# Molecular mechanisms of eastern equine encephalitis virus pathogenesis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $460,149

## Abstract

ABSTRACT
 North American strains of eastern equine encephalitis virus (NA-EEEV) are the most
neurovirulent of the arthropod-borne alphaviruses and one of the most acutely virulent
viruses known, causing mortality in 30-70% of symptomatic human cases and almost
uniform mortality in equines. Furthermore, NA-EEEV is considered a potential
bioweapon and is an NIH Category B priority pathogen and USDA/CDC Select Agent.
The endemic range of NA-EEEV is expanding within the US, numbers of human cases
are increasing and the virus has recently been isolated from mosquito species with
aggressive human feeding behavior, raising the potential for increased outbreaks of
severe encephalitis. Yet, no licensed vaccines or antiviral therapeutics are available and
the virus remains critically understudied.
 Human infections are characterized by a limited prodromal disease and rapid onset
of encephalitis signs, often observed as the first indication of infection. Recent work has
shown that two phenotypes of the virus are largely responsible for the severity of EEEV
infection: 1) avoidance of virus particle access to lymphoid tissues and exacerbation of
neuron infection due to heparan sulfate receptor binding by the virus; and 2) restriction
of EEEV replication in myeloid cells, particularly macrophages and dendritic cells, by
binding of the hematopoietic cell-specific microRNA, miR142-3p, to the virus genome.
Together, these activities essentially block lymphoid tissue replication by EEEV, greatly
suppress innate immune responses and directly promote neuron infection leading to
severe and often fatal encephalitis.
 In this renewal application, we seek to provide an integrated understanding of
relationship of HS binding and miR142-3p restriction, to 1) the role of specific
proteoglycan receptors in EEEV infectivity in vitro and tropism and disease in vivo; 2)
susceptibility of different human and non-human hosts to EEEV replication and disease;
and 3) variability of HS binding and miR142-3p restriction phenotypes during infection of
mammalian hosts and the effects of this variation on responses of myeloid cells to
interactions with EEEV.

## Key facts

- **NIH application ID:** 9948546
- **Project number:** 5R01AI095436-08
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** WILLIAM B KLIMSTRA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $460,149
- **Award type:** 5
- **Project period:** 2012-02-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948546

## Citation

> US National Institutes of Health, RePORTER application 9948546, Molecular mechanisms of eastern equine encephalitis virus pathogenesis (5R01AI095436-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948546. Licensed CC0.

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