Biology subjects

Madej, J.

Publications and source records attributed to Madej, J..

3 recordsLinked to original sources

bioRxiv2024

A type IVB secretion system contributes to the pathogenicity of Yersinia pseudotuberculosis strains responsible for the Far East scarlet-like fever

Yersinia pseudotuberculosis is a food-borne pathogen responsible for a self-limiting gastrointestinal disease in humans known as mesenteric lymphadenitis. A phylogenetically distinct Y. pseudotuberculosis cluster from lineages 1 and 8 is associated to a specific syndrome called the Far East scarlet-like fever (FESLF), characterized by skin rash, hyperemic tongue and desquamation. Genome sequencing of FESLF strains previously revealed the presence in the plasmid pVM82 of dot/icm genes, homologous to those known to encode a T4BSS in the intracellular pathogens Legionella pneumophila and Coxiella burnetii. In the present article, we characterized the genomic features and functionality of the Y. pseudotuberculosis T4BSS (yT4BSS). We found higher dot/icm gene identity between Y. pseudotuberculosis and Pseudomonas putida genes than with those of L. pneumophila or C. burnetii. We validated the presence of all essential dot/icm genes required for the structure of a T4BSS. We then evaluated the conditions required for yT4BSS gene expression in vitro and identified an influence of temperature, with higher expression at 37{degrees}C, which mimicks the mammalian host temperature. The yT4BSS is also expressed in cellulo during the Y. pseudotuberculosis intracellular life cycle and in vivo during mouse infection. Although T4BSS functions are well characterized in the intracellular life cycle of L. pneumophila and C. burnetii, the yT4BSS appears to not be required for the intracellular survival nor for the establishment of a replication niche within cells of Y. pseudotuberculosis. Interestingly, the yT4BSS is implicated in Y. pseudotuberculosis FESLF strain pathogenicity when orally inoculated to mice but not during intravenous inoculation. Despite a role in virulence during oral infection, the yT4BSS does not influence organ colonization. However, the yT4BSS appears to be implicated in induction of important necrosis lesions in mesenteric lymph nodes and caeca of mice. Cytokine profil analyses revealed an induction of production of innate immunity related cytokines and chemokines depending on the yT4BSS in cellulo using a mouse bone marrow-derived macrophages infection model. Thus, the yT4BSS modulates cytokine responses of the host innate immune system during oral infection. In conclusion, the yT4BSS is a newly characterized virulence factor implicated in pathogenicity of Y. pseudotuberculosis strains from lineage 8 responsible for FESLF.

microbiology↗

bioRxiv2023

Reply to Barton et al: signatures of natural selection during the Black Death

Barton et al.1 raise several statistical concerns regarding our original analyses2 that highlight the challenge of inferring natural selection using ancient genomic data. We show here that these concerns have limited impact on our original conclusions. Specifically, we recover the same signature of enrichment for high FST values at the immune loci relative to putatively neutral sites after switching the allele frequency estimation method to a maximum likelihood approach, filtering to only consider known human variants, and down-sampling our data to the same mean coverage across sites. Furthermore, using permutations, we show that the rs2549794 variant near ERAP2 continues to emerge as the strongest candidate for selection (p = 1.2x10-5), falling below the Bonferroni-corrected significance threshold recommended by Barton et al. Importantly, the evidence for selection on ERAP2 is further supported by functional data demonstrating the impact of the ERAP2 genotype on the immune response to Y. pestis and by epidemiological data from an independent group showing that the putatively selected allele during the Black Death protects against severe respiratory infection in contemporary populations.

genomics↗

bioRxiv2022

Mitochondrial Function is Preserved Under Cysteine Starvation via Glutathione Catabolism in NSCLC

Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that mitochondrial glutathione sustains the function of the Fe-S proteins critical to oxidative metabolism. This is achieved through CHAC1 catabolism of the cysteine-containing tripeptide within the mitochondrial matrix. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a novel mechanism of mitochondrial resilience in response to nutrient stress.

cancer biology↗