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Principal Investigator: Shannon Ronca
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $3,842,980
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract – Project 3: Peribunyaviridae Pathogenesis and Vaccine Testing
The orthobunyaviruses (OBVs) of Peribunyviridae cause disease in humans manifesting with fever, nausea,
fatigue, and viral encephalitis, as well as long-term neurological complications. Identifying receptors and immune
factors mediating infection will highlight additional avenues of therapeutic development to work in tandem with
vaccination efficacy approaches. As these viruses are increasing in prevalence and vector range, their emergent
potential is high, and there is a critical need to better understand their pathogenesis and develop safe and
effective vaccines against OBVs. As part of this U19, this project will focus on identifying additional vaccine
targets while validating protein-adjuvant and mRNA vaccines developed in Projects 1 and 2. Importantly, these
studies will define both acute and long-term correlates of protection. The long-term goals are to 1) validate
immunogenic, multi-platform vaccines for OBVs, targeting LACV, OROV, and CVV as representative viruses; 2)
delineate mechanisms of OBV pathogenesis; and 3), define the role vaccines play in preventing sequelae. This
will test the hypothesis that 1) differential cytokine expression drives early and late stage OBV disease, 2)
vaccination prevents both acute and long-term effects of infection, and 3) OBVs exploit conserved receptors for
entry into the CNS. The first aim will define host immune responses to OBV infection in vivo. To determine
early and late-stage host immune responses to OBV infection, we will assess innate and adaptive immunity in
humanized immuno-competent and -compromised mouse models after infection with LACV, OROV, or CVV.
Serum cytokine levels, regulation of immune signaling genes, and histopathology will be assessed. This will
define key immunological mechanisms of protection against OBV infection and highlight avenues for additional
therapeutic development. The second aim will assess short and long-term protection against OBV infection
with adjuvanted subunit and mRNA vaccines in vivo. Adjuvanted subunit vaccines and mRNA vaccines
targeting Gc/Gn and NP antigens will be tested for protection against short- and long-term OBV outcomes in
animal models to identify lead vaccine candidates. MRI and behavioral analyses will be applied to understand
vaccine protection against disease sequelae. The third aim will identify conserved host cell receptors for
OBV attachment and entry mediating CNS tropism. The Antibody Generation, Epitope Mapping, and Machine
Learning Core will provide computational interaction screening, after which candidates will be verified in
permissive CNS cells and mouse models. Promising receptors will be blocked with inhibitors and knocked out
by CRISPR/Cas9 with subsequent infectivity measured in mouse and brain co-culture systems. Receptor
deficient mice will also be evaluated for changes in viral replication. Mouse models of severe infection will be
treated with receptor inhibitors to characterize changes to survival, immune responses, blood brain barrier
permeability, and long-term complications of infection.
Terms: <Acute><Adjuvant><Animal Model><Animal Models and Related Studies><Antibodies><Antigens><BBB permeabilization><BBB permeable><Behavioral><Blood Serum><Brain><Brain Nervous System><Bunyavirus><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cache Valley virus><Cas nuclease technology><Cell Body><Cell model><Cells><Cellular model><Chemokine Receptor Gene><Chemotactic Cytokines><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Co-culture><Cocultivation><Coculture><Coculture Techniques><Consult><Development><Disease><Disease Outcome><Disorder><Dose><Encephalon><Epitope Mapping><Family><Fatigue><Fever><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><Generations><Genes><Glycoproteins><Goals><Harvest><Histologic><Histologically><Histopathology><Homologous Chemotactic Cytokines><Human><IFN><Immune><Immune response><Immune signaling><Immunes><Immunization Programs><Immunochemical Immunologic><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunologic><Immunologic Factors><Immunological><Immunological Factors><Immunological response><Immunologically><Immunologics><Immunomodulation><Immunosuppressed Host><Infection><Innate Immunity><Integrins><Integrins Extracellular Matrix><Intercrines><Interferons><Knock-out><Knockout><La Crosse encephalitis virus><La Crosse virus><LaCrosse encephalitis virus><LaCrosse virus><Lack of Energy><Lead><Lectin><Licensing><Long-Term Effects><Longitudinal Studies><Longterm Effects><MR Imaging><MR Tomography><MRI><MRIs><Machine Learning><Magnetic Resonance Imaging><Measures><Mediating><Medical><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medicine><Mice><Mice Mammals><Modern Man><Murine><Mus><NMR Imaging><NMR Tomography><Native Immunity><Natural Immunity><Nausea><Neurologic><Neurological><Non-Specific Immunity><Nonspecific Immunity><Nuclear Magnetic Resonance Imaging><Nucleoproteins><Nucleosides><Organ><Oropouche><Oropouche virus><Orthobunyavirus><Outcome><Pathogenesis><Pb element><Play><Prevalence><Process><Proteins><Pyrexia><RNA Seq><RNA sequencing><RNA vaccine><RNA-based vaccine><RNAseq><Receptor Cell><Receptor Protein><Regimen><Research Resources><Resources><Role><SIS cytokines><Serum><Subunit Vaccines><System><Testing><Tropism><Vaccination><Vaccination Programs><Vaccines><Viral><Viral Encephalitis><Viral Infectious Encephalomyelitis><Viremia><Virginia><Virus><Virus Replication><Work><Zeugmatography><adaptive immunity><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier permeabilization><bloodbrain barrier permeable><chemoattractant cytokine><chemokine><chemokine receptor><college><collegiate><combat><consults><cross immunity><cross protection><cross reactivity><cytokine><develop a vaccine><develop vaccines><development of a vaccine><developmental><efficacy validation><evaluate vaccines><febrile><febris><flow cytophotometry><heavy metal Pb><heavy metal lead><host response><immune competent><immune modulation><immune regulation><immune system response><immunogen><immunogenic><immunologic reactivity control><immunologic substance><immunological substance><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressed patient><in vivo><inhibitor><long-term study><longitudinal outcome studies><longterm study><mRNA vaccine><mRNA-based vaccine><machine based learning><model of animal><mouse model><murine model><neutralizing antibody><outbreak response><pandemic disease preparedness><pandemic planning><pandemic preparedness><pandemic readiness><permissiveness><prevent><preventing><prototype><receptor><receptor expression><response><screening><screenings><social role><therapeutic agent development><therapeutic development><therapeutic target><transcriptome sequencing><transcriptomic sequencing><vaccine candidate><vaccine development><vaccine evaluation><vaccine platform><vaccine screening><vaccine testing><validate efficacy><vector><viraemia><viral multiplication><viral replication><viral sepsis><virus multiplication><virusemia>