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Principal Investigator: George Dimopoulos
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $749,082
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
Arboviruses remain an immense public health threat, causing yearly large epidemics. The overarching aim
of this research is to better understand the role of the Aedes aegypti RNA interference (RNAi) pathway in
antiviral defense and innate immunity, and to generate knowledge and tools for the development of new
methods to control arbovirus transmission. Population replacement of wild-type with genetically modified
mosquitoes incapable of pathogen transmission is emerging as a promising complement to other disease
control methods. Because Ae. aegypti transmits multiple arbovirus pathogens that are frequently sympatric, it
is important for a transgenic mosquito to be resistant to multiple pathogens. The siRNA pathway-mediated
antiviral defense system is known to act against a broad range of viruses. However, despite the RNAi
pathway's emergence as the major pan-antiviral defense system it remains understudied in mosquitoes. Our
research plan is designed to test the overarching hypothesis that the A. aegypti proteins, Dicer-2 (Dcr-2), R2D2
and Argonaute-2 (Ago-2), are key components mediating an RNA silencing response that is broadly protective
against arbovirus infections. We will use of siRNA-deficient loss-of-function mutants and transgenic
mosquitoes over-expressing Dcr-2, Ago-2 and R2D2 that will be generated in Aim 1. With these genetic tools
we will clarify the temporal and spatial specificity of the antiviral response in Aim 2, and investigate possible
inter-tissue signaling and regulation of vertical transmission in Aim 3. In Aim 4 we will address interactions
between the RNAi pathway and other innate immunity defense systems. This project utilizes the
complementary expertise of Drs Dimopoulos and Myles with the arbovirus infection systems, mosquito
transgenesis, mosquito innate immunity and RNAi/small RNA biology. Our proposed project will also generate
powerful tools for studying other aspects of the RNAi pathway in Ae. aegypti biology.
Terms: <Address><Aedes><Anti-viral Response><Arboviral><Arboviral infections><Arbovirus Infections><Arboviruses><Area><Arthropod-Born Viral Infection><Arthropod-Borne Viruses><Bio-Informatics><Bioinformatics><Biology><Body Tissues><Breakbone Fever Virus><CHIKV><Cell Communication and Signaling><Cell Signaling><Chikungunya virus><Complement><Complement Proteins><Culicidae><DENV><Dengue Virus><Dengue fever virus><Development><Disease Vectors><Drosophila melanogaster><Epidemic><Fat Body><Gene Inactivation><Gene Modified><Gene Silencing><Gene Transfer Techniques><Genes><Genetic><Goals><Immune><Immune signaling><Immune system><Immunes><Immunity><Infection><Innate Immunity><Intracellular Communication and Signaling><Knowledge><La Crosse encephalitis virus><La Crosse virus><LaCrosse encephalitis virus><LaCrosse virus><Laboratories><Mediating><Methods><Midgut><Molecular><Molecular Genetics><Molecular Virology><Mosquitoes><Movement><NGS Method><NGS system><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Ovary><Pathway interactions><Population Replacements><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proteins><Public Health><RNA Interference><RNA Interference Pathway><RNA Silencing><RNAi><Regulation><Research><Research Resources><Resistance><Resources><Role><Salivary Glands><Salivary Glands Head and Neck><Sequence-Specific Posttranscriptional Gene Silencing><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Sindbis Virus><Small Interfering RNA><Small RNA><Specificity><System><Testing><Tissues><Transgenesis><Transgenic Organisms><Transmission><Vertical Transmission><Viral><Virus><Work><Yellow Fever><ZIKV><Zika Virus><anti-viral immunity><antiviral immunity><arthropod transmission><arthropod transmitted><arthropod-borne><arthropod-borne infection><arthropodborne><arthropodborne infection><biological signal transduction><body movement><combinatorial><complementation><design><designing><developmental><disease control><disorder control><gene modification><genetically modified><human pathogen><innate immune pathways><interdisciplinary approach><loss of function><model organism><multidisciplinary approach><mutant><new approaches><next gen sequencing><next generation sequencing><nextgen sequencing><novel><novel approaches><novel strategies><novel strategy><overexpress><overexpression><pathogen><pathogenic virus><pathway><resistant><response><siRNA><social role><spatiotemporal><tool><tool development><transcriptional silencing><transgene expression><transgenic><transmission process><vector><viral RNA><viral pathogen><virus RNA><virus pathogen><zikav>