# Mechanism of Lassa fever virus Z protein in immune suppression and viral virulence

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $739,394

## Abstract

Abstract
Title: Mechanism of Lassa fever virus Z protein in immune suppression and viral virulence
 Lassa fever virus (LASV) is the most significant arenavirus pathogen that causes endemic and lethal
hemorrhagic fever (HF) in humans in West Africa with thousand of death annually. Importation of LASV
infection to USA and other Western counties has been repeatedly documented due to increased human travel
to and from the endemic countries. Currently there is no vaccine and limited treatment options against LASV.
Among LASV-infected individuals, there are significant heterogeneity in disease severity, which ranges from
asymptomatic infections to multi-organ failure and death, the reason for which is unknown but may partly be
due to the different LASV isolates that show sequence variations up to 32%. Molecular determinants for LASV
virulence remain unknown. LASV pathogenesis has not been well understood but is associated with a general
host immune suppression that is characterized by the lack of early innate immune responses and the absence
of effective adaptive immunity. The long-term goal of our work is to understand the mechanisms of LASV
virulence and disease pathogenesis in order to develop the much-needed vaccines and antivirals. We have
recently discovered a unique ability of the Z protein of several known pathogenic arenaviruses (including
LASV) to inhibit the human RIG-i-like receptors (RLRs) RIG-i and MDA5, which are the intracellular sensors of
RNA viruses. We have also obtained preliminary evidence to show that the Z proteins from different LASV
isolates vary in their ability to inhibit RLRs. In addition, we show that this Z-mediated RLR binding and
inhibition is species specific, which may explain the observed differences in disease pathogenesis in different
animal species. We hypothesize that the virus- and host-dependent inhibition of RLRs by LASV Z proteins is a
novel virulence determinant and propose the following aims to test this hypothesis.
Aim 1: Dissect the molecular mechanism of LASV Z-mediated RLR inhibition.
Aim 2: Determine the biological role of LASV Z-mediated RLR inhibition in viral virulence.
Aim 3: Investigate the species-specific mechanism of LASV Z-mediated of RLR inhibition.
 These studies focus on a novel immune suppressive and virulent mechanism mediated by LASV Z
protein, which will not only make major impacts on both basic and translational research of arenavirus
pathogens, but also provide new knowledge in host-pathogen interactions, host antiviral responses, and viral
immune evasion mechanisms.

## Key facts

- **NIH application ID:** 9873911
- **Project number:** 5R01AI131586-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** YUYING LIANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $739,394
- **Award type:** 5
- **Project period:** 2017-03-08 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873911

## Citation

> US National Institutes of Health, RePORTER application 9873911, Mechanism of Lassa fever virus Z protein in immune suppression and viral virulence (5R01AI131586-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9873911. Licensed CC0.

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