Biology subjects

Gregory, W. F.

Publications and source records attributed to Gregory, W. F..

4 recordsLinked to original sources

bioRxiv2024

Histone lactylation: a new epigenetic mark in the malaria parasite Plasmodium

Epigenetic processes play important roles in the biology of the malaria parasite Plasmodium falciparum. Here, we characterised a new epigenetic mark, histone lactylation, recently discovered in humans: it was found in two human malaria parasites, P. falciparum and P. knowlesi, and also in vivo in two rodent malaria models. Histones were lactylated rapidly in response to elevated lactate levels, and rapidly delactylated when lactate levels fell. Thus, this mark is well-placed to act as a metabolic sensor, since severe falciparum malaria characteristically leads to hyperlactataemia. Mass spectrometry showed that lysines on several parasite histones could be lactylated, as well as many non-histone chromatin proteins. Histone lactylation was less abundant and less inducible in P. knowlesi than P. falciparum, suggesting that P. falciparum may have evolved particular epigenetic responses to this characteristic feature of its pathology. Finally, in the rodent model P. yoelii, hyperlactataemia correlated with parasite transcriptomic programmes that suggested metabolic dormancy.

microbiology↗

bioRxiv2022

Large-scale proteomic analysis of T. spiralis muscle-stage ESPs identifies a novel upstream motif for in silico prediction of secreted products

The Trichinella genus contains parasitic nematodes capable of infecting a wide range of hosts including mammals, birds and reptiles. Like other helminths, T. spiralis secretes a complex mixture of bioactive molecules capable of modulating its immediate surroundings and creating a hospitable environment for growth, survival and ultimately transmission. The constitution of these excretory-secretory products (ESPs) changes depending on the tissue niche and the specific stage of parasite development. Unique to T. spiralis is a true intracellular stage wherein larvae develop inside striated myotubes. Remarkably, the parasite larvae do not destroy the host cell but rather reprogram it to support their presence and growth. This transformation is largely mediated through stage-specific secretions released into the host cell cytoplasm. In this study, we apply state of the art proteomics and computational approaches to elucidate the composition and functions of muscle-stage T. spiralis ESPs. Moreover, we define a commonly-occurring, upstream motif that we believe is associated with the stichosome, the main secretory organ of this worm, and can thus be used to predict secreted proteins across experimentally less tractable T. spiralis life cycle stages. Author SummaryTrichinella spiralis is the only helminth parasite with a true intracellular stage. Newborn larvae penetrate the intestinal wall of the host, enter the circulation and preferentially infect muscle cells. Remarkably, they do not destroy the host cell but rather initiate a series of modulatory events that transform it into a nurse cell complex, a collagenated cyst that can persist for years. Each stage of T. spiralis development is guided by host-targeted secretions released by the worm directly into its immediate environment, mediating events such as immunoregulation, cell cycle control and angiogenesis. As such, these worm effectors hold therapeutic potential for chronic and autoimmune diseases. The composition of excretory-secretory products (ESPs) changes according to what the worm needs to accomplish and what tissue niche it is occupying at the time, with many deriving from the stichosome, the worms dedicated secretory organ. In this study, we characterise ESPs of muscle-stage T. spiralis larvae using proteomic and bioinformatic approaches and we define a regulatory motif associated with stichosome-derived proteins.

cell biology↗

bioRxiv2020

A truncated form of HpARI stabilises IL-33, amplifying responses to the cytokine.

1The murine intestinal nematode Heligmosomoides polygyrus releases the H. polygyrus Alarmin Release Inhibitor (HpARI) - a protein which binds to IL-33 and to DNA, effectively tethering the cytokine in the nucleus of necrotic cells. Previous work showed that a non-natural truncation consisting of the first 2 domains of HpARI (HpARI_CCP1/2) retains binding to both DNA and IL-33, and inhibited IL-33 release in vivo. Here, we show that the affinity of HpARI_CCP1/2 for IL-33 is significantly lower than that of the full-length protein, and that HpARI_CCP1/2 lacks the ability to prevent interaction of IL-33 with its receptor. When HpARI_CCP1/2 was applied in vivo it potently amplified IL-33-dependent immune responses to Alternaria alternata allergen, Nippostrongylus brasiliensis infection and recombinant IL-33 injection. Mechanistically, we found that HpARI_CCP1/2 is able to bind to and stabilise IL-33, preventing its degradation and maintaining the cytokine in its active form. This study highlights the importance of IL-33 inactivation, the potential for IL-33 stabilisation in vivo, and describes a new tool for IL-33 research.

immunology↗

bioRxiv2017

Human Herpes Virus 6 (HHV-6) - Pathogen or Passenger? A pilot study of clinical laboratory data and next generation sequencing

ABSTRACT\n\nBackgroundHuman herpes virus 6 (HHV-6) is a ubiquitous organism that can cause a variety of clinical syndromes ranging from short-lived rash and fever through to life-threatening encephalitis.\n\nObjectivesWe set out to generate observational data regarding the epidemiology of HHV-6 infection in clinical samples from a UK teaching hospital and to compare different diagnostic approaches.\n\nStudy designFirst, we scrutinized HHV-6 detection in samples submitted to our hospital laboratory through routine diagnostic pathways. Second, we undertook a pilot study using Illumina next generation sequencing (NGS) to determine the frequency of HHV-6 in CSF and respiratory samples that were initially submitted to the laboratory for other diagnostic tests.\n\nResultsOf 72 samples tested for HHV-6 by PCR at the request of a clinician, 24 (33%) were positive for HHV-6. The majority of these patients were under the care of the haematology team (30/41, 73%), and there was a borderline association between HHV-6 detection and both Graft versus Host Disease (GvHD) and Central nervous system (CNS) disease (p=0.05 in each case). We confirmed detection of HHV-6 DNA using NGS in 4/20 (20%) CSF and respiratory samples.\n\nConclusionsHHV-6 is common in clinical samples submitted from a high-risk haematology population, and enhanced screening of this group should be considered. NGS can be used to identify HHV-6 from a complex microbiomee, but further controls are required to define the sensitivity and specificity, and to correlate these results with clinical disease. Our results underpin ongoing efforts to develop NGS technology for viral diagnostics.

microbiology↗