Biology subjects

Monticelli, S.

Publications and source records attributed to Monticelli, S..

10 recordsLinked to original sources

bioRxiv2026

Finding the Goldilocks zone: Modulating glycoprotein cleavage and fusogenicity optimizes the efficacy of a candidate Crimean-Congo hemorrhagic fever virus vaccine

Crimean-Congo hemorrhagic fever virus (CCHFV) is the etiologic agent of a lethal hemorrhagic disease spread by ticks throughout Europe, the Middle East, Africa and Asia. The lack of approved medical countermeasures and fundamental understanding of molecular mechanisms of viral assembly and egress have thus far curtailed disease prevention. Here, we identify and characterize key residues within the viral glycoprotein through forward and reverse genetics for vesicular stomatitis virus (VSV)-based vaccine candidates that are highly protective in animal models. These residues are broadly applicable across divergent CCHFV strains and lead to greater protection in vivo against heterologous challenge. We further characterize the essential role of proteolytic processing in the maintenance of a stable fusogenic state required for effective VSV-based CCHFV vaccines. This study establishes a toolkit for better understanding orthonairovirus glycoprotein processing and vaccine development.

microbiology↗

bioRxiv2025

MYC/MAX balance dictates cell progenitor fate by altering the HOX program in the Drosophila eye

The transcription factor MYC acts canonically as heterodimer with MAX to promote growth, proliferation, and metabolic adaptation. Although MYC and MAX relative levels are normally kept in balance under physiological conditions, those levels are often dysregulated in many human cancers where MYC is overexpressed and MAX can sometimes be reduced. How altered stoichiometry of MYC/MAX can impact on cell biology is not completely understood. Using the Drosophila eye amenable to genetic modifications, we demonstrate that the relative abundance of the fly MYC ortholog dMyc and its partner dMax affect progenitor cell fate. Elevating the dMyc/dMax ratio--through dMyc or human MYCN overexpression, dMax depletion, or combined manipulations--disrupts photoreceptor differentiation and ectopically induces the thoracic HOX gene Antennapedia within the eye disc. When such a ratio is driven to an extreme degree, the change in cell fate results in eye-to-wing transdetermination. Conversely, restoring dMax levels rescues these phenotypes, demonstrating that stoichiometry, not absolute MYC levels, shapes the response. Transcriptomic profiling reveals global repression of eye-specific regulators (e.g., eyegone and prospero) and ectopic activation of wing determinants (e.g., vestigial and nubbin) while genetic interactions identify the cephalic HOX gene Deformed as a key mediator modulating MYC-dependent identity changes. Our findings uncover MYC/MAX imbalance as a developmental switch that can rewire HOX expression and reprogram progenitor identity, suggesting a conserved mechanism underlying MYC-driven cellular plasticity in cancer.

developmental biology↗

bioRxiv2025

Brain infiltrating T cells mediate microglial dysregulation and neuronal loss following SAH

The contribution of T cells to neuroinflammation after aneurysmal subarachnoid hemorrhage (SAH) remains poorly understood. Using a murine pre-chiasmatic injection model of SAH we demonstrate that T cell infiltration into the brain modulates microglial activation and promotes neuronal death. Targeted transcriptomic profiling revealed a sustained neuroimmune response at 7 days post injury (dpi) characterized by a major involvement of T cells and microglia activation. Immunohistochemistry confirmed focal CD3+ T cell infiltration, predominantly CD4+, in the brain at the site of blood injection (BI), choroid plexus and meninges in SAH mice at 3- and 7-dpi. This temporal pattern was also observed in the CSF of a human SAH cohort. T cell presence spatially correlated with regions of microglial reactivity and neuronal loss. Notably, CD3-knockout mice exhibited reduced microglial activation and preserved neuronal viability. These findings identify T cells as key amplifiers of post-SAH neuroinflammation and neuronal damage. Targeting T cell-microglia crosstalk may represent a novel therapeutic avenue for SAH. Summary statementThis study shows that brain T-cell infiltration after subarachnoid hemorrhage drives microglial activation and neuronal loss in mice, with similar patterns observed in patients. Data indicate T cells as key mediators of post-injury neuroinflammation with therapeutic implications.

neuroscience↗

bioRxiv2025

NimA promotes cell adhesion at the blood brain barrier of Drosophila nervous system

Glial cells are crucial for nervous system development and function, by clearing debris, protecting neurons, and ensuring neuronal survival. In Drosophila, glia also form the blood-brain barrier (BBB), which regulates neural stem cell proliferation and shields the nervous system while maintaining organism-wide communication. To uncover glial-specific roles, we compared their transcriptome with that of neurons and macrophages. Our study identifies NimA, an uncharacterized member of the Nimrod scavenger receptor family, as a glial-specific protein consistently expressed during development. Unlike other family members, i.e. NimC1 (macrophage-specific), Draper (shared by glia and macrophages), and NimC4/Simu (restricted to embryonic stages), NimA is not involved in phagocytosis. Instead, it regulates cell-cell interactions and adhesion, crucial for maintaining the tight septate junctions of the larval BBB. Loss of NimA compromises BBB integrity, delays development, reduces brain size and impairs neural stem cell proliferation. Altogether, the identification of a novel molecular player and more in general, of the glial-specific molecular landscape, are key to understand the contribution of glia to the construction and the function of the nervous system.

developmental biology↗

bioRxiv2024

Engineering, structure, and immunogenicity of a Crimean-Congo hemorrhagic fever virus pre-fusion heterotrimeric glycoprotein complex

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that can cause severe disease in humans with case fatality rates of 10-40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we used structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-GnH-DS-Gc). A cryo-EM structure of this complex provides the molecular basis for GP38s association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-GnH-DS-Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development.

microbiology↗

bioRxiv2024

Crosstalk between the RNA-binding proteins Regnase-1 and -3 shapes mast cell survival and cytokine expression

Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) impacts immune cell responses, including mast cell functionality. Despite their importance in immune regulation, the functional role of most RBPs remains to be understood. By manipulating the expression of specific RBPs in mast cells, coupled with mass spectrometry and transcriptomic analyses, we found that the Regnase family of proteins acts as a potent regulator of mast cell physiology. Specifically, Regnase-1 is required to maintain basic cell proliferation and survival, while both Regnase-1 and -3 cooperatively regulate the expression of inflammatory transcripts upon mast cell activation, with Tnf being a primary target of both proteins. In mast cells, Regnase-3 directly interacts with Regnase-1 and is necessary to restrain Regnase-1 expression through the destabilization of its transcript. Overall, our study identifies protein interactors of endogenously expressed Regnase factors, characterizes the regulatory interplay between Regnase family members in mast cells, and establishes their role in the control of mast cell homeostasis and inflammatory responses.

immunology↗

bioRxiv2023

Gcm alleviates the inflammatory phenotype induced by Toll activation in Drosophila hemocytes

Hemocytes, the myeloid-like immune cells of Drosophila, fulfil a variety of functions that are not completely understood, ranging from phagocytosis to transduction of inflammatory signals. We here show that downregulating the hemocyte-specific Glide/Gcm transcription factor enhances the inflammatory response to the constitutive activation of the Toll pathway. This correlates with lower levels of glutathione S transferase, suggesting an implication of Glide/Gcm in ROS signaling and calling for a widespread anti-inflammatory potential of Glide/Gcm. We show the expression of neurotransmitter receptors in hemocytes and that Toll activation affects their expressions, disclosing a novel aspect of the inflammatory response mediated by neurotransmitters. Finally, we provide evidence for acetylcholine receptor nAchRalpha6 regulating hemocyte proliferation. Altogether, this study provides new insights on the molecular pathways involved in the inflammatory response.

immunology↗

bioRxiv2022

Gcm: a novel anti-inflammatory transcriptional cascade conserved from flies to humans

Innate immunity is an ancestral process that can induce pro- and anti-inflammatory states. A major challenge is to characterise the transcriptional cascades that modulate the response to chronic and acute inflammatory challenges. The Drosophila melanogaster Gcm transcription factor represents an interesting candidate for its potential anti-inflammatory role. Here we explore its evolutionary conservation and its mode of action. We found that the murine ortholog Gcm2 (mGcm2) is expressed upon aging, which is considered as a state of chronic inflammation. mGcm2 is found in a subpopulation of microglia, the innate immune cells of the central nervous system (CNS). Its expression is also induced by a lyso-phosphatidylcholine (LPC)-induced CNS demyelination (acute inflammation) and mGcm2 conditional knock out mice show an increased inflammatory phenotype upon aging or LPC injection. In agreement with the role of this transcriptional cascade in inflammation, the human ortholog hGCM2 is expressed in active demyelinating lesions of Multiple Sclerosis (MS) patients. Finally, Drosophila gcm expression is induced upon aging as well as during an acute inflammatory response and its overexpression decreases the inflammatory phenotype. Altogether, our data show that the inducible Gcm pathway is highly conserved from flies up to humans and represents a potential therapeutic anti-inflammatory target in the control of the inflammatory response.

neuroscience↗

bioRxiv2021

IL-1α secreted by subcapsular sinus macrophages promotes melanoma metastasis in the sentinel lymph node by upregulating STAT3 signaling in the tumor.

During melanoma metastasization, tumor cells originated in the skin migrate via lymphatic vessels to the sentinel lymph node (sLN) in a process that facilitates their spread across the body. Here, we characterized the innate inflammatory responses to melanoma metastasis in the sLN. For this purpose, we confirmed the migration of fluorescent metastatic melanoma cells to the sLN and we characterized the inflammatory response in the metastatic microenvironment. We found that macrophages located in the subcapsular sinus (SSM), produce pro-tumoral IL-1 after recognition of tumor antigens. Moreover, we confirmed that the administration of an anti-IL-1 depleting antibody reduced metastasis. Conversely, the administration of recombinant IL-1 accelerated the lymphatic spreading of the tumor. Additionally, the elimination of the macrophages significantly reduced the progression of the metastatic spread. To understand the mechanism of action of IL-1 in the context of the lymph node microenvironment, we applied single-cell RNA sequencing to dissected metastases obtained from animals treated with an anti-IL-1 blocking antibody. Amongst the different pathways affected, we identified STAT3 as one of the main targets of IL-1 signaling in metastatic cells. Moreover, we found that the anti-IL-1 anti-tumoral effect was not mediated by lymphocytes, as IL-1R1 KO mice did not show any improvement in metastasis growth. Finally, we found a synergistic anti-metastatic effect of the combination of IL-1 blocking and the STAT3 inhibitor (STAT3i) stattic. In summary, we described a new mechanism by which SSM support melanoma metastasis, highlighting a new target for immunotherapy.

immunology↗

bioRxiv2018

The age-regulated zinc finger factor ZNF367 is a new modulator of embryonic neurogenesis

Global population aging is one of the major social and economic challenges of contemporary society. During aging the progressive decline in physiological functions has serious consequences for all organs including brain. The age-related incidence of neurodegenerative diseases coincides with the sharp decline of the amount and functionality of adult neural stem cells. Recently, we identified a short list of brain age-regulated genes by means of next-generation sequencing. Among them znf367 codes for a transcription factor that represents a central node in gene coregulation networks during aging but its function, in the central nervous system (CNS), is completely unknown. As proof of concept we analyzed the role of znf367 during neurogenesis. By means of a gene loss of function approach limited to the CNS, we suggested that znf367 might act as a key controller of the neuroblasts cell cycle, particularly in the progression of mitosis and spindle check-point. Using a candidate gene approach, based on a weighted-gene co-expression network analysis, we suggested possible targets of znf367 such as fancd2 and ska3. The age-related decline of znf367 well correlated with its role during embryonic neurogenesis opening new lines of investigation to improved maintenance and even repair of neuronal function.

developmental biology↗