Biology subjects

Perin, S.

Publications and source records attributed to Perin, S..

6 recordsLinked to original sources

bioRxiv2026

Plant pathogens cleave 2′cADPR to suppress TIR immune signaling

Small molecules produced by TIR (Toll-interleukin-1 receptor) domains are essential for plant immune signaling. A central TIR-derived signal is 2'cADPR, a cyclic ADP-ribose (ADPR) molecule that is generated by plant TIR-domain proteins upon sensing pathogen infection. Here we show that XopQ, a virulence protein widespread in plant pathogenic bacteria, cleaves 2'cADPR and converts it into an inactive, linear ADPR molecule. Steady-state kinetic analyses revealed that XopQ is a highly efficient enzyme that hydrolyzes 2'cADPR with near diffusion-limited catalytic efficiency, while displaying high specificity and no detectable activity toward closely related molecules such as 3'cADPR. We show that XopQ eliminates 2'cADPR in planta and prevents accumulation of pRib-AMP, a derivative of 2'cADPR that activates the downstream immune complex EDS1-PAD4. Our data demonstrate that XopQ inhibits PAD4-dependent plant immunity and can promote pathogen virulence even when the pathogen carries an avirulence effector that triggers TIR-mediated immune signaling. Finally, we show that XopQ can also inhibit type VI Thoeris, a bacterial anti-phage defense system that relies on 2'cADPR signaling, possibly explaining why XopQ and type VI Thoeris are not observed co-occurring in bacterial genomes. Our findings uncover a widespread and conserved strategy used by plant pathogens to directly target host TIR signaling.

Plant Biology↗

bioRxiv2025

Functional and molecular rescue of aganglionic colon by human enteric nervous system progenitor transplantation in Hirschsprung disease

Hirschsprung disease (HSCR) is a devastating congenital disorder characterised by absence of the enteric nervous system (ENS) in the distal gut. Cell therapy, using human pluripotent stem cell-derived ENS progenitors, offers an attractive alternative to treat this life-limiting disorder. Here we provide an in-depth characterisation of the HSCR phenotype in the B6;129-Ednrbtm1Ywa/J mouse model including molecular analyses highlighting the wide-ranging molecular effects of aganglionosis in HSCR colon. We show that transplantation of hPSC-derived ENS progenitors leads to significant increases in contractile function with formation of extensive donor-derived neuronal networks in colonic explants. Moreover, post-transplantation, we show that integration of ENS progenitors rescues many of the biological pathways impacted in the HSCR aganglionic microenvironment. These novel results provide strong evidence that human ENS progenitor transplantation can modulate critical signalling pathways affected in HSCR and exert positive impacts on contractile function, in aganglionic tissue, supporting further translational development of this regenerative medicine approach.

cell biology↗

bioRxiv2025

Purinergic signalling and calcium dynamics: potential drivers in the onset of coordinated intestinal motility in human fetal development

Background and aimsIntestinal motility relies on inputs from multiple cells within a complex neuromuscular syncytium located in the gut wall. While it is known that motility is dependent on the development of motor patterns which govern coordinated contractile activity within the gut wall, knowledge regarding the onset of coordinated motor activity in humans is still lacking. This study assessed the emergence of coordinated motor patterns, and the molecular mechanisms underpinning developing motility, in the human fetal gut. MethodsHuman fetal gut samples (obtained via the MRC-Wellcome Trust Human Developmental Biology Resource-UK) were characterised by live imaging, spatiotemporal mapping, immunohistochemistry and RNAseq. ResultsHuman small intestinal samples displayed the presence of key cell types including enteric neurons, interstitial cells of Cajal, platelet-derived growth factor receptor alpha positive (PDGFR+) cells and smooth muscle at post conception week (PCW) 12. Between PCW12 and PCW16, functional assessment revealed a marked increase in the velocity (p= 0.0341) of propagating contractions. Subsequently, between PCW16 and PCW20 the number of contraction initiation sites reduced drastically (p=0.0053), enabling the emergence of long-distance propagating contractions. Expression analyses showed the development of coordinated motor activity was coincident with increased expression of various genes involved in calcium and purinergic signalling pathways. ConclusionsThese findings provide the first direct mechanistic evidence of the temporal development of coordinated contractile activity in the human fetal intestine, highlighting the role of calcium dynamics, purinergic signalling and interstitial cells in early stages of human motility development, potentially informing an improved understanding of the pathogenesis of gut motility disorders.

developmental biology↗

bioRxiv2025

Misregulation of the jasmonate signaling pathway leads to altered plant microbiota interaction and plant stress responses

The model plant Arabidopsis thaliana hosts diverse microbial communities collectively known as the microbiota. The plant microbiota is generally taxonomically structured. Some of the members can promote plant fitness including growth and stress tolerance. However, microbial imbalance can also result in deleterious effects, a phenomenon known as dysbiosis that was first coined in the gut microbiome field. To unveil the regulatory mechanism to maintain plant homeostatic interaction with microbiota, we performed screening using defined synthetic bacterial communities. We identified an Arabidopsis mutant with altered microbial profiles, an overall increase of microbial load and microbiota-dependent growth defects. Transcriptomic and chemical complementation analyses confirmed that the aforementioned microbiota-dependent phenotypes are contributed by an upregulation of the jasmonate signaling pathway. Upregulation of the jasmonate pathway further promotes microbial growth, possibly forming a positive feedback loop. Even though activation of the jasmonate signaling pathway is known to enhance plant stress tolerance, hyperactivation of the pathway alters plant tolerance or resistance against multiple stressors. Plant association with the microbiota together with proper regulation of the jasmonate signaling pathway are thus essential to maintain plant response to environmental stressors.

plant biology↗

bioRxiv2024

Immune regulators EDS1 and PAD4 constrain ADR1-dependent disease resistance in rice

Withdrawal StatementThe authors have withdrawn this manuscript owing to finding inconsistencies in genotyping of kitaake rice eds1 pad4 double mutant lines and to establishing that combined loss of EDS1 and PAD4 does not underlie the stunted autoimmune-like phenotype reported in this preprint. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding authors: Jane Parker, Thomas Kroj and Haitao Cui (co-corresponding)

plant biology↗

bioRxiv2020

SARS-CoV-2 infection and replication in human fetal and pediatric gastric organoids

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global public health emergency. COVID-19 typically manifests as a respiratory illness but an increasing number of clinical reports describe gastrointestinal (GI) symptoms. This is particularly true in children in whom GI symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. By contrast, fetuses seem to be rarely affected by COVID-19, although the virus has been detected in placentas of affected women. These observations raise the question of whether the virus can infect and replicate within the stomach once ingested. Moreover, it is not yet clear whether active replication of SARS-CoV-2 is possible in the stomach of children or in fetuses at different developmental stages. Here we show the novel derivation of fetal gastric organoids from 8-21 post-conception week (PCW) fetuses, and from pediatric biopsies, to be used as an in vitro model for SARS-CoV-2 gastric infection. Gastric organoids recapitulate human stomach with linear increase of gastric mucin 5AC along developmental stages, and expression of gastric markers pepsinogen, somatostatin, gastrin and chromogranin A. In order to investigate SARS-CoV-2 infection with minimal perturbation and under steady-state conditions, we induced a reversed polarity in the gastric organoids (RP-GOs) in suspension. In this condition of exposed apical polarity, the virus can easily access viral receptor angiotensin-converting enzyme 2 (ACE2). The pediatric RP-GOs are fully susceptible to infection with SARS-CoV-2, where viral nucleoprotein is expressed in cells undergoing programmed cell death, while the efficiency of infection is significantly lower in fetal organoids. The RP-GOs derived from pediatric patients show sustained robust viral replication of SARS-CoV-2, compared with organoids derived from fetal stomachs. Transcriptomic analysis shows a moderate innate antiviral response and the lack of differentially expressed genes belonging to the interferon family. Collectively, we established the first expandable human gastric organoid culture across fetal developmental stages, and we support the hypothesis that fetal tissue seems to be less susceptible to SARS-CoV-2 infection, especially in early stages of development. However, the virus can efficiently infect gastric epithelium in pediatric patients, suggesting that the stomach might have an active role in fecal-oral transmission of SARS-CoV-2.

cell biology↗