Biology subjects

Eldridge, M. J. G.

Publications and source records attributed to Eldridge, M. J. G..

4 recordsLinked to original sources

bioRxiv2023

An oxadiazole-based compound potentiates anti- tuberculosis treatment by increasing host resistance via zinc poisoning

Anti-tuberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multi-resistant strains of Mycobacterium tuberculosis are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, using high content imaging, we identified novel 1,2,4-oxadiazole-based compounds, that allow human macrophages to control MTB replication. Genome-wide gene expression analysis revealed that these molecules induced zinc remobilization inside cells, resulting in bacterial zinc intoxication. More importantly, we also demonstrated that, upon treatment with these novel compounds, M. tuberculosis became even more sensitive to anti-tuberculosis drugs, in vitro and in vivo, in a mouse model of tuberculosis. Manipulation of heavy metal homeostasis holds thus great promise to be exploited to develop host-directed therapeutic interventions.

microbiology↗

bioRxiv2022

IL-1β turnover by TRIP12 and AREL1 ubiquitin ligases and UBE2L3 limits inflammation

The cytokine interleukin-1{beta} (IL-1{beta}) has pivotal roles in antimicrobial immunity, but also incites inflammatory pathology. Bioactive IL-1{beta} is released following proteolytic maturation of the pro-IL-1{beta} precursor by caspase-1 inflammasomes. UBE2L3/UBCH7, a conserved ubiquitin conjugating enzyme, promotes pro-IL-1{beta} ubiquitylation and proteasomal disposal. However, UBE2L3 actions in vivo and ubiquitin ligases involved in this process are unknown. Here we report that deletion of Ube2l3 in mice markedly reduces pro-IL-1{beta} turnover in macrophages, leading to excessive mature IL-1{beta} production, neutrophilic inflammation and disease symptoms following inflammasome activation. A family-wide siRNA screen identified two ubiquitin ligases, TRIP12 and AREL1, which we show add K27-, K29- and K33- poly-ubiquitin chains on lysine residues in the pro domain and destabilise pro-IL-1{beta}. Mutation of ubiquitylation sites increased pro-IL-1{beta} stability, but did not affect proteolysis by caspase-1. The extent of mature IL-1{beta} production is therefore determined by precursor abundance, and UBE2L3, TRIP12 and AREL1 limit inflammation by shrinking the cellular pool of pro-IL-1{beta}. Our study has uncovered fundamental processes governing IL-1{beta} homeostasis and provided molecular insights that could be exploited to mitigate its adverse actions in disease.

immunology↗

bioRxiv2022

Pneumococcus triggers NFkB degradation in COMMD2 aggresome-like bodies.

NF-{kappa}B driven cellular immunity is essential for both pro- and anti-inflammatory responses to microbes, which makes it one of the most frequently targeted pathways by bacteria during pathogenesis. How NF-{kappa}B tunes the epithelial response to Streptococcus pneumoniae across the spectrum of commensal to pathogenic outcomes is not fully understood. In this study, we compare a commensal-like 6B ST90 strain to an invasive TIGR4 isolate and demonstrate, through comparative mass spectrometry of the p65 interactome, TIGR4 challenge triggers a novel interaction of COMMD2 with p65 and p62. Mechanistically, we show this complex mediates export of p65 for degradation and COMMD2 is necessary for altering host cellular immunity. With these results, we reveal for the first time a new bacterial pathogenesis mechanism to repress host inflammatory response though COMMD2 and p65 degradation while presenting a paradigm for diverging NF-{kappa}B responses to pneumococcus.

microbiology↗

bioRxiv2021

Histone H3 deacetylation promotes host cell viability for efficient infection by Listeria monocytogenes

For many intracellular bacterial pathogens manipulating host cell survival is essential for maintaining a replicative niche, and is a common strategy used to promote infection. The bacterial pathogen Listeria monocytogenes is well known to hijack host machinery for its own benefit, such as targeting the host histone H3 for modification by SIRT2. However, in what way this modification benefits infection, as well as the molecular players involved, remain unknown. Here we show that SIRT2 activity supports Listeria intracellular survival by maintaining genome integrity and host cell viability. This protective effect is dependent on H3K18 deacetylation, which safeguards the host genome by counteracting infection-induced DNA damage. Mechanistically, infection causes SIRT2 to interact with the nucleic acid binding protein TDP-43 and localise to genomic R-loops, where H3K18 deacetylation occurs. This work highlights novel functions of TDP-43 and R-loops during bacterial infection and identifies the mechanism through which L. monocytogenes co-opts SIRT2 to allow efficient infection.

molecular biology↗