Biology subjects

Pearson, F.

Publications and source records attributed to Pearson, F..

3 recordsLinked to original sources

bioRxiv2025

Non-canonical inflammasome drives intrinsic anti-microbial responses in human Natural Killer (NK) cells.

Inflammasome pathways are critical for detecting pathogens and initiating inflammatory responses, yet how individual cell types configure these signalling platforms remains poorly understood. Here, we demonstrate that human Natural Killer cells possess distinct inflammasome machinery, lacking canonical components and innate sensors (NLRP3, NLRC4, TLR4) but harbour a functional non-canonical inflammasome (NCI). Using Salmonella enterica Typhimurium infection of primary human NK cells, we show that cytosolic bacterial access triggers caspase-4-dependent pyroptosis and IL-18 secretion, without canonical inflammasome activation or IL-1{beta} production. Strikingly, murine NK cells express inflammasome transcripts but lack functional caspase-11 protein and do not undergo pyroptosis upon infection, revealing species-specific post-transcriptional regulation. We further identify IL-12, but not IFN{gamma}, as a priming signal for NCI components in human NK cells, a functional distinction from macrophages and epithelial cells. Together, these findings reveal that human NK cells have evolved a specialised inflammasome with unique regulatory inputs, establishing these cells as autonomous sensors of intracellular Gram-negative infection.

immunology↗

bioRxiv2025

The 1-Cys peroxiredoxin, PRDX-6, suppresses a pro-survival response, including the Flavin monoxygenase, FMO-2, that protects against fungal and bacterial infection

Reactive oxygen species (ROS)-induced cell damage contributes to many diseases. However, ROS also contribute to cell signaling and immune defences. As ubiquitous thiol peroxidases, peroxiredoxins (Prdx) play integral roles in balancing ROS functions. High levels of Prdx6 are associated with increased metastasis and resistance to chemotherapy, rendering Prdx6 a therapeutic target for treatment of a broad range of cancers. However, Prdx6, has additional activities, in lipid signalling and selenocysteine metabolism, and it remains unclear how Prdx6s thiol peroxidase activity contributes to disease or ageing. Here we have investigated the role/s of Prdx6 in the stress responses and ageing of the nematode worm Caenorhabditis. elegans. Unexpectedly, we have found that C. elegans lacking prdx-6, have an increased resistance to oxidative stress and extended lifespan under some conditions. Moreover, prdx-6 mutant worms are also more resistant to infection with two opportunistic human pathogens; the gram-positive bacteria Staphylococcus aureus and the dimorphic yeast Candida albicans. Our data suggest that increased ROS levels in prdx-6 mutant worms lead to increased cell death in the germ line, and increased expression of the Flavin monooxygenase, FMO-2 in other tissues. FMO-2 has a conserved pro-survival function and is upregulated by the NHR-49(PPAR/HNF4) transcriptional regulator in response to various stresses, including peroxides and S. aureus infection. Here we reveal that fmo-2 expression is also increased as an NHR-49-dependent protective response to C. albicans. Thus, in addition to its anti-ageing role, FMO-2 protects C. elegans against both fungal and bacterial infections. Accordingly, we propose that elevated fmo-2 expression contributes to the increased stress resistance, lifespan and innate immunity of prdx-6 mutant animals. These findings further illustrate the complex roles that ROS/PRDX can play in stress resistance, immunity and ageing. HighlightsO_LIPRDX-6 is expressed in specific interneurons and intestine C_LIO_LILoss of PRDX-6 increases germ cell apoptosis C_LIO_LILoss of PRDX-6 increases C. elegans stress resistance, innate immunity and longevity C_LIO_LILoss of PRDX-6 and infection increase expression of the flavin monooxygenase fmo-2 C_LIO_LIFMO-2 protects against infection with the fungal pathogen Candida albicans C_LI

immunology↗

bioRxiv2021

A framework for evaluating edited cell libraries created by massively parallel genome engineering

Genome engineering methodologies are transforming biological research and discovery. Approaches based on CRISPR technology have been broadly adopted and there is growing interest in the generation of massively parallel edited cell libraries. Comparing the libraries generated by these varying approaches is challenging and researchers lack a common framework for defining and assessing the characteristics of these libraries. Here we describe a framework for evaluating massively parallel libraries of edited genomes based on established methods for sampling complex populations. We define specific attributes and metrics that are informative for describing a complex cell library and provide examples for estimating these values. We also connect this analysis to generic phenotyping approaches, using either pooled (typically via a selection assay) or isolate (often referred to as screening) phenotyping approaches. We approach this from the context of creating massively parallel, precisely edited libraries with one edit per cell, though the approach holds for other types of modifications, including libraries containing multiple edits per cell (combinatorial editing). This framework is a critical component for evaluating and comparing new technologies as well as understanding how a massively parallel edited cell library will perform in a given phenotyping approach.

genomics↗