# Mechanisms of Neuronal Infection by Prototype Emerging Bunyaviruses

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $757,645

## Abstract

PROJECT SUMMARY/ABSTRACT
Bunyaviruses are a diverse group of animal and human pathogens of global health relevance. Bunyavirales
order encompasses viral families with similar genome and protein organization despite divergent sequences.
Common to these vector-borne viruses is the ability to cause central nervous system (CNS) disease with
concomitant morbidity and occasional mortality. Lack of definition of key target cells in the brain and the effect
of virus infection on the brain microenvironment are major limitations in our knowledge of bunyavirus
neuropathogenesis that has also limited our ability to develop countermeasures. The consequences of target
cell infection are unknown, and viral determinants of neurologic disease have not been delineated. To overcome
this limitation, we propose a comparative analysis of the neuropathogenesis of 3 medically important prototype
emerging bunyaviruses and define contributors to infection and pathogenesis in relevant neuronal cells. La
Crosse virus (LACV) is found in North America and is the primary cause of pediatric viral encephalitis in the
United States. Rift Valley Fever virus (RVFV), a WHO Priority Disease, causes outbreaks of hemorrhagic fever
and encephalitis throughout Africa. Oropouche virus (OROV), is found in South America and has caused more
than 30 large epidemics resulting in over 500,000 human cases of febrile illness. Due lack of direct comparisons,
substantial gaps remain in our understanding of bunyavirus neuropathogenesis, including molecular
mechanisms. This proposal will provide comparative analysis of all 3 viruses with regards to CNS cell tropism,
innate immune responses, and cell death pathways using novel in vitro and ex vivo model systems. Our recently
published data shows that the host cell protein LDL-receptor related protein 1 (Lrp1) is important for efficient
cellular infection by RVFV and OROV. Preliminary data on the role of Lrp1 in LACV infection further supports
similar tropisms by divergent viruses. We hypothesize that these neurovirulent viruses share overlapping target
cells in the CNS mediated by the host cell protein Lrp1. Viral non-structural protein produced from the small
genome segment (NSs) functions as the main antagonist of host cell antiviral responses and a key modulator
during infection. We further hypothesize that the degree of neurovirulence of each virus is related to NSs protein
function. Our highly collaborative and synergistic team is led by Dr. Amy Hartman (PI), an expert in the
pathogenesis of RVFV and Dr. Gaya Amarasinghe (Co-I), a biochemist with expertise in host-pathogen
interactions. Two additional Co-I’s are Dr. Leonard D’Aiuto and Dr. Zachary Wills, are experts in viral infection of
human neurons and rodent neurobiology, respectively. This R01 proposal represents a multidisciplinary
approach to advance our understanding of bunyavirus interactions with neurons.

## Key facts

- **NIH application ID:** 10900658
- **Project number:** 5R01AI178378-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Amy L Hartman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $757,645
- **Award type:** 5
- **Project period:** 2023-08-07 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900658

## Citation

> US National Institutes of Health, RePORTER application 10900658, Mechanisms of Neuronal Infection by Prototype Emerging Bunyaviruses (5R01AI178378-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10900658. Licensed CC0.

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