Biology subjects

Sanvito, F.

Publications and source records attributed to Sanvito, F..

5 recordsLinked to original sources

bioRxiv2024

Microbiome Modulation Uncouples Efficacy and Toxicity Induced by Programmed Death-1/Programmed Death-Ligand1 Blockade

While asymptomatic smoldering multiple myeloma (SMM) holds an overall risk of progression to multiple myeloma (MM) at 10% per year, only active surveillance is offered to most patients affected by SMM, which leaves them in anxiety and frustration. Intestinal microbiota and gut-born T helper 17 (Th17) lymphocytes may act as drivers of MM evolution. In transgenic Vk*MYC mice developing de novo MM, which invariably evolves from Early-MM that mimics SMM to full-blown Late-MM, we investigated the impact of gut microbiota modulation on disease progression and susceptibility to immune checkpoint blockade (ICB). We report that administering the human commensal Prevotella melaninogenica to mice affected by Early-MM significantly delayed evolution to Late-MM. Mechanistically, treatment with P. melaninogenica induced increased production of short chain fatty acids. Butyrate prevented skew of dendritic cells towards a pro-Th17 phenotype and treated mice accumulated less disease induced Th17 cells in their bone marrow. P. melaninogenica also synergized with anti-PD-L1 antibodies by restraining Th17 cell expansion while unleashing ICB-induced full effector CD8+ T cells, eventually blocking progression to full-blown disease. Similar results were obtained in mice challenged with bortezomib-resistant Vk*MYC tumor cells, a model of more aggressive MM. When mice were exposed to imiquimod to mimic ICB-associated psoriasis-like lesions, P. melaninogenica ameliorated skin lesions caused by ICB. Thus, modulation of the gut microbiota with P. melaninogenica might represent a treatment for patients affected by SMM and would allow fully exploiting the antitumor potential of ICB in plasma cell dyscrasias. Key pointsAdministration of the human commensal Prevotella melaninogenica to Vk*MYC mice delayed evolution to symptomatic multiple myeloma; P. melaninogenica therapeutically synergized with PD-1/PD-L1 blockade also limiting immune-related adverse events.

immunology↗

bioRxiv2023

DeltaF508-Cftr mutation in genetically diverse Collaborative Cross mice yields novel disease-relevant phenotypes for cystic fibrosis

Mutations of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) lead to Cystic Fibrosis (CF), but the substantial phenotypic variations are determined by non-CFTR allelic diversity. To map novel disease phenotypes in a CF mouse model, we used Collaborative Cross (CC) mice, a highly genetically diverse mouse resource population.{Delta} F508-Cftr homozygosity produced a fully penetrant lethal phenotype by eight weeks in two CC lines. The lethality of CC006{Delta}F508/{Delta}F508 was fully prenatal while CC037{Delta}F508/{Delta}F508 showed either prenatal or postnatal lethality. Novel phenotypes of CC037{Delta}F508/{Delta}F508 were revealed early in life including respiratory and systemic inflammatory profiles, and blood, bone marrow, pancreas, heart, and reproductive tract pathologies. Severe intestinal blockage was observed as common in other CF mouse models. These results suggest that the exploration of CF disease phenotypes in a mouse population with diverse genetic profiles is needed to map the genetic origin of currently unidentified disease traits and their potential translation to humans.

pathology↗

bioRxiv2021

Full-length native CGRP neuropeptide and its stable analogue SAX, but not CGRP peptide fragments, inhibit mucosal HIV-1 transmission

The vasodilator neuropeptide calcitonin gene-related peptide (CGRP) plays both detrimental and protective roles in different pathologies. CGRP is also an essential component of the neuro-immune dialogue between nociceptors and mucosal immune cells. We previously reported that CGRP strongly inhibits human immunodeficiency virus type 1 (HIV-1) infection, by suprresing Langerhans cells (LCs)-mediated HIV-1 transfer to T-cells during trans-infection. To understand the requirements for CGRP receptor (CGRP-R) activation during inhibition of HIV-1 transmission, we here investigated the anti-HIV-1 activities of full-length native CGRP and its recently developed stable analogue SAX, as well as several CGRP peptide fragments containing its binding C-terminal and activating N-terminal regions. We show that SAX significantly inhibits LCs-mediated HIV-1 trans-infection but with lower potency than CGRP, while all CGRP peptide fragments tested have no effect. In addition, CGRP readily enters the epithelial compartment of mucosal tissues and does not modify the distribution and density of mucosal immune cells. In-vivo, a single CGRP treatment in humanized mice, before vaginal challenge with high-dose HIV-1, restricts the increase in plasma viral load and maintains higher CD4+ T-cell counts. Together, our results call for the optimization and design of CGRP analogues and agonists, which could be harnessed for prevention of mucosal HIV-1 transmission.

microbiology↗

bioRxiv2020

A new model of chronic Mycobacterium abscessus lung infection in immunocompetent mice

Pulmonary infections caused by Mycobacterium abscessus (MA) have increased over recent decades affecting individuals with underlying pathologies such as chronic obstructive pulmonary disease, bronchiectasis and, especially, cystic fibrosis. The lack of a representative and standardized model of chronic infection in mice has limited steps forward in the field of MA pulmonary infection. To overcome this challenge we refined the method of agar beads to establish MA chronic infection in immunocompetent mice. We evaluated bacterial count, lung pathology and markers of inflammation and we performed longitudinal studies with magnetic resonance imaging (MRI) up to three months after MA infection. In this model, MA was able to establish a persistent lung infection up to two months and with minimal systemic spread. Lung histopathological analysis revealed granulomatous inflammation around bronchi characterized by the presence of neutrophils, lymphocytes and aggregates of vacuolated foamy cells, mimicking the damage observed in humans. Furthermore, MA lung lesions were successfully monitored for the first time by MRI. The availability of this murine model and the introduction of the successfully longitudinal monitoring of the murine lung lesions with MRI pave the way for further investigations on the impact of MA pathogenesis and the efficacy of novel treatments.

microbiology↗

bioRxiv2020

Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes

Globoid Cell Leukodystrophy (GLD, or Krabbe disease) is a rare lysosomal storage disease caused by inherited deficiency of {beta}-galactocerebrosidase (GALC). The build-up of galactosylsphingosine (psychosine) and other undegraded galactosylsphingolipids in the nervous system causes severe demyelination and neurodegeneration. The molecular mechanisms of GLD are poorly elucidated in neural cells and whether murine systems recapitulate critical aspects of the human disease is still to be defined. Here, we established a collection of GLD patient-specific induced pluripotent stem cell (iPSC) lines. We differentiated iPSCs from two patients (bearing different disease-causing mutations) into neural progenitors cells (NPCs) and their neuronal/glial progeny, assessing the impact of GALC deficiency and lentiviral vector-mediated GALC rescue/overexpression by means of phenotypic, biochemical, molecular, and lipidomic analysis. We show a progressive increase of psychosine during the differentiation of GLD NPCs to neurons and glia. We report an early and persistent impairment of oligodendroglial and neuronal differentiation in GLD cultures, with peculiar differences observed in the two GLD lines. GLD cells display a global unbalance of lipid composition during the iPSC to neural differentiation and early activation of cellular senescence, depending on the disease-causing mutation. Restoration of GALC activity normalizes the primary pathological hallmarks and partially rescues the differentiation program of GLD NPCs. Our results suggest that multiple mechanisms besides psychosine toxicity concur to CNS pathology in GLD and highlight the need of a timely regulated GALC expression for proper lineage commitment and differentiation of human NPCs. These findings have important implications for establishing tailored gene therapy strategies to enhance disease correction in GLD.

genetics↗