Biology subjects

Locatelli, G.

Publications and source records attributed to Locatelli, G..

4 recordsLinked to original sources

bioRxiv2025

The "Grove-First" Framework: Starting in the Grove to Find Therapies for Huanglongbing

Citrus greening disease, also known as huanglongbing (HLB), is the most serious vector-borne bacterial disease of citrus world-wide1,2. There is an immediate global need to provide the citrus industry with relief from HLB and a return to profitable citrus production. Standard screening methods for HLB therapeutic treatments typically involve various laboratory-based assays to select treatments with antimicrobial properties3, which then advance to greenhouse and eventually field testing in a workflow that takes multiple years. Unlike traditional lab-first screening, we present a design of experiments framework4,5, referred to as Grove-First, that rapidly screens treatments with regulatory-friendly profiles in commercial citrus groves using trunk injection to select treatments that improve tree health and fruit yield over the course of a single growing season. Using this framework, we identified candidate treatments with effects comparable to or better than the standard oxytetracycline (OTC) on visual tree-health and/or yield indices in an initial screen of HLB-positive 8-year-old Valencia sweet orange trees. Expanded trials in commercial citrus groves allowed us to validate the initial screening results at other locations and in other citrus varieties. Grove-First rapidly accelerated the identification and large-scale field testing of HLB therapies, some of which are available for growers to use immediately and others that require further field testing and/or regulatory actions.

plant biology↗

bioRxiv2025

Experimental Autoimmune Encephalomyelitis Causes Skeletal Muscle Dysfunction in Mice

Multiple sclerosis (MS) is a neuroinflammatory disease affecting the brain and spinal cord and characterized by demyelination, neurodegeneration and chronic inflammation. More than 90% of people with MS present with peripheral muscle dysfunction and a progressive decline in mobility. Current treatments attenuate the inflammatory processes but do not prevent disease progression. Therefore, there remains an unmet medical need for new and/or additional therapeutic approaches that specifically improve muscle function in this patient population. The development of novel treatments targeting skeletal muscle dysfunction in MS will depend on suitable preclinical models that can mimic the human musculoskeletal manifestations of MS. Using a non-invasive approach to assess muscle function, we demonstrate in vivo that Experimental Autoimmune Encephalomyelitis (EAE) impairs skeletal muscle strength. Our data reveal a 28.3% (p<0.0001) lower muscle force in animals with EAE compared to healthy control mice during electrically evoked tetanic muscle contractions that occur at intervals of 0.25 seconds and thus mimic fatiguing tasks. As we conduct force measurements by direct transcutaneous muscle stimulation in anesthetized animals, our setup allows for the repeated evaluation of muscle function, and in the absence of primary fatigue or reduced nerve input which constitute important confounding factors in MS. Taken together, our data highlight important similarities between MS in humans and EAE in mice with regards to skeletal muscle contractile impairments, and provide first evidence for a non-invasive in-vivo setup that will enable the preclinical profiling of novel drug candidates directed at specifically improving muscle function in MS.

physiology↗

bioRxiv2023

Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions

Inflammation in the central nervous system (CNS) can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

neuroscience↗

bioRxiv2020

Monocyte recruitment to the inflamed central nervous system: migration pathways and distinct functional polarization

The central nervous system (CNS) parenchyma is enclosed by anatomical interfaces including multilayered meninges, the blood-brain barrier (BBB), the choroid plexuses within ventricles and the glia limitans. These border areas hold distinct functional specializations which control the trafficking of monocyte-derived cells toward the CNS parenchyma, altogether maintaining CNS homeostasis. By crossing activated endothelial, epithelial and glial borders, circulating leukocytes gain however access to the CNS parenchyma in several inflammatory diseases including multiple sclerosis. Studies in animal models of neuroinflammation have helped describing the phenotypic specifications of these invading monocyte-derived cells, able to exert detrimental or beneficial functions depending on the local environment. In this context, in vivo visualization of iNOS+ pro-inflammatory and arginase-1+ anti-inflammatory macrophages has recently revealed that these distinct cell phenotypes are highly compartmentalized by CNS borders. While arginase-1+ macrophages densely populate the leptomeninges, iNOS+ macrophages rather accumulate in perivascular spaces and at the pia mater-CNS parenchymal interface. How and where these macrophages acquire their functional commitment, and whether differentially-activated monocyte-derived cells infiltrate the CNS through distinct gateways, remains however unclear. In this study, we have investigated the interaction of monocyte-derived macrophages with endothelial (BBB) and epithelial (choroid plexus) barriers of the CNS, both in vitro and in vivo. By using primary mouse brain microvascular endothelial cells as in vitro model of the BBB, we observed that, compared to unpolarized primary macrophages, adhesion of functionally-committed macrophages to endothelial cells was drastically reduced, literally abrogating their diapedesis across the BBB. Conversely, when interacting with an activated choroid plexus epithelium, both pro- and anti-inflammatory macrophages displayed substantial adhesive and migratory properties. Accordingly, in vivo analysis of choroid plexuses revealed increased macrophage trafficking and a scattered presence of polarized cells upon induction of anti-CNS inflammation. Altogether, we show that acquisition of distinct macrophage polarizations significantly alters the adhesive and migratory properties of these cells in a barrier-specific fashion. While monocytes trafficking at the level of the BBB seem to acquire their signature phenotype only following diapedesis, other anatomical interfaces can be the entry site for functionally activated monocyte-derived cells. Our study highlights the choroid plexus as a key access gateway for macrophages during neuroinflammation, and its stroma as a potential priming site for their functional polarization.

immunology↗