Latest Publications
Jeremy Keown publications
Structural and functional characterization of the interaction between the influenza A virus RNA polymerase and the CTD of host RNA polymerase II
Keown, Jeremy, Baazaoui, Alaa, Šebesta, Marek, Štefl, Richard, Carrique, Loïc, Fodor, Ervin, Grimes, Jonathan M.
Influenza A viruses, causing seasonal epidemics and occasional pandemics, rely on interactions with host proteins for their RNA genome transcription and replication. The viral RNA polymerase utilizes host RNA polymerase II (Pol II) and interacts with the serine 5 phosphorylated (pS5) C-terminal domain (CTD) of Pol II to initiate transcription. Our study, using single-particle electron cryomicroscopy (cryo-EM), reveals the structure of the 1918 pandemic influenza A virus polymerase bound to a synthetic pS5 CTD peptide composed of four heptad repeats mimicking the 52 heptad repeat mammalian Pol II CTD.. Our findings not only deepen our understanding of the influenza virus life cycle but also pinpoint a potential target for antiviral development. By elucidating the structural and functional aspects of the influenza virus polymerase-host Pol II interaction, this research provides a foundation for designing interventions to disrupt viral replication and transcription, offering promising avenues for future antiviral therapies.
Structures of H5N1 influenza polymerase with ANP32B reveal mechanisms of genome replication and host adaptation
Replication of avian IAVs in mammalian cells is hindered by species-specific variation in acidic nuclear phosphoprotein 32 (ANP32) proteins, which are essential for viral RNA genome replication. Adaptive mutations enable the IAV RNA polymerase (FluPolA) to surmount this barrier. Here, we present cryo-electron microscopy structures of monomeric and dimeric avian H5N1 FluPolA with human ANP32B. ANP32B interacts with the PA subunit of FluPolA in the monomeric form, at the site used for its docking onto the C-terminal domain of host RNA polymerase II during viral transcription. ANP32B acts as a chaperone, guiding FluPolA towards a ribonucleoprotein-associated FluPolA to form an asymmetric dimer—the replication platform for the viral genome. These findings offer insights into the molecular mechanisms governing IAV genome replication, while enhancing our understanding of the molecular processes underpinning mammalian adaptations in avian-origin FluPolA. Nature Communications. May 2024
Extreme mortality during a historical measles outbreak on Rotuma is consistent with measles immunosuppression
Susie Cant, G. Dennis Shanks, Matt J. Keeling and Bridget S. Penman
In 1911, Rotuma in Fiji was hit by a measles pidemic, which killed 13% of the island population. Detailed records show two mortality peaks, with individuals reported as dying solely from measles in the first and from measles and diarrhoea in the second. MeHere, we investigate whether the pattern of mortality on Rotuma in 1911 was a consequence of the immunosuppressive effects of measles. We use a compartmental model to simulate measles infection and immunosuppression. Whilst immunosuppressed, we assume that individuals are vulnerable to dysfunctional reactions triggered by either (i) a newly introduced infectious agent arriving at the same time as measles or (ii) microbes already present in the population in a pre-existing equilibrium state. We show that both forms of the immunosuppression model provide a plausible fit to the data and that the inclusion of immunosuppression in the model leads to more realistic estimates of measles epidemiological parameters than when immunosuppression is not included.
ArcKR expression modifies synaptic plasticity following epileptic activity: Differential effects with in vitro and in vivo seizure-induction protocols
Amol Bhandare, Maisy Haley, Vanessa Torrico Anderson, Luana B. Domingos, Marcia Lopes, Sonia A. L. Corrêa, Mark J. Wall
Pathological forms of neural activity, such as epileptic seizures, modify the expression pattern of multiple proteins, leading to persistent changes in brain function. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which is critically involved in protein-synthesis–dependent synaptic plasticity underlying learning and memory. In the present study, we have investigated how the expression of ArcKR, a form of Arc in which the ubiquitination sites have been mutated, resulting in slowed Arc degradation, modifies group I metabotropic glutamate receptor–mediated long-term depression (G1-mGluR-LTD) following seizures. We have shown that expression of ArcKR, a form of Arc in which degradation is reduced, significantly modulates the magnitude of G1-mGluR-LTD following epileptic seizures. However, the effect of ArcKR on LTD depends on the epileptic model used, with enhancement of LTD in an in vitro model and a reduction in the kainate mouse model.
The 2024 Europe report of the Lancet Countdown on health and climate change: unprecedented warming demands unprecedented action
Kim R van Daalen et al incl. Orin Courtenay
The Lancet Countdown in Europe was established in 2021, to assess the health profile of climate change aiming to stimulate European social and political will to implement rapid health-responsive climate mitigation and adaptation actions. In 2022, the collaboration published its indicator report, tracking progress on health and climate change via 33 indicators and across five domains. This new report tracks 42 indicators highlighting the negative impacts of climate change on human health, the delayed climate action of European countries, and the missed opportunities to protect or improve health with health-responsive climate action. Considering that negative climate-related health impacts and the responsibility for climate change are not equal at the regional and global levels, this report also endeavours to reflect on aspects of inequality and justice by highlighting at-risk groups within Europe and Europe's responsibility for the climate crisis.
Epidemiological and health economic implications of symptom propagation in respiratory pathogens : a mathematical modelling investigation
Asplin, Phoebe, Keeling, Matt J., Mancy, Rebecca and Hill, Edward M.
We propose a novel framework for incorporating different levels of symptom propagation into models of infectious disease transmission via a single parameter, α. Varying α tunes the model from having no symptom propagation (α = 0, as typically assumed) to one where symptoms always propagate (α = 1). For parameters corresponding to three respiratory pathogens—seasonal influenza, pandemic influenza and SARS-CoV-2—we explored how symptom propagation impacted the relative epidemiological and health-economic performance of three interventions, conceptualised as vaccines with different actions: symptom-attenuating (labelled SA), infection-blocking (IB) and infection-blocking admitting only mild breakthrough infections (IB_MB). Overall, the preferred intervention type depended on the combination of the strength of symptom propagation and uptake. Given the importance of determining robust public health responses, we highlight the need to gather further data on symptom propagation, with our modelling framework acting as a template for future analysis.
Unveiling novel Neocosmospora species from Thai mangroves as potent biocontrol agents against Colletotrichum species
Klomchit, A, Calabon, MS, Worabandit, S, Weaver, JA, Karima, EM, Alberti, F, Greco, C and Mahanil, S
This study aims to investigate the taxonomy, biosynthetic potential, and application of three newly isolated Neocosmospora species from mangrove habitats in the southern part of Thailand using phylogeny, bioactivity screening, genome sequencing, and bioinformatics analysis.
Two fungal isolates of Neocosmospora and a new species of N. mangrovei were reported in this study. These fungal strains showed activity against pathogenic fungi causing anthracnose in chili. In addition, full genome sequencing and bioinformatics analysis of N. mangrovei MFLUCC 17–0253 were obtained.