Alun Vaughan Jackson

All Publications

• Differentiation of human induced pluripotent stem cells to authentic macrophages using a defined, serum-free, open-source medium (vol 16, pg 1735, 2021) STEM CELL REPORTS Vaughan-Jackson, A., Stodolak, S., Ebrahimi, K. H., Browne, C., Reardon, P. K., Pires, E., Gilbert-Jaramillo, J., Cowley, S. A., James, W. S. 2021; 16 (12): 3093

  View details for DOI 10.1016/j.stemcr.2021.11.010

  View details for Web of Science ID 000731607400008

  View details for PubMedID 34910900

  View details for PubMedCentralID PMC8693763

• Efficacy of NS5A inhibitors against unusual and potentially difficult-to-treat HCV subtypes commonly found in sub-Saharan Africa and South East Asia. Journal of hepatology Nguyen, D., Smith, D., Vaughan-Jackson, A., Magri, A., Barnes, E., Simmonds, P. 2020; 73 (4): 794-799

  Abstract

  The efficacy of NS5A inhibitors against several less common subtypes of hepatitis C virus (HCV) is poorly characterised. Some subtypes including 3b, 3g, 6u and 6v commonly harbour amino acid residues in NS5A that may confer resistance to direct-acting antivirals (DAAs) in other common subtypes. Data from patients also suggest that 1l and 4r with amino acid substitutions at positions 28-31 and 93 in NS5A are relatively resistant to DAA therapy.In this study, we tested the efficacy of daclatasvir, elbasvir, ledipasvir, pibrentasvir and velpatasvir against these subtypes using the SGR-JFH1 replicon backbone.NS5A inhibitors showed different levels of efficacy with only pibrentasvir effective against all tested subtypes. Daclatasvir and ledipasvir were ineffective against 6u and 6v (half maximal effective concentration [EC50] values of 239-321 nM) while 3b and 3g were only susceptible to pibrentasvir. Analysis of effects of individual mutations indicated that Q30R in 1l increased the EC50 of ledipasvir by 18-fold, conferring intermediate resistance, while those of L31M and Y93H in 4r induced increases in EC50 values of 2,100- and 3,575-fold (high-level resistance).The high ledipasvir EC50 values of 1l with the Q30R substitution, 4r L31M and 4r Y93H may explain the treatment failure in patients who were infected with these viruses and treated with ledipasvir + sofosbuvir. This study also shows the ineffectiveness of the first generation NS5A inhibitors against 6u and 6v, and confirms the inherent resistance of 3b and 3g to most NS5A inhibitors. Clinical studies to confirm in vivo sensitivity to NS5A inhibitors are urgently needed so that rational, effective treatment strategies may be developed for unusual subtypes.Little is known about the efficacy of NS5A inhibitors against some "unusual" hepatitis C virus (HCV) subtypes including 1l, 3b, 3g, 4r, 6u and 6v. In this study, we manufactured HCV replicons which express the NS5A protein from the unusual HCV subtypes 1l, 3b, 3g, 4r, 6u, 6v. We then tested the effect of the NS5A inhibitors daclatasvir, elbasvir, ledipasvir, pibrentasvir and velpatasvir on blocking replication, using these replicons. We show that these replicons are resistant at some level to all NS5A inhibitors other than pibrentasvir.

  View details for DOI 10.1016/j.jhep.2020.05.029

  View details for PubMedID 32470499

• Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication. Scientific reports Borrmann, H., Davies, R., Dickinson, M., Pedroza-Pacheco, I., Schilling, M., Vaughan-Jackson, A., Magri, A., James, W., Balfe, P., Borrow, P., McKeating, J. A., Zhuang, X. 2020; 10 (1): 13271

  Abstract

  Human immunodeficiency virus 1 (HIV-1) is a life-threatening pathogen that still lacks a curative therapy or vaccine. Despite the reduction in AIDS-related deaths achieved by current antiretroviral therapies, drawbacks including drug resistance and the failure to eradicate infection highlight the need to identify new pathways to target the infection. Circadian rhythms are endogenous 24-h oscillations which regulate physiological processes including immune responses to infection, and there is an emerging role for the circadian components in regulating viral replication. The molecular clock consists of transcriptional/translational feedback loops that generate rhythms. In mammals, BMAL1 and CLOCK activate rhythmic transcription of genes including the nuclear receptor REV-ERBα, which represses BMAL1 and plays an essential role in sustaining a functional clock. We investigated whether REV-ERB activity regulates HIV-1 replication and found REV-ERB agonists inhibited HIV-1 promoter activity in cell lines, primary human CD4 T cells and macrophages, whilst antagonism or genetic disruption of REV-ERB increased promoter activity. The REV-ERB agonist SR9009 inhibited promoter activity of diverse HIV-subtypes and HIV-1 replication in primary T cells. This study shows a role for REV-ERB synthetic agonists to inhibit HIV-1 LTR promoter activity and viral replication, supporting a role for circadian clock components in regulating HIV-1 replication.

  View details for DOI 10.1038/s41598-020-70170-3

  View details for PubMedID 32764708

  View details for PubMedCentralID PMC7413328

• Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis. Nature communications Ryzhakov, G., West, N. R., Franchini, F., Clare, S., Ilott, N. E., Sansom, S. N., Bullers, S. J., Pearson, C., Costain, A., Vaughan-Jackson, A., Goettel, J. A., Ermann, J., Horwitz, B. H., Buti, L., Lu, X., Mukhopadhyay, S., Snapper, S. B., Powrie, F. 2018; 9 (1): 3797

  Abstract

  Inflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs. However, the specific gene that controls disease susceptibility remains unknown. Here we identify a Hiccs locus gene, Alpk1 (encoding alpha kinase 1), as a potent regulator of intestinal inflammation. In response to infection with the commensal pathobiont Helicobacter hepaticus (Hh), Alpk1-deficient mice display exacerbated interleukin (IL)-12/IL-23 dependent colitis characterized by an enhanced Th1/interferon(IFN)-γ response. Alpk1 controls intestinal immunity via the hematopoietic system and is highly expressed by mononuclear phagocytes. In response to Hh, Alpk1-/- macrophages produce abnormally high amounts of IL-12, but not IL-23. This study demonstrates that Alpk1 promotes intestinal homoeostasis by regulating the balance of type 1/type 17 immunity following microbial challenge.

  View details for DOI 10.1038/s41467-018-06085-5

  View details for PubMedID 30228258

  View details for PubMedCentralID PMC6143560