Biology subjects

Scholz, D.

Publications and source records attributed to Scholz, D..

3 recordsLinked to original sources

bioRxiv2023

Inhibition of potassium ion channels reduces Semliki Forest virus genome replication

IntroductionSemliki forest virus (SFV) is a model virus used to investigate the Alphavirus genus, which includes human pathogens Chikungunya virus and Ross River virus. Viruses harness cellular machinery to facilitate various steps of their replicative cycles. Ion channels are one group of cellular proteins required for the efficient replication of some viruses, including Influenza A viruses, Ebola virus and members of the Betacoronavirus genus. This study focussed on understanding SFVs requirement for functional ion channels during replication. MethodsThe effect of ion channel inhibitors on in vitro SFV infections was measured to investigate the contribution of ion channels in its replication cycle. ResultsIn vitro SFV infections carried out in the presence or absence of different ion channel inhibitors showed broad-range K+ channel inhibitors reproducibly attenuated virus replication and reduced its cytotoxicity in two mammalian cell lines. These broad-range K+ channel inhibitors disrupted an early, post-entry step causing a delay or reduction in SFV protein and RNA synthesis. Screens using inhibitors of specific K+ channel families showed that two-pore domain K+ channel (2pK) inhibitors attenuated SFV replication. Confocal microscopy revealed decreased detection of dsRNA and SFV protein in the presence of inhibitor but no change in RNA and protein colocalisation, which would indicate disruption of replication complexes. Broad-range K+ and 2pK inhibitors decreased viral RNA replication and transcription from the subgenomic promoter. ConclusionsK+ channel inhibitors attenuate in vitro SFV replication by inhibiting an early, post-entry step of virus replication, potentially RNA synthesis. ImportanceNo antiviral therapies have been approved for clinical use against diseases caused by members of the Alphavirus genus. Work presented in this manuscript shows for the first time that SFV genome replication and virus induced cytotoxicity can be reduced in vitro by treating infected cells with K+ channel inhibitors. This work provides the basis for investigating the effectiveness of K+ channel inhibitors against other alphaviruses both in vitro and in vivo and, because many ion channel inhibiting drugs are already in clinical use, rapid repurposing against alphavirus infections would be possible.

microbiology↗

bioRxiv2022

A novel antiviral formulation inhibits SARS-CoV-2 infection of human bronchial epithelium

A novel proprietary formulation, ViruSAL, has previously been demonstrated to inhibit diverse enveloped viral infections in vitro and in vivo. We evaluated the ability of ViruSAL to inhibit SARS-CoV-2 infectivity, using physiologically relevant models of the human bronchial epithelium, to model early infection of the upper respiratory tract. ViruSAL potently inhibited SARS-CoV-2 infection of human bronchial epithelial cells cultured as an air-liquid interface (ALI) model, in a concentration- and time-dependent manner. Viral infection was completely inhibited when ViruSAL was added to bronchial airway models prior to infection. Importantly, ViruSAL also inhibited viral infection when added to ALI models post-infection. No evidence of in vitro cellular toxicity was detected in ViruSAL treated cells at concentrations that completely abrogated viral infectivity. Moreover, intranasal instillation of ViruSAL to a rat model did not result in any toxicity or pathological changes. Together these findings highlight the potential for ViruSAL as a novel and potent antiviral for use within clinical and prophylactic settings.

pharmacology and toxicology↗

bioRxiv2020

Long-term persistence of crAss-like phage crAss001 is associated with phase variation in Bacteroides intestinalis

The crAss-like phages are ubiquitous and highly abundant members of the human gut virome that infect commensal bacteria of the order Bacteroidales. Although incapable of classical lysogeny, these viruses demonstrate unexplained long-term persistence in the human gut microbiome, dominating the virome in some individuals. Here we demonstrate that rapid phase variation of alternate capsular polysaccharides plays an important role in dynamic equilibrium between phage sensitivity and resistance in B. intestinalis cultures, allowing phage and bacteria to multiply in parallel. The data also suggests the role of concomitant phage persistence mechanisms associated with delayed lysis of infected cells, such as carrier state infection. From an ecological and evolutionary standpoint this type of phage-host interaction is consistent with the Piggyback-the-Winner model, which suggests a preference towards lysogenic or other "benign" forms of phage infection when the host is stably present at high abundance. TeaserCrAss-like phage persistence in Bacteroides is associated with capsule phase-variation and additional unexplored mechanisms.

microbiology↗