Immunomodulatory RIG-I Agonist SLR14 Confers Protection Against a Range of Highly Pathogenic Negative Sense RNA viruses
- 1Boston University
Abstract
Emerging and re-emerging zoonotic RNA viruses, including filoviruses, henipaviruses and Rift Valley Fever virus (RVFV), pose a significant threat to human health. Due to their epidemic potential and high pathogenicity, these viruses are categorized as WHO priority pathogens, yet we still lack effective medical countermeasures (MCMs) against most of these dangerous pathogens, supporting that host-directed antivirals will be advantageous for broadly acting MCMs. Here we assessed the antiviral efficacy of SLR14, an immunomodulatory stem-loop RNA that activates RIG-I, for its activity against a panel of highly pathogenic viruses. SLR14 treatment provided broad-spectrum protection, markedly reducing infection with Ebola virus (EBOV), Marburg virus, and Sudan virus in human primary monocyte-derived macrophages, and Nipah virus replication in iPSC-derived endothelial cells, whether administered prophylactically or therapeutically. In vivo, a single dose of SLR14 protected mice against lethal RVFV infection when administered prophylactically, and, notably, retained significant efficacy when administered up to two days post-infection. Therapeutic SLR14 administration also improved survival rates of EBOV-infected mice. Although EBOV infection and SLR14 treatment activated overlapping innate immune pathways in human macrophages, viral infection induced a nonprotective response, whereas SLR14 elicited a well-regulated, markedly stronger and protective interferon-stimulated and inflammatory gene signature while avoiding prolonged IFN gene upregulation. Our data identify SLR14 as a potent host-directed therapeutic with broad antiviral efficacy against some of the most lethal viral pathogens.
Related
- A human-derived two-antibody cocktail confers prophylactic and therapeutic protection against authentic Mpox virus.
- PIM6 Induces Tolerance and Confers Protection against Mycobacterium tuberculosis in Primary Macrophages
- A tri-modular feline infectious peritonitis virus nanoparticle vaccine confers complete protection in female cats without detectable antibody-dependent enhancement
- Recombinant NDV-vectored vaccine expressing mosaic HA and M2e confers broad and early protection against H9N2 avian influenza virus
- Ether glycerophospholipid control of peroxisome degradation confers protection from ischemia
BibTeX
@misc{meier2026immunomodulatory,
title = {{Immunomodulatory RIG-I Agonist SLR14 Confers Protection Against a Range of Highly Pathogenic Negative Sense RNA viruses}},
author = {K. Meier and J. Olejnik and J. M. Reyes and J. B. Westover and P. Bawa and E. R. Wrobel and C. W. Henderson and P. Hu and A. J. Hume and A. M. Holtz and O. Fedorova and G. Mostoslavsky and D. N. Kotton and J. H. Connor and A. Marzi and B. B. Gowen and A. M. Pyle and E. Muhlberger},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757743},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757743v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Immunomodulatory RIG-I Agonist SLR14 Confers Protection Against a Range of Highly Pathogenic Negative Sense RNA viruses
AU - K. Meier
AU - J. Olejnik
AU - J. M. Reyes
AU - J. B. Westover
AU - P. Bawa
AU - E. R. Wrobel
AU - C. W. Henderson
AU - P. Hu
AU - A. J. Hume
AU - A. M. Holtz
AU - O. Fedorova
AU - G. Mostoslavsky
AU - D. N. Kotton
AU - J. H. Connor
AU - A. Marzi
AU - B. B. Gowen
AU - A. M. Pyle
AU - E. Muhlberger
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757743
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757743v1
AB - Emerging and re-emerging zoonotic RNA viruses, including filoviruses, henipaviruses and Rift Valley Fever virus (RVFV), pose a significant threat to human health. Due to their epidemic potential and high pathogenicity, these viruses are categorized as WHO priority pathogens, yet we still lack effective medical countermeasures (MCMs) against most of these dangerous pathogens, supporting that host-directed antivirals will be advantageous for broadly acting MCMs. Here we assessed the antiviral efficacy of SLR14, an immunomodulatory stem-loop RNA that activates RIG-I, for its activity against a panel of highly pathogenic viruses. SLR14 treatment provided broad-spectrum protection, markedly reducing infection with Ebola virus (EBOV), Marburg virus, and Sudan virus in human primary monocyte-derived macrophages, and Nipah virus replication in iPSC-derived endothelial cells, whether administered prophylactically or therapeutically. In vivo, a single dose of SLR14 protected mice against lethal RVFV infection when administered prophylactically, and, notably, retained significant efficacy when administered up to two days post-infection. Therapeutic SLR14 administration also improved survival rates of EBOV-infected mice. Although EBOV infection and SLR14 treatment activated overlapping innate immune pathways in human macrophages, viral infection induced a nonprotective response, whereas SLR14 elicited a well-regulated, markedly stronger and protective interferon-stimulated and inflammatory gene signature while avoiding prolonged IFN gene upregulation. Our data identify SLR14 as a potent host-directed therapeutic with broad antiviral efficacy against some of the most lethal viral pathogens.
ER -