• Caenorhabditis elegans, a model organism for investigating immunity.

      Marsh, Elizabeth K; May, Robin C; University of Birmingham (2012-03-09)
      The nematode Caenorhabditis elegans has been a powerful experimental organism for almost half a century. Over the past 10 years, researchers have begun to exploit the power of C. elegans to investigate the biology of a number of human pathogens. This work has uncovered mechanisms of host immunity and pathogen virulence that are analogous to those involved during pathogenesis in humans or other animal hosts, as well as novel immunity mechanisms which appear to be unique to the worm. More recently, these investigations have uncovered details of the natural pathogens of C. elegans, including the description of a novel intracellular microsporidian parasite as well as new nodaviruses, the first identification of viral infections of this nematode. In this review, we consider the application of C. elegans to human infectious disease research, as well as consider the nematode response to these natural pathogens.
    • Pellino-1 regulates the responses of the airway to viral infection

      Marsh, Elizabeth K; Prestwich, Elizabeth C; Marriott, Helen M; Williams, Lynne; Hart, Amber R; Muir, Claire F; Parker, Lisa C; Jonker, Marnix R; Heijink, Irene H; Timens, Wim; et al. (Frontiers, 2020-08-31)
      Exposure to respiratory pathogens is a leading cause of exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pellino-1 is an E3 ubiquitin ligase known to regulate virally-induced inflammation. We wished to determine the role of Pellino-1 in the host response to respiratory viruses in health and disease. Pellino-1 expression was examined in bronchial sections from patients with GOLD stage 2 COPD and healthy controls. Primary bronchial epithelial cells (PBECs), in which Pellino-1 expression had been knocked down, were extracellularly challenged with the TLR3 agonist poly(I:C). C57BL/6 Peli1-/- mice and wild type littermates were subjected to intranasal infection with clinically-relevant respiratory viruses; rhinovirus (RV1B) and influenza A. We find that Pellino-1 is expressed in the airways of normal subjects and those with COPD, and that Pellino-1 regulates TLR3 signalling and responses to airways viruses. In particular we observed that knockout of Pellino‐1 in the murine lung resulted in increased production of proinflammatory cytokines IL‐6 and TNFα upon viral infection, accompanied by enhanced recruitment of immune cells to the airways, without any change in viral replication. Pellino-1 therefore regulates inflammatory airway responses without altering replication of respiratory viruses.
    • The role of protein kinase A regulation of the E6 PDZ-binding domain during the differentiation-dependent life cycle of human papillomavirus type 18.

      Delury, Craig P; Marsh, Elizabeth K; James, Claire D; Boon, Siaw Shi; Banks, Lawrence; Knight, Gillian L; Roberts, Sally; University of Birmingham (American Society for Microbiology, 2013-08-13)
      Human papillomavirus (HPV) E6 proteins of high-risk alpha types target a select group of PSD95/DLG1/ZO1 (PDZ) domain-containing proteins by using a C-terminal PDZ-binding motif (PBM), an interaction that can be negatively regulated by phosphorylation of the E6 PBM by protein kinase A (PKA). Here, we have mutated the canonical PKA recognition motif that partially overlaps with the E6 PBM in the HPV18 genome (E6153PKA) and compared the effect of this mutation on the HPVl8 life cycle in primary keratinocytes with the wild-type genome and with a second mutant genome that lacks the E6 PBM (E6ΔPDZ). Loss of PKA recognition of E6 was associated with increased growth of the genome-containing cells relative to cells carrying the wild-type genome, and upon stratification, a more hyperplastic phenotype, with an increase in the number of S-phase competent cells in the upper suprabasal layers, while the opposite was seen with the E6ΔPDZ genome. Moreover, the growth of wild-type genome-containing cells was sensitive to changes in PKA activity, and these changes were associated with increased phosphorylation of the E6 PBM. In marked contrast to E6ΔPDZ genomes, the E6153PKA mutation exhibited no deleterious effects on viral genome amplification or expression of late proteins. Our data suggest that the E6 PBM function is differentially regulated by phosphorylation in the HPV18 life cycle. We speculate that perturbation of protein kinase signaling pathways could lead to changes in E6 PBM function, which in turn could have a bearing on tumor promotion and progression.
    • A two-gene balance regulates Salmonella typhimurium tolerance in the nematode Caenorhabditis elegans.

      Marsh, Elizabeth K; van den Berg, Maaike C W; May, Robin C; University of Birmingham (Public Library of Science, 2011-03-02)
      Lysozymes are antimicrobial enzymes that perform a critical role in resisting infection in a wide-range of eukaryotes. However, using the nematode Caenorhabditis elegans as a model host we now demonstrate that deletion of the protist type lysozyme LYS-7 renders animals susceptible to killing by the fatal fungal human pathogen Cryptococcus neoformans, but, remarkably, enhances tolerance to the enteric bacteria Salmonella Typhimurium. This trade-off in immunological susceptibility in C. elegans is further mediated by the reciprocal activity of lys-7 and the tyrosine kinase abl-1. Together this implies a greater complexity in C. elegans innate immune function than previously thought.