Biology subjects

Dorrell, N.

Publications and source records attributed to Dorrell, N..

5 recordsLinked to original sources

bioRxiv2026

Characterisation of novel Campylobacter jejuni Type VI secretion system (T6SS) effectors and exploration of the roles of the C. jejuni T6SS in bacterial antagonism and human host cell interaction

Campylobacter jejuni is a leading global cause of acute foodborne gastroenteritis however, C. jejuni lacks some of the classic virulence determinants associated with other common enteric bacterial pathogens. In recent years an increasing number of C. jejuni isolates have been identified to encode Type Six Secretion System (T6SS), an apparatus utilised by Gram-negative bacteria to secrete toxic bacterial effectors into neighbouring cells. Despite the prevalence of the T6SS and previous investigations, the roles of the C. jejuni T6SS are still not well characterised especially when compared to our knowledge of other clinically relevant T6SS-positive bacterial species. Additionally, as of yet, no C. jejuni T6SS cargo effectors have been characterised. In this study, we show the C. jejuni 488 strain T6SS displays contact-dependent antagonistic behaviour towards T6SS-negative C. jejuni, Campylobacter coli, Escherichia coli and Enterococcus faecium strains suggesting the presence of the T6SS contributes to the competitive capacity of this C. jejuni T6SS-positive strain. Moreover, this antagonistic activity is linked to the functionality of CJ488_0980 and CJ488_0982, two novel putative Tox-REase-7 domain-containing effectors, which were identified through bioinformatical analysis of the C. jejuni 488 strain genome. Additionally, our investigations propose the C. jejuni 488 T6SS contributes to interaction, invasion and intracellular survival in human intestinal epithelial cells (IEC). Collectively, these initial findings are the first examples of in vitro investigation of putative cargo effectors in Campylobacter spp. and provide valuable insights into the roles of C. jejuni T6SS effectors in bacterial competition and pathogenesis. This study highlights the importance of T6SS as an emerging virulence determinant in Campylobacter spp. warranting further investigation.

microbiology↗

bioRxiv2025

Unfolded protein response is a critical mediator in Campylobacter jejuni pathogenesis and host defence

Campylobacter jejuni is the major bacterial cause of foodborne gastroenteritis worldwide. How this pathogen interacts with the host defence machinery of human intestinal epithelial cells (IECs) and is involved in pathogenesis remains elusive. Bacterial pathogens utilise strategies to gain access to the eukaryotic cell machinery that can involve subversion of biological processes in host. Unfolded protein response (UPR) is a highly conserved host cell stress response to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and is a conserved evolutionary response against invading pathogens. Several bacterial pathogens can induce the UPR for their own survival and thus design a dual scenario where UPR can both protect and facilitate pathogen evasion. Herein, we investigated whether UPR represents a virulence mechanism exploited by C. jejuni during bacterial invasion in human IECs. Our data show that following C. jejuni infection, we observe upregulation of protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) pathways of the UPR, albeit differentially in human T84 and Caco-2 cells. Chemical induction of UPR by thapsigargin in host cells reduced intracellular survival of C. jejuni while conversely pretreatment with UPR inhibitors increased intracellular survival of C. jejuni and attenuated IL-8 release. Finally, we show that C. jejuni mutant C. jejuni capsular polysaccharide and flagella contribute to UPR activation in IECs. Collectively, these findings provide mechanistic insights into how C. jejuni infection leads to UPR activation and inflammation, potentially contributing to downstream C. jejuni-mediated damage. Author SummaryCampylobacter jejuni is one of the most prevalent bacterial causes of foodborne human gastroenteritis worldwide. The common symptoms of campylobacteriosis include diarrhoea, abdominal pain and fever. C. jejuni-induced diarrhoea is associated with disruption of tight junctions and adherens junctions, downregulation of epithelial sodium channels and disruption of bile reabsorption. In addition, C. jejuni-induced diarrhoea in part result from intestinal inflammation caused by increased C. jejuni colonisation and invasion due to dysfunctional intestinal barrier. C. jejuni was reported to cause an inflammatory signalling cascade via ligand recognition by Toll-like receptor 2 (TLR2), TLR4 and nucleotide-binding oligomerisation domain (NOD) in IECs. However, other potential mechanisms of C. jejuni-induced inflammation, with respect to the IEC responses remains unknown. In this study, we demonstrate UPR activation following C. jejuni infection. The UPR is a conserved eukaryotic regulatory response which is initiated to relieve ER stress and recover ER homeostasis, however several bacteria have evolved to exploit UPR pathways for their own survival and replication, creating a dual scenario where UPR can both protect and facilitate pathogen evasion. This study shows that the activation of the PERK pathway of host UPR is activated in the presence of live C. jejuni or its structural components, flagella and a capsular polysaccharide. Furthermore, we propose that although activation of the UPR is a conserved evolutionary response against invading pathogens, UPR induction induces inflammation which potentially contributes to C. jejuni-mediated damage.

microbiology↗

bioRxiv2022

Campylobacter jejuni modulates reactive oxygen species production and NADPH oxidase 1 expression in human intestinal epithelial cells

Campylobacter jejuni is the major bacterial cause of foodborne gastroenteritis worldwide. Mechanistically, how this pathogen interacts with intrinsic defence machinery of human intestinal epithelial cells (IECs) remains elusive. To address this, we investigated how C. jejuni counteracts the intracellular and extracellular reactive oxygen species (ROS) in IECs. Our work shows that C. jejuni differentially regulates intracellular and extracellular ROS production in human T84 and Caco-2 cells. C. jejuni downregulates the transcription and translation of Nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (Nox1), a key ROS-generating enzyme in IECs and antioxidant defence genes cat and sod1. Furthermore, inhibition of Nox1 by diphenylene iodonium (DPI) and siRNA reduced C. jejuni ability to interact, invade and intracellularly survive within T84 and Caco-2 cells. Collectively, these findings provide mechanistic insight into how C. jejuni modulates the IEC defence machinery.

microbiology↗

bioRxiv2020

Impact of industrial production system parameters on chicken microbiomes: mechanisms to improve performance and reduce Campylobacter

BackgroundThe factors affecting host-pathogen ecology in terms of the microbiome remain poorly studied. Chickens are a key source of protein with gut health heavily dependent on the complex microbiome which has key roles in nutrient assimilation and vitamin and amino acid biosynthesis. The chicken gut microbiome may be influenced by extrinsic production system parameters such as Placement Birds/m2 (stocking density), feed type and additives. Such parameters, in addition to on-farm biosecurity may influence performance and also pathogenic bacterial numbers such as Campylobacter. In this study, three different production systems Normal (N), Higher Welfare (HW) and Omega-3 Higher Welfare (O) were investigated "in a natural environment" at day 7 and day 30 with a range of extrinsic parameters assessing performance in correlation with microbial dynamics and Campylobacter presence. ResultsOur data identified production system N as significantly dissimilar from production systems HW and O when comparing the prevalence of genera. An increase in Placement Birds/m2 density led to a decrease in environmental pressure influencing the microbial community structure. Prevalence of genera such as Eisenbergiella within HW and O, and likewise Alistipes within N were representative. These genera have roles directly relating to energy metabolism, amino acid, nucleotide and short chain fatty acid (SCFA) utilisation. Thus, an association exists between consistent and differentiating parameters of the production systems, that affect feed utilisation, advance our knowledge of mechanistic underpinnings, leading to competitive exclusion of genera based on competition for nutrients and other factors. Campylobacter was identified within specific production system and presence was linked with the increased diversity and increased environmental pressure on microbial community structure. Addition of Omega-3 though did alter prevalence of specific genera, in our analysis did not differentiate itself from HW production system. However, Omega-3 was linked with a positive impact on weight gain. ConclusionsOverall, our results show that microbial communities in different industrial production systems are deterministic in elucidating the underlying biological confounders, and these recommendations are transferable to farm practices and diet manipulation leading to improved performance and better intervention strategies against Campylobacter within the food chain. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/084251v2_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@c43951org.highwire.dtl.DTLVardef@8efa5corg.highwire.dtl.DTLVardef@d6db70org.highwire.dtl.DTLVardef@1e09fb9_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2018

Comprehensive longitudinal microbiome analysis of the chicken cecum reveals a shift from competitive to environmental drivers and a window of opportunity for Campylobacter

Chickens are a key food source for humans yet their microbiome contains bacteria that can be pathogenic to humans, and indeed potentially to chickens themselves. Campylobacter is present within the chicken gut and is the leading cause of bacterial foodborne gastroenteritis within humans worldwide. Infection can lead to secondary sequelae such as Guillain-Barre syndrome and stunted growth in children from low-resource areas. Despite the global health impact and economic burden of Campylobacter, how and when Campylobacter appears within chickens remains unclear. As such, there has been a motivation to decrease the number of Campylobacter within chickens and thus reduce the risk of infection to humans. The lack of day-to-day microbiome data with replicates, relevant metadata, and a lack of natural infection studies have delayed our understanding of the chicken gut microbiome and Campylobacter. Here, we performed a comprehensive day-to-day microbiome analysis of the chicken cecum from day 3 to 35 (12 replicates each day; n=396) combining metadata such as chicken weight and feed conversion rates to investigate what the driving forces are for the microbial changes within the chicken gut over time, and how this relates to Campylobacter appearance within a natural habitat setting. We found a rapidly increasing microbial diversity up to day 12 with variation observed both in terms of genera and abundance, before a stabilisation of the microbial diversity after day 20. In particular, we identified a shift from competitive to environmental drivers of microbial community from days 12 to 20 creating a window of opportunity whereby Campylobacter appears. Campylobacter was identified at day 16 which was one day after the most substantial changes in metabolic profiles observed. In addition, microbial variation over time is most likely influenced by the diet of the chickens whereby significant shifts in OTU abundances and beta dispersion of samples often corresponded with changes in feed. This study is unique in comparison to the most recent studies as neither sampling was sporadic nor Campylobacter was artificially introduced, thus the experiments were performed in a natural setting. We believe that our findings can be useful for future intervention strategies and can help elucidate the mechanism through which Campylobacter within chickens can be reduced.

microbiology↗