Holtz, A. M. | Search bioRxiv

bioRxiv2026

Immunomodulatory RIG-I Agonist SLR14 Confers Protection Against a Range of Highly Pathogenic Negative Sense RNA viruses

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.

microbiology↗

bioRxiv2026

A chimeric human-mouse lung vascular model using induced pluripotent stem cells reveals insights into the pathogenesis of BMPR2-related pulmonary hypertension

Advances in tissue biology have revealed remarkable transcriptomic heterogeneity of endothelial cells between and within organ systems. This necessitates more precise models of organ-specific endothelium to understand the pathogenesis of genetic vascular disorders, such as pulmonary hypertension (PH), where gene-disease associations have implicated endothelial cell dysfunction as a key driver of disease pathogenesis. Towards this end, human induced pluripotent stem cells (hiPSCs) hold immense promise for PH disease modeling where hiPSCs are generated from an affected individual and undergo gene correction to generate syngeneic controls that can be differentiated to endothelial cells (hiEndos), providing a limitless source of material for downstream studies; however, the ability to generate lung-specific hiEndos to model pulmonary vascular disease has been limited. To overcome this challenge, we developed a chimeric human-mouse lung vascular model wherein hiEndos are first patterned via BMP9-induced signaling towards a lung-like molecular phenotype in vitro and are then intravenously transplanted into the mouse lung vasculature in vivo to generate orthotopic lung-specific endothelium for downstream studies. Transplanted pre-patterned hiEndos form functional connections to the native mouse lung vasculature and upregulate differentiated lung-specific molecular cell subtype profiles that include capillary- and arterial-like cell populations. To apply this approach for disease modeling, we generated new hiPSC lines by reprogramming fibroblasts from individuals of the 2001 landmark cohort of BMPR2 gene variant-associated PH and developed a novel in vivo competitive lung endothelial reconstitution assay to quantify functional and molecular differences between human BMPR2-variant vs syngeneic gene-corrected/edited hiEndos. Our approach revealed novel insights into PH disease pathogenesis, not previously evident with prior models, including BMPR2 variant-induced in vivo defects in human lung capillary gene expression, elevated lncRNA H19 expression, increased AHR signaling, and diminished functional capacity to repopulate the pulmonary vascular endothelium.

genetics↗