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Principal Investigator: Alison Kell
Organization: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
Fiscal Year: 2024
Award: $237,136
Funding agency: National Institute of Allergy and Infectious Diseases
Mammalian hantaviruses (order Bunyavirales, genus Orthohantavirus) are zoonotic RNA viruses that cause
severe vascular inflammatory disease in humans, with case-fatality rates of up to 40%. These negative-sense,
tri-segmented viruses are maintained, persistently and asymptomatically, within wild rodent and insectivore
reservoir populations worldwide. As the first line of antiviral defense, innate immune signaling and type I
interferon (IFN) act to limit viral replication and production of infectious progeny, preventing tissue dissemination
and systemic infection. A dominant hypothesis posits that asymptomatic reservoir persistence is maintained
through innate immune suppression, which allows for sustained viral replication without damaging inflammation.
Evidence to support this hypothesis includes observations by our group and others that hantavirus infection of
natural reservoir target endothelial cells (EC) results in dampened innate immune signaling and IFN-stimulated
gene (ISG) expression. We now show that EC from the natural reservoir host (Rattus norvegicus) for Seoul virus
(Orthohantavirus seoulense, SEOV) support sustained viral replication and infectious virion production in the
presence of exogenous type I IFN and robust ISG expression. In contrast, the related Hantaan virus is highly
susceptible to IFN-mediated restriction in human and rat EC, both of which represent non-reservoir hosts.
Similarly, SEOV replication in human EC was reduced in the context of type I IFN signaling, either through
exogenous treatment or induced by viral recognition receptors. Together, this led to our overall hypothesis that,
through coevolution, SEOV has developed mechanisms to directly target rat antiviral effector proteins induced
by type I IFN and inhibit their functionality. Our data further suggests that mechanisms of inhibition seen in rat
cells are ineffective in the setting of human infection. The unique tractability of the natural rat host and the distinct
divergence in immune modulation provides an opportunity to identify critical SEOV protein – host antiviral protein
interfaces that prevent viral restriction in reservoir, but not human EC. Our team brings decades of experience
in virology, innate immune signaling, and in identifying human host protein interactors for diverse families of RNA
viruses, as well as all of the necessary reagents, assays, and expertise for success. Using novel monoclonal
antibodies directed at each of the SEOV proteins to capture authentic viral protein complexes in the context of
infection, we will undertake an innovative comparative proteomics approach to contrast the SEOV interactome
in reservoir rat and non-reservoir human primary EC (Aim 1). In Aim 2, we will perform validation and functional
analysis of selected IFN-induced antiviral host partners isolated in Aim 1 to test their significance for viral
replication and progeny production in reservoir and non-reservoir host cells. This approach to identify unique
virus-host interactors is the first described for a reservoir host of any hantavirus species and will yield insights
into mechanisms of persistence and human disease.
Terms: <Acute><Affinity Chromatography><Andes Virus><Argentina><Assay><Bioassay><Biological Assay><Blood Vessels><Body Tissues><Bunyavirales><Canada><Case Fatality Rates><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemotactic Cytokines><Clinical Treatment Moab><Common Rat Strains><Complex><Data><Disease><Disease Outbreaks><Disorder><Endothelial Cells><Ensure><Epidemic Hemorrhagic Fever Virus><Event><FDA approved><Family><Four Corners Virus><Four Corners hantavirus><Frequencies><Gene Expression><Genomics><Hantaan virus><Hantavirus><Hantavirus Infections><Hemorrhagic Nephroso-Nephritis Virus><Homologous Chemotactic Cytokines><Hospital Admission><Hospitalization><Human><IFN><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Interferon><Immune response><Immune signaling><Immunes><Immunity><Immunological response><Immunology><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Impairment><Infection><Inflammation><Inflammatory><Inhalation><Inhaling><Intercrines><Interferon Gamma><Interferon Type I><Interferon Type II><Interferons><Intracellular Communication and Signaling><Knock-out><Knockout><Knowledge><Korean Hemorrhagic Fever Virus><Laboratories><Maintenance><Mammalia><Mammals><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Methodology><Mice><Mice Mammals><Modeling><Modern Man><Monoclonal Antibodies><Muerto Canyon Virus><Murine><Mus><Nature><Norway Rats><Outbreaks><Pathogenicity><Population><Position><Positioning Attribute><Predisposition><Production><Proteins><Proteome><Proteomics><RNA Viruses><Rat><Rats Mammals><Rattus><Rattus norvegicus><Reagent><Receptor Protein><Research><Resistance><Rodent><Rodentia><Rodents Mammals><Role><SIS cytokines><Sentinel><Seoul virus><Severity of illness><Shrews><Signal Transduction><Signal Transduction Systems><Signaling><Sin Nombre hantavirus><Sin Nombre virus><Supporting Cell><Survivors><Susceptibility><System><Systemic infection><Testing><Therapeutic><Time><Tissues><Transmission><Vaccines><Validation><Viral><Viral Burden><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Hemorrhagic Fevers><Viral Load><Viral Load result><Viral Proteins><Viremia><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Work><Zoonoses><Zoonotic><Zoonotic Infection><affinity purification><antagonism><antagonist><anti-viral immunity><antiviral immunity><biological signal transduction><chemoattractant cytokine><chemokine><comparative><cost><disease severity><effective therapy><effective treatment><experience><hemorrhagic fever><host response><human disease><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vitro Assay><in vivo><infected rodent><infected vector rodent><innovate><innovation><innovative><insight><lFN-Gamma><mAbs><monoclonal Abs><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><novel virus><particle><pressure><prevent><preventing><protein complex><protein expression><receptor><resistant><social role><success><transmission process><validations><vascular><viraemia><viral RNA><viral infection><viral multiplication><viral replication><viral sepsis><virology><virus RNA><virus host interaction><virus infection><virus multiplication><virus protein><virus-induced disease><virusemia>