neuropathy><Acute Infective Polyneuritis><Acute Inflammatory Demyelinating Polyradiculoneuropathy><Acute Inflammatory Polyneuropathy><Acute Inflammatory Polyradiculoneuropathy><Acylation><Affect><Americas><Antiviral Agents><Antiviral Drugs><Antivirals><Attenuated><Attenuated Live Virus Vaccine><Biological><Biology><Brain><Brain Nervous System><Cell Body><Cells><Clinical><Code><Coding System><Complement><Complement Proteins><Complex><Congenital Disorders><Culicidae><DNA Molecular Biology><Defect><Development><Disease><Disease Outcome><Disorder><Egypt 101 virus><Elements><Encephalon><Epidemic><Family><Fetal Diseases><Flavivirus><Functional RNA><Genetic Alteration><Genetic Change><Genetic Translation><Genetic defect><Genome><Goals><Group B Arbovirus><Guillain-Barré Syndrome><Guillaine-Barre Syndrome><Hydroxyl><Hydroxyl Radical><Impairment><Knowledge><Landry's paralysis><Landry-Guillain-Barre Syndrome><Link><Live-attenuated Vaccine><Measures><Medical><Messenger RNA><Microcephaly><Molecular><Molecular Biology><Mosquitoes><Mutation><Neurologic><Neurological><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleotides><Pathogenesis><Pattern><Play><Powassan virus><Primer Extension><RNA><RNA Folding><RNA Gene Products><RNA analysis><Research><Resolution><Ribonucleic Acid><Role><Structure><Testing><Therapeutic><Time><Untranslated RNA><Vaccine Design><Vaccines><Viral><Viral Diseases><Viral Genome><Viral Pathogenesis><Virulence><Virus Diseases><Virus Replication><WNV><West Nile><West Nile virus><Yellow fever virus><ZIKA><ZIKV><ZIKV disease><ZIKV infection><Zika Virus><Zika vaccine><Zika virus disease><Zika virus infection><Zika virus vaccine><acute idiopathic polyneuritis><acute post-infectious polyneuropathy><acute postinfectious polyneuropathy><anti-viral agents><anti-viral drugs><anti-virals><computer program><computer programming><design><designing><developmental><embryo/fetus disorder><entire genome><fetal disorders><fetus disorder><full genome><genome mutation><genome wide analysis><genome wide studies><genome-wide analysis><genome-wide identification><in vivo><infant infection><infected infant><infected neonate><infected newborn><insight><intervention design><mRNA><mRNA Leader Sequences><mRNA Translation><micrencephaly><microencephaly><mosquito-borne><mosquitoborne><neonatal infection><new drug treatments><new drugs><new therapeutics><new therapy><new vaccines><newborn infection><next generation therapeutics><next generation vaccines><noncoding><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><novel vaccines><nuclease><pathogen><prevent><preventing><social role><stem><therapy design><treatment design><viral RNA><viral infection><viral multiplication><viral replication><virus RNA><virus genome><virus infection><virus multiplication><virus pathogenesis><virus-induced disease><whole genome><zika disease><zika infection><zika viral infection><zikav>