Finnegan, M. | bioRxiv Science

bioRxiv2025

MARCO is an IFN-restricted immunometabolic decoy LPS receptor

Intracellular sensing of lipopolysaccharide (LPS) is an essential component of pathogen detection that governs the innate immune response. However, how this process is controlled to maintain homeostasis and resolve inflammation is unclear. Here, we show that MARCO is a decoy LPS sensor crucial for restraining caspase 11 activity and the non-canonical inflammasome. Remarkably, MARCO expression is controlled by a non-canonical TLR signaling pathway involving the metabolite itaconate, the autophagy adaptor protein p62, and the transcription factor NRF2. In the presence of IFN, non-canonical TLR signaling is impaired and NRF2 dependent gene expression is terminated. Thus, impairing MARCO expression and licensing optimal activation of the non-canonical inflammasome. Loss of MARCO augments non-canonical inflammasome activation and sensitizes mice to septic shock. Together, this study identifies MARCO as a previously unknown LPS sensor that is regulated by a non-canonical TLR signaling pathway and reveals an intricate homeostatic switch that allows for optimal immune responses and resolution of inflammation.

immunology↗

bioRxiv2024

Hurdles to Horizontal Gene Transfer: Synonymous variation determines antibiotic resistance phenotype across species

Evidence that synonymous mutations and synonymous gene variants have fitness effects have accumulated recently. Since horizontal gene transfer represents a change in the genome of expression of the transferred gene, we hypothesized that the codon usage preferences of a horizontally transferred gene could determine the conferred fitness advantage or disadvantage, condition the immediate success of the transfer and in the longer term orient transfers. To test this hypothesis, we characterized resistance levels of synonymous variants of a gentamicin resistance gene, inserted into a broad-host range plasmid and transformed into three different bacterial species Escherichia coli, Acinetobacter baylyi and Pseudomonas aeruginosa. We revealed a strong species effect, explained in part by differences in plasmid copy number between host species. Importantly, the relative levels of resistance conferred by each synonymous variant were not conserved across species, indicating that these phenotypic effects are due to differing compatibility between the transferred variants and the receiver bacterial genomes. This species-variant interaction confirms that the codon composition of a gene can be a determinant of post-horizontal gene transfer success. However, the similarity in codon usage between the synonymous variants and the host genome only explained the phenotypic differences between variants in one species, P. aeruginosa. Further investigations of the effects of local codon usage, translation bottlenecks and internal Shine-Dalgarno sequences did not reveal common universal mechanisms across our three bacterial species and point to multiple paths leading from the synonymous sequence to phenotype and a species-specific sensitivity to these different paths.

evolutionary biology↗