# Role of Type I IFN Signaling in Seoul Orthohantavirus Pathogenesis

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $381,250

## Abstract

PROJECT SUMMARY
Hantaviruses are a family of zoonotic RNA viruses found in insectivore and rodent hosts worldwide. The Old
World hantaviruses, Hantaan virus (HTNV) and Seoul virus (SEOV), are the etiologic agents of hemorrhagic
fever with renal syndrome (HFRS), the most common hemorrhagic fever disease in Asia. Hantaviruses primarily
target endothelial cells for infection and drive vascular leakage and dysregulation, through poorly defined means.
In their respective reservoir hosts, hantaviruses establish asymptomatic, persistent infections. The mechanisms
underlying these divergent infection outcomes remain unknown and no therapeutic exists to treat HFRS. Our
previously published data demonstrates that type I interferon (IFN) effectively limits HTNV replication and that
the cytoplasmic RNA recognition receptors RIG-I and MDA5 are required for initiating the type I IFN response in
human endothelial cells during hantavirus infection. Here we show that, in contrast, SEOV infection in its natural
reservoir host does not result in innate immune transcriptional activation in vitro and, more interestingly, IFNβ
treatment does not limit SEOV replication in reservoir cells. Further, global transcriptomic analysis of human and
rat endothelial cells infected with SEOV reveal striking, host-specific patterns of differential gene expression for
the IFN and leukocyte extravasation pathways. Predicted network analysis identified differential regulation of the
vascular endothelial growth factor (VEGF) receptor signaling pathway, with increased gene expression related
to activation and migration in human endothelial cells compared to reservoir endothelial cells. These data, along
with substantial literature in the field demonstrating a significant effect of type I IFN on vascular function, lead us
to hypothesize that type I IFN signaling following SEOV infection in humans drives endothelial cell activation,
vascular dysregulation, and recruitment of proinflammatory neutrophils that are the hallmarks of HFRS. Further,
we hypothesize that the reservoir host for SEOV, the common rat, escapes severe disease through viral-induced
inhibition of type I IFN activation and reduced inflammation. We will test this hypothesis by: 1) dissecting the
virus-host interactions that initiate and antagonize reservoir and non-reservoir innate immunity, 2) investigating
the contribution of type I IFN signaling to vascular dysfunction in SEOV-infected endothelial cells, and 3) defining
the role of type I IFN signaling in neutrophil activation and extravasation across SEOV-infected endothelial cells
from reservoir and human hosts. While similar comparative immunology approaches to understanding
pathogenesis for other zoonotic RNA viruses have been successful, the limited tractability of most reservoir
rodent hosts has significantly limited progress in the hantavirus field. Thus, the intentional selection to study
SEOV and its natural reservoir, the common laboratory rat, provides us wi...

## Key facts

- **NIH application ID:** 10868600
- **Project number:** 5R01AI171289-03
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Alison Kell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2022-07-19 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868600

## Citation

> US National Institutes of Health, RePORTER application 10868600, Role of Type I IFN Signaling in Seoul Orthohantavirus Pathogenesis (5R01AI171289-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10868600. Licensed CC0.

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