Grzelak, J. | bioRxiv Science

bioRxiv2023

The hepatocyte Epidermal Growth Factor Receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche

Background & AimsLiver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of profibrotic factors are not well characterized. The Epidermal Growth Factor Receptor (EGFR) signaling in hepatocytes is essential for the regenerative process of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Approach & ResultsOur group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes ({Delta}EGFR mice). Here, we have analyzed the response of WT and {Delta}EGFR mice to chronic treatment with CCl4. Resultsindicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated {Delta}EGFR mice when compared to WT mice, coinciding with a faster resolution of the fibrotic process and an ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable change in the population of M2 macrophages, more related to fibrosis resolution, as well as an increase in the population of lymphocytes related to eradication of the damage. Transcriptomic analysis of hepatocytes and secretome studies from extracellular media in in vitro studies allowed to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-inflammatory and pro-fibrotic mediators. ConclusionsOur results support a pro-inflammatory and pro-fibrogenic role for the hepatocyte EGFR pathway during chronic liver damage.

pathology↗

bioRxiv2023

Inferring patterns of recombination and divergence with ancient and modern treponemal genomes

BackgroundTreponemal diseases pose significant global health risks, presenting severe challenges to public health due to their serious health impacts if left untreated. Despite numerous genomic studies on Treponema pallidum and the known possible biases introduced by the choice of the reference genome used for mapping, few investigations have addressed how these biases affect phylogenetic and evolutionary analysis of these bacteria. In this study, we assessed the impact of selecting an appropriate genomic reference on phylogenetic and evolutionary analyses of T. pallidum. ResultsWe designed a multiple-reference-based (MRB) mapping strategy using four different reference genomes and compared it to traditional single-reference mapping. To conduct this comparison, we created a genomic dataset comprising 77 modern and ancient genomes from the three subspecies of T. pallidum, including a newly sequenced 17th-century genome (35X coverage) of a syphilis-causing strain (designated as W86). Our findings show that recombination detection was consistent across different references, but the choice of reference significantly affected ancient genome reconstruction and phylogenetic inferences. The high-coverage W86 genome obtained here also provided a new calibration point for Bayesian molecular clock dating, improving the reconstruction of the evolutionary history of treponemal diseases. Additionally, we identified novel recombination events, positive selection targets, and refined dating estimates for key events in the species history. ConclusionsThis study highlights the importance of considering methodological implications and reference genome bias in High-Throughput Sequencing-based whole-genome analysis of T. pallidum, especially of ancient or low-coverage samples, contributing to a deeper understanding of this pathogen and its subspecies.

microbiology↗