The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies (GWAS) identified the 3p21.31 region as conferring a two-fold increased risk of respiratory failure. Here, using a combined multiomics and machine-learning approach, we identify the gain-of-function risk A allele of a single-nucleotide polymorphism (SNP), rs17713054G>A, as a probable causative variant. We show with chromosome conformation capture and gene expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, Leucine Zipper Transcription Factor Like 1 ( LZTFL1 ). Selective spatial transcriptomic analysis of COVID-19 patient lung biopsies shows the presence of signals associated with epithelial-mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1 . We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely to be responsible for the 3p21.31 associated risk. As the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may provide a therapeutic target.

Introduction: Vesicular stomatitis virus (VSV) has long been a useful research tool in virology and recently become an essential part of medicinal products. Vesiculovirus research is growing quickly following its adaptation to clinical gene and cell therapy and oncolytic virotherapy.Areas covered: This article reviews the versatility of VSV as a research tool and biological reagent, its use as a viral and vaccine vector delivering therapeutic and immunogenic transgenes and an oncolytic virus aiding cancer treatment. Challenges such as the immune response against such advanced therapeutic medicinal products and manufacturing constraints are also discussed. Expert opinion: The field of in vivo gene and cell therapy is advancing rapidly with VSV used in many ways. Comparison of VSV's use as a versatile therapeutic reagent unveils further prospects and problems for each application. Overcoming immunological challenges to aid repeated administration of viral vectors and minimizing harmful host-vector interactions remains one of the major challenges. In the future, exploitation of reverse genetic tools may assist the creation of recombinant viral variants that have improved onco-selectivity and more efficient vaccine vector activity. This will add to the preferential features of VSV as an excellent advanced therapy medicinal product (ATMP) platform.

Vesicular stomatitis virus Indiana strain glycoprotein (VSVind.G) mediates broad tissue tropism and efficient cellular uptake. Lentiviral vectors (LVs) are particularly promising, as they can efficiently transduce non-dividing cells and facilitate stable genomic transgene integration; therefore, LVs have an enormous untapped potential for gene therapy applications, but the development of humoral and cell-mediated anti-vector responses may restrict their efficacy. We hypothesized that G proteins from different members of the vesiculovirus genus might allow the generation of a panel of serotypically distinct LV pseudotypes with potential for repeated in vivo administration. We found that mice hyperimmunized with VSVind.G were not transduced to any significant degree following intravenous injection of LVs with VSVind.G envelopes, consistent with the thesis that multiple LV administrations would likely be blunted by an adaptive immune response. Excitingly, bioluminescence imaging studies demonstrated that the VSVind-neutralizing response could be evaded by LV pseudotyped with Piry and, to a lesser extent, Cocal virus glycoproteins. Heterologous dosing regimens using viral vectors and oncolytic viruses with Piry and Cocal envelopes could represent a novel strategy to achieve repeated vector-based interventions, unfettered by pre-existing anti-envelope antibodies.