Biology subjects

Hurwitz, R.

Publications and source records attributed to Hurwitz, R..

7 recordsLinked to original sources

bioRxiv2025

Infection-Induced Elevation of Gut Glycosaminoglycans Fosters Microbiota Expansion in Drosophila melanogaster

While host genetics influence the composition of intestinal microbial communities, host genetic factors controlling the abundance of intestinal commensals remain to be determined. Here, we performed a genome-wide association (GWA) study in the fruit fly Drosophila melanogaster to identify host genetic variants linked to the abundance of Lactiplantibacillus plantarum - a major gut commensal of fruit flies. Our GWA study uncovered significant association between polymorphisms in genes involved in heparan sulfate synthesis and L. plantarum load. RNAi mediated knockdown of some of these genes resulted in reduced heparan sulfate synthesis and L. plantarum abundance. Mechanistically, heparan sulfate facilitates adhesion of L. plantarum to host epithelium and promotes biofilm formation. We further showed that infection induces heparan sulfate synthesis by the host via activation of the Nf-kB immune signaling cascade. Increased availability of heparan sulfate during infection results in the expansion of L. plantarum population in the gut and protection of the host from intestinal pathogens via colonization resistance. Furthermore, heparan sulfate is required for infection-induced expression of immune effectors and for prevention of intestinal dysplasia. These findings underscore heparan sulfate as a crucial modulator of intestinal homeostasis, pivotal in microbiota control, intestinal defense, and epithelial renewal.

microbiology↗

bioRxiv2023

Myeloperoxidase-dependent tyrosine halogenation potentiates alpha-defensins functions

Neutrophils are immune cells that eliminate microbes using a powerful arsenal of reactive oxygen species, hypohalous acids, proteases, and antimicrobial peptides -- yet how these cytotoxic effectors act in concert remains poorly understood. Here, we identify an unrecognized synergy between oxidative and non-oxidative neutrophil defenses. We show that myeloperoxidase-derived hypohalous acids selectively halogenate -defensins (HNP1-3) at conserved tyrosine residues. This post-translational modification occurs in both human and rat neutrophils and is prominent in diseases marked by neutrophil-rich inflammation, including cystic fibrosis, bacterial pneumonia, and Staphylococcus aureus abscesses. Halogenation increases HNP1 hydrophobicity without altering its structure, reprogramming these peptides into potent immunomodulatory mediators. Using single-cell transcriptomics and a in vivo peritonitis model, we demonstrate that halogenated HNP1s amplify immune signaling. Our analysis of the human haloproteome reveals a novel oxidative mechanism by which hypohalous acids rewire immune protein functions, uncovering an unexpected layer of cooperation between neutrophil effector systems. The discovery of halogenated HNP1s represents, to our knowledge, the first characterization of a protein halogenation that has biologically significance in human immunity.

biochemistry↗

bioRxiv2023

Resistance to host antimicrobial peptides mediates resilience of gut commensals during infection and aging in Drosophila

Resilience to short-term perturbations, like inflammation, is a fundamental feature of microbiota, yet the underlying mechanisms of microbiota resilience are incompletely understood. Here we show that Lactiplantibacillus plantarum, a major Drosophila commensal, stably colonizes the fruit fly gut during infection and is resistant to Drosophila antimicrobial peptides (AMPs). By transposon screening, we identified L. plantarum mutants sensitive to AMPs. These mutants were impaired in peptidoglycan O-acetylation or teichoic acid D-alanylation, resulting in increased negative cell surface charge and higher affinity to cationic AMPs. AMP-sensitive mutants were cleared from the gut after infection and aging-induced gut inflammation in wild-type, but not in AMP-deficient flies, suggesting that resistance to host AMPs is essential for commensal resilience in an inflamed gut environment. Thus, our work reveals that in addition to the host immune tolerance to the microbiota, commensal-encoded resilience mechanisms are necessary to maintain the stable association between host and microbiota during inflammation.

microbiology↗

bioRxiv2023

Deprivation of arginine and lysine interferes with growth of patient-derived tumor xenografts

In recent years, a novel treatment method for cancer emerged, which is based on the starvation of tumors of amino acids like arginine. The deprivation of arginine in serum is based on enzymatic degradation and can be realized by arginine deaminases like the L-amino acid oxidase found in the ink toxin of the sea hare Aplysia punctata. Previously isolated from the ink, the L-amino acids oxidase was described to oxidate the essential amino acid L-lysine and L-arginine to their corresponding deaminated alpha-keto acids. Here, we present the recombinant production and functionalization of amino acid oxidase Aplysia Punctata ink toxin (APIT). PEGylated APIT (APIT-PEG) increased the blood circulation time. APIT-PEG treatment of patient-derived xenografted mice shows a significant dose dependent reduction of tumor growth over time mediated by amino acid starvation of the tumor. Treatment of mice with APIT-PEG which lead to deprivation of arginine was well tolerated.

cancer biology↗

bioRxiv2019

SpikeInterface, a unified framework for spike sorting

Much development has been directed towards improving the performance and automation of spike sorting. This continuous development, while essential, has contributed to an over-saturation of new, incompatible tools that hinders rigorous benchmarking and complicates reproducible analysis. To address these limitations, we developed SpikeInterface, a Python framework designed to unify preexisting spike sorting technologies into a single codebase and to facilitate straightforward comparison and adoption of different approaches. With a few lines of code, researchers can reproducibly run, compare, and benchmark most modern spike sorting algorithms; pre-process, post-process, and visualize extracellular datasets; validate, curate, and export sorting outputs; and more. In this paper, we provide an overview of SpikeInterface and, with applications to real and simulated datasets, demonstrate how it can be utilized to reduce the burden of manual curation and to more comprehensively benchmark automated spike sorters.

neuroscience↗

bioRxiv2018

The Aryl Hydrocarbon Receptor senses the Henna pigment Lawsone and mediates Yin-Yang effects on skin homeostasis

As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. Tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocytes and epidermis equivalents, Lawsone exposure enhances the production of late epidermal proteins, impacts keratinocyte differentiation and proliferation, and regulates skin inflammation. To determine the potential use of Lawsone for therapeutic application, we harnessed human, murine and zebrafish models. In skin regeneration models, Lawsone interferes with physiological tissue regeneration and inhibits wound healing. Conversely, in a human acute dermatitis model, topical application of a Lawsone-containing cream ameliorates skin irritation. Altogether, our study reveals how a widely used natural plant pigment is sensed by the host receptor AhR, and how the physiopathological context determines beneficial and detrimental outcomes.

cell biology↗

bioRxiv2018

ADP heptose, a novel pathogen-associated molecular pattern associated with Helicobacter pylori type 4 secretion

The gastric pathogen Helicobacter pylori activates the NF-{kappa}B pathway in human epithelial cells via the -kinase 1 (Alpk1)-TIFA axis. We and others have previously shown that heptose 1,7-bisphosphate (HBP) acts as a pathogen-associated molecular pattern (PAMP). HBP is an intermediate of lipopolysaccharide (LPS) synthesis in H. pylori and other gram-negative bacteria. Deletion of the hldE (rfaE) gene encoding the enzyme responsible for HBP synthesis, as well as deletion of further upstream genes, causes loss of NF-{kappa}B stimulation by H. pylori, while deletion of the downstream phosphatase encoding gene gmhB does not. This has led to the conclusion that HBP is the PAMP responsible for NF-{kappa}B induction. Here, our attempts to identify HBP in lysates of H. pylori revealed surprisingly low amounts that fail to explain NF-{kappa}B activation. Instead, we identified ADP heptose, a major downstream metabolite of HdlE, as the predominant PAMP in H. pylori lysates, exhibiting [~]100-fold stronger activity compared to HBP. It therefore appears that synthesis of ADP heptose from HBP in H. pylori occurs independently of GmhB. The data lead us to conclude that ADP heptose constitutes the key PAMP, secreted via the pathogens cagPAI encoded type 4 secretion (T4SS).

microbiology↗