Biology subjects

Lorenzon, L.

Publications and source records attributed to Lorenzon, L..

3 recordsLinked to original sources

bioRxiv2026

NLRP3 inflammasome signaling orchestrates hepatic granuloma organization and protective immunity

Granulomas are organized immune structures that contribute to host defense against persistent pathogens, yet the mechanisms that coordinate their assembly and protective function remain incompletely understood. Here, using experimental visceral leishmaniasis caused by Leishmania infantum and samples from patients with active disease, we identify the NLRP3 inflammasome as a regulator of protective hepatic granulomatous immunity. Inflammasome-associated mediators were elevated in patients and correlated with systemic inflammation. In mice, L. infantum induced NLRP3 inflammasome activation within hepatic granulomas, while single-cell and spatial transcriptomic analyses revealed enrichment of inflammasome-associated transcription in hepatic macrophages and granuloma-associated regions. NLRP3 deficiency did not prevent granuloma initiation but impaired granuloma expansion, cellular organization, and leukocyte accumulation. This response required Caspase-1/11 and IL-18, but was independent of IL-1{beta}. Loss of NLRP3 also impaired parasite control despite reducing hepatic inflammation and histopathological alterations. Together, our findings identify NLRP3-Caspase-1/11-IL-18 signaling as a mechanism that coordinates the cellular and spatial organization of protective hepatic granulomas, revealing granuloma architecture as a previously unrecognized function of inflammasome-mediated immunity and providing mechanistic insight into host resistance in visceral leishmaniasis, a potentially fatal neglected tropical disease.

immunology↗

bioRxiv2026

An IGF2-anchored oncofetal state and relapse-associated transcriptomic module define systemic progression risk in early-onset colorectal cancer

The epidemiological surge of early-onset colorectal cancer (EOCRC) is characterized by accelerated biological kinetics and disproportionately high rates of systemic relapse following curative-intent surgery. Because standard anatomical staging (TNM) lacks the resolution to accurately capture the intrinsic regenerative capacity of microscopic residual disease, we investigated the transcriptomic architecture of post-surgical failure in a strictly defined, curative-intent clinical pan-cohort. Unbiased transcriptomic profiling of the localized (M0) discovery sub-cohort identified IGF2 as the most significantly upregulated correlate of metachronous relapse. High-resolution isoform analysis revealed that this transcriptional output is predominantly driven by the embryonic (P4) and placental (P5) promoters. Systematic allele-specific expression (ASE) analysis supported widespread biallelic IGF2 expression consistent with relaxation of imprinting-domain control. This signal was not restricted to relapsing tumors, suggesting a recurrence-independent oncofetal baseline across the EOCRC spectrum. Because this foundational epigenetic unlocking is functionally insufficient on its own to execute systemic metastasis, we distilled the additional transcriptional plasticity required for dissemination into an internally derived and bootstrap-stabilized 5-gene recurrence-risk module Multivariable analysis across the combined pan-cohort supported an independent association between the high-risk module and systemic relapse (p < 0.001), capturing prognostic dimensions completely unresolved by classical pathological covariates and baseline staging. Ultimately, our findings reframe EOCRC aggressiveness as the product of a dual-hit architecture. This framework resolves the clinical paradox of widespread IGF2 LOI co-existing with heterogeneous outcomes, offering a biologically grounded basis for molecular risk stratification beyond anatomical boundaries.

cancer biology↗

bioRxiv2021

Functional study of Leishmania braziliensis protein arginine methyltransferases (PRMTs) reveals that PRMT1 and PRMT5 are required for macrophage infection

In trypanosomatids, regulation of gene expression occurs mainly at the posttranscriptional level, and RNA-binding proteins (RBPs) are key players in determining the fates of transcripts. RBPs are major targets of protein arginine methyltransferases (PRMTs), which posttranslationally regulate the RNA-binding capacity and other macromolecular interactions of RBPs by transferring methyl groups to protein arginine residues. Herein, we present the results of a study that functionally characterized the five predicted PRMTs in Leishmania braziliensis by gene knockout and endogenous protein HA tagging using CRISPR/Cas9 gene editing. We report that arginine methylation profiles vary among Leishmania species and that target protein methylation changes across different L. braziliensis life cycle stages, with higher PRMT expression in the promastigote stages than in the axenic amastigote stage. Knockout of some of the L. braziliensis PRMTs led to significant changes in global arginine methylation patterns without affecting promastigote axenic growth. Deletion of either PRMT1 or PRMT3 disrupted most type I PRMT activity, resulting in a global increase in monomethyl arginine (MMA) levels, which is mainly catalyzed by PRMT7. Putative targets and/or PRMT-interacting proteins were identified by coimmunoprecipitation using HA-tagged PRMTs, revealing a network of target RBPs and suggesting functional interactions between them and a relevant participation in epigenetic control of gene expression. Finally, we demonstrate that L. braziliensis PRMT1 and PRMT5 are required for efficient macrophage infection in vitro, and that in the absence of PRMT1 and PRMT5, axenic amastigote proliferation is impaired. The results indicate that arginine methylation is modulated across life cycle stages in L. braziliensis and show possible functional overlap and cooperation among the different PRMTs in targeting proteins. Overall, our data suggest important regulatory roles of these proteins throughout the L. braziliensis life cycle, showing that arginine methylation is important for parasite-host cell interactions.

molecular biology↗