Biology subjects

Foster, T. L.

Publications and source records attributed to Foster, T. L..

3 recordsLinked to original sources

bioRxiv2026

Comparative analysis identifies a shared topological organisation among divergent intergenic RNAs

Biological function is often inferred from sequence conservation or structural similarity. However, many viral RNAs maintain regulatory functions despite extensive diversification of both sequence and structures. Using arenavirus intergenic regions (IGRs) as a model system, we investigated what level of RNA organization remains conserved when these conventional sequence-structure-function relationships break down. Combining cryogenic OrbiSIMS guided RNA structure determination with graph theory-based analysis of fifty-eight IGRs across phylogenetically diverse arenaviruses, we discovered that IGR topology, defined by the connectivity and relative integration of individual stem-loop elements, is consistently arranged around a highly connected helical core that persists across divergent IGR folds. Quantitative centrality analyses further revealed that topologically peripheral stem-loops are comparatively sparse and variable across the phylogenetic classes. Investigation of the functional consequence of the peripheral elements in Golden Gate virus (a reptile arenavirus) S-IGR revealed selective association with interferon-induced and antiviral RNA-binding proteins in human host cells infected with recombinant Lymphocytic Choriomeningitis virus (a distantly related human arenavirus). Taken together, these findings identify graph-defined topology as a recurrent organisational feature among divergent arenavirus IGRs that is not captured by sequence identity or global RNA-structure similarity. The data are consistent with a model in which a topologically central helical organisation may be associated with conserved regulatory capacity, whereas structurally variable peripheral elements may contribute to lineage- or segment-specific host-factor interaction profiles.

biophysics↗

bioRxiv2021

Inhibition of arenavirus entry and replication by the cell-intrinsic restriction factor ZMPSTE24 is enhanced by IFITM antiviral activity

In the absence of effective vaccines and treatments, annual outbreaks of severe human haemorrhagic fever caused by arenaviruses, such as Lassa virus, continue to pose a significant human health threat. Understanding the balance of cellular factors that inhibit or promote arenavirus infection may have important implications for the development of effective antiviral strategies. Here, we identified the cell-intrinsic zinc transmembrane metalloprotease, ZMPSTE24, as a restriction factor against arenaviruses. Notably, CRISPR-Cas9-mediated knockout of ZMPSTE24 in human alveolar epithelial A549 cells increased arenavirus glycoprotein-mediated viral entry in pseudoparticle assays and live virus infection models. As a barrier to viral entry and replication, ZMPSTE24 may act as a downstream effector of interferon-induced transmembrane protein (IFITM) antiviral function; though through a yet poorly understood mechanism. Overexpression of IFITM1, IFITM2 and IFITM3 proteins did not restrict the entry of pseudoparticles carrying arenavirus envelope glycoproteins and live virus infection, yet depletion of IFITM protein expression enhanced virus entry and replication. Furthermore, gain-of-function studies revealed that IFITMs augment the antiviral activity of ZMPSTE24 against arenaviruses, suggesting a cooperative effect of viral restriction. We show that ZMPSTE24 and IFITMs affect the kinetics of cellular endocytosis, suggesting that perturbation of membrane structure and stability is likely the mechanism of ZMPSTE24-mediated restriction and cooperative ZMPSTE24-IFITM antiviral activity. Collectively, our findings define the role of ZMPSTE24 host restriction activity in the early stages of arenavirus infection. Moreover, we provide insight into the importance of cellular membrane integrity for productive fusion of arenaviruses and highlight a novel avenue for therapeutic development. Author SummaryIncreased human travel, virus genome evolution and expansion of the host rodent reservoir outside of endemic areas has contributed to increasing cases of the highly fatal arenaviral haemorrhagic disease, Lassa fever in Western Africa. These annual seasonal outbreaks present a serious global public health and socioeconomic burden, particularly in the absence of approved vaccines and antiviral countermeasures. Development of novel and effective therapeutic strategies against arenavirus infection is reliant on a better understanding of the molecular mechanisms of key host-virus interactions that antagonise or potentiate disease pathogenesis. We demonstrate the inhibition of arenavirus infection by the antiviral restriction factor ZMPSTE24 and describe a cooperative action with the innate immunity-stimulated family of interferon-induced transmembrane proteins (IFITMs). This work adds to our understanding of the mechanism of ZMPSTE24 and IFITM-mediated restriction of enveloped viruses and importantly suggests that these proteins may play a significant role in the pathogenesis of arenavirus infections.

microbiology↗

bioRxiv2019

Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza

Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable.\n\nRational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic \"swine\" H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance.

microbiology↗