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Principal Investigator: Cynthia McMillen
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $124,838
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Emerging infectious diseases pose a significant threat to human and agricultural health; therefore, it is imperative
that we take a proactive approach toward understanding virus and host factors that are associated with infection
and pathogenesis. Many bunyavirus infections, including Rift Valley fever (RVFV), Cache Valley (CVV), and
Schmallenberg (SBV) viruses, cause massive abortogenic events in livestock that lead to significant economic
strain and increased susceptibility of human infection. La Crosse virus (LCV), a related bunyavirus, is not known
to cause vertical transmission in livestock, however vertical transmission has been implicated upon experimental
infection. Two cases of vertical transmission of RVFV have occurred in pregnant women and those infected with
RVFV have a higher risk for late-term miscarriages. Whether vertical transmission occurs in ruminants and
humans due to LACV infection or in humans from SBV and CVV infection is unknown. Given LACV and
CVV infections can cause life-threatening diseases in humans, it is plausible that congenital infection may simply
be overlooked due to the mild nature of most bunyavirus infections. We hypothesize that SBV, CVV, and LACV
can infect human and ruminant placentas and that virulence factors, such as NSm, and variable induction of
antiviral responses across viruses dictate pathogenesis severity, and thus teratogenicity, across host species.
This proposal will utilize two model systems to study bunyavirus infection of the placenta. First, we will
examine whether LACV, CVV, SBV, and RVFV infect placenta explants from humans, sheep, and rats in vitro.
Using wild type and NSm knockout viruses, we will identify whether NSm contributes to host or cellular tropism,
immune responses to infection, programmed cell death pathways, and congenital pathogenesis. Second, we
will utilize genetically tractable 2D human trophoblast and trophoblast organoid (TO) systems to compare cell-
specific differences in immune responses and cell death pathways upon bunyavirus infection. This will be the
first study to utilize human placenta organoids to study congenital bunyavirus infection. To successfully complete
the proposed project, I have developed an exceptional career development plan under the primary mentorship
of Dr. Amy Hartman (University of Pittsburgh (U Pitt)) and co-mentors, Drs. Carolyn Coyne (Duke University)
and Leonard D’Aiuto (U Pitt). My training will consist of hands-on and didactic training in human organoid
development in addition to didactic training in pathology, cross-species placenta biology, and immunology. U Pitt
provides the necessary environment to support the proposed research and training through accessibility to
outstanding scientists, high containment laboratory and animal facilities, training opportunities in laboratory
management, responsible conduct of research and grantsmanship, and opportunities to present research.
Successful training and completion of the proposed research will support my ultimate career goal to establish an
independent research program studying the cross virus- and host-species mechanisms of bunyavirus congenital
infections with a special niche in human and ruminant placenta organoid research and congenital pathology.
Terms: <Affect><Agriculture><Anti-viral Response><Apoptosis><Apoptosis Pathway><Apoptotic><Arboviral><Arboviruses><Arthropod-Borne Viruses><Autophagocytosis><Biologic Models><Biological Models><Biological Response Modifiers><Biomodulators><Birth><Body Tissues><Bunyaviridae Infections><Bunyavirus><Bunyavirus Infections><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cache Valley virus><Cell Body><Cell Death><Cells><Cells Placenta-Tissue><Cellular Tropism><Common Rat Strains><Communities><Containment><Culicidae><Data><Development><Development Plans><Disease><Disorder><Economics><Emerging Communicable Diseases><Emerging Infectious Diseases><Environment><Event><Farm Animal><Fetal Death><Gene Expression><Generations><Genetic><Goals><Health><Host Factor><Host Factor Protein><Human><IFN><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune response><Immunological response><Immunology><In Vitro><Infection><Inhibition of Apoptosis><Innate Immune Response><Innate Immunity><Integration Host Factors><Interferon Type I><Interferons><Investigation><Knock-out><Knockout><La Crosse encephalitis virus><La Crosse virus><LaCrosse encephalitis virus><LaCrosse virus><Laboratories><Life><Livestock><M protein><Maternal-Fetal Exchange><Mediating><Mediator><Medical><Mentors><Mentorship><Miscarriage><Model System><Modeling><Modern Man><Mosquitoes><Native Immunity><Natural Immunity><Nature><Non-Specific Immunity><Non-structural Protein><Nonspecific Immunity><Nonstructural Protein><Normal Placentoma><Organoids><Orthobunyavirus><Ovine><Ovis><Parturition><Pathogenesis><Pathogenicity Factors><Pathology><Pathway interactions><Placenta><Placenta Biology><Placenta Embryonic Tissue><Placental Biology><Placentome><Plants><Predisposition><Pregnant Women><Process><Productivity><Programmed Cell Death><Proteins><Rat><Rats Mammals><Rattus><Research><Rift Valley Fever><Rift Valley fever virus><Ruminantia><Ruminants><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Scientist><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severities><Sheep><Spontaneous abortion><Susceptibility><Syncytiotrophoblast><System><Teratogenic><Teratogenicity><Teratogens><Tissues><Training><Transmission><Transplacental Exposure><Tropism><Universities><Vertical Transmission><Viral><Viral Diseases><Viral Pathogenesis><Virulence Factors><Virus><Virus Diseases><Virus Replication><animal facility><autophagy><career><career development><congenital infection><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><developmental><economic><expectant mother><expecting mother><experience><fetal><fetus death><high risk><host response><immune system response><immunomodulatory biologics><immunoresponse><laboratory facility><maternal-fetal interface><multiple myeloma M Protein><necrocytosis><novel><pathway><permissiveness><placenta infection><placental infection><pregnant><pregnant mothers><prevent><preventing><programs><prototype><responsible research conduct><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><tissue tropism><training opportunity><transmission process><trophoblast><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus pathogenesis><virus-induced disease><zoonotic spillover>