Biology subjects

Morin, C.

Publications and source records attributed to Morin, C..

6 recordsLinked to original sources

bioRxiv2023

Structure-based design of small molecule inhibitors of the cagT4SS ATPase Cagα of Helicobacter pylori

We here describe the structure-based design of small molecule inhibitors of the type IV secretion system of Helicobacter pylori. The secretion system is encoded by the{square}cag{square}pathogenicity island, and we chose Cag, a hexameric ATPase and member of the family of VirB11-like proteins, as target for inhibitor design. We first solved the crystal structure of Cag in a complex with the previously identified small molecule inhibitor 1G2. The molecule binds at the interface between two Cag subunits and mutagenesis of the binding site identified Cag residues F39 and R73 as critical for 1G2 binding. Based on the inhibitor binding site we synthesized 98 small molecule derivates of 1G2 to improve binding of the inhibitor. We used the production of interleukin-8 of gastric cancer cells during H. pylori infection to screen the potency of inhibitors and we identified five molecules (1G2_1313, 1G2_1338, 1G2_2886, 1G2_2889 and 1G2_2902) that have similar or higher potency than 1G2. Differential scanning fluorimetry suggested that these five molecules bind Cag, and enzyme assays demonstrated that some are more potent ATPase inhibitors than 1G2. Finally, scanning electron microscopy revealed that 1G2 and its derivatives inhibit the assembly of T4SS-determined extracellular pili suggesting a mechanism for their anti-virulence effect.

biochemistry↗

bioRxiv2023

C-section and systemic inflammation synergize to disrupt the neonatal gut microbiota and brain development in a model of prematurity

Infants born very preterm (below 28 weeks of gestation) are at high risk of developing neurodevelopmental disorders, such as intellectual deficiency, autism spectrum disorders, and attention deficit. Preterm birth often occurs in the context of perinatal systemic inflammation due to chorioamnionitis and postnatal sepsis (Dammann, O. and Leviton, A., Intermittent or sustained systemic inflammation and the preterm brain. Pediatr Res, 2014. 75(3): p. 376-80). In addition, C-section is often performed for very preterm neonates to avoid hypoxia during a vaginal delivery (Luca, A.,et al., Birth trauma in preterm spontaneous vaginal and cesarean section deliveries: A 10-years retrospective study. PloS one,2022, 17(10), e0275726.) We have developed and characterized a mouse model based on intraperitoneal injections of IL-1{beta} between postnatal days one and five to reproduce perinatal systemic inflammation (Favrais, G.,et al., Systemic inflammation disrupts the developmental program of white matter. Ann Neurol,2011. 70(4): p. 550-65). This model replicates several neuropathological, brain imaging, and behavioral deficits observed in preterm infants. We hypothesized that C-sections could synergize with systemic inflammation to induce more severe brain abnormalities. We observed that C-sections significantly exacerbated the deleterious effects of IL-1{beta} on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced functional connectivity in the brain relative to vaginal delivery plus intraperitoneal saline. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation on brain maldevelopment and malfunction, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders. Significance StatementIn a well-established mouse model of the encephalopathy of prematurity, we observed that C-section exacerbates the deleterious effects of neonatal systemic inflammation (intraperitoneal injections of IL-1{beta} between postnatal days one and five) on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced brain functional connectivity. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders.

neuroscience↗

bioRxiv2023

Inhibition of the type IV secretion system from antibiotic-resistant Helicobacter pylori clinical isolates supports the potential of Cagα as an anti-virulence target

Helicobacter pylori resistance to antibiotics is a growing problem and it increasingly leads to treatment failure. While the bacterium is present worldwide, the severity of the clinical outcomes is highly dependent on the geographical origin and genetic characteristics of the strains. One of the major virulence factors identified in H. pylori is the cag pathogenicity island (cagPAI), which encodes a type IV secretion used to translocate effectors into human cells. Here, we investigated the genetic variability of the cagPAI among 13 antibiotic-resistant H. pylori strains that were isolated from patient biopsies in Quebec. Seven of the clinical strains carried the cagPAI, but only four could be readily cultivated under laboratory conditions. We observed variability of the sequences of CagA and CagL proteins that are encoded by the cagPAI. All clinical isolates induce interleukin-8 secretion and morphological changes upon co-incubation with epithelial gastric cancer cells and two of them produce extracellular T4SS pili. Finally, we demonstrate that molecule 1G2, a small molecule inhibitor of the Cag protein from the model strain H. pylori 26695, reduces interleukin-8 secretion in one of the clinical isolates. Co-incubation with 1G2 also inhibits the assembly of T4SS pili, suggesting a mechanism for its action on T4SS function.

microbiology↗

bioRxiv2023

Development of a computational model to inform environmental surveillance sampling plans for Salmonella enterica serovar Typhi in wastewater

Typhoid fever - an acute febrile disease caused by infection with the bacterium Salmonella enterica serotype Typhi (S. Typhi) - continues to be a leading cause of global morbidity and mortality, especially in developing countries with limited access to safe drinking water and adequate sanitation. Environmental surveillance, the process of detecting and enumerating disease-causing agents in wastewater, enables estimating disease prevalence and trends within a community and is a useful tool to monitor the circulation of typhoid fever in endemic regions. This study presents a computational model, which combines dynamic and probabilistic modeling techniques, to predict - on a spatial and temporal scale - the probability of detecting S. Typhi in a wastewater system. This model may be utilized in communities to inform environmental surveillance sampling plans and may provide useful insight into selecting appropriate sampling locations and times.

microbiology↗

bioRxiv2022

Diffusion MR imaging in the corticospinal tract of idiopathic scoliosis

Many studies have shown that idiopathic scoliosis is not only a deformity of the spine. It is often associated with neurological impairment without any macroscopic abnormality in the brain. In our previous diffusion MRI study, we demonstrated that children with right-thoracic idiopathic scoliosis had abnormal white matter microstructure of the crossing premotor fibres in the corpus callosum. Based on this, we hypothesized that similar microstructural changes could affect the main descending white matter tracts, the corticospinal tract. We compared the fractional anisotropy values along the corticospinal tracts in ten patients with right-thoracic and ten patients with left-thoracic idiopathic scoliosis to 49 healthy controls. We found abnormal left-right asymmetry of the fractional anisotropy values in scoliosis patients at the level of the pons. Whereas at upper levels the values were similar across all groups. Our results suggest that abnormal sensorimotor integration at the level of the pons is associated with the development of idiopathic scoliosis.

neuroscience↗

bioRxiv2022

Surface motility favors co-dependent interaction between Pseudomonas aeruginosa and Burkholderia cenocepacia

Interactions between different bacterial species shape bacterial communities and their environments. The opportunistic pathogens Pseudomonas aeruginosa and Burkholderia cenocepacia both can colonize the lungs of individuals affected by cystic fibrosis. Using the social surface behavior called swarming motility as a study model of interactions, we noticed intricate interactions between B. cenocepacia K56-2 and P. aeruginosa PA14. While strain K56-2 does not swarm under P. aeruginosa favorable swarming conditions, co-inoculation with a non-motile PA14 flagellum-less {Delta}fliC mutant restored spreading for both strains. We show that P. aeruginosa provides the wetting agent rhamnolipids allowing K56-2 to perform swarming motility, while aflagellated PA14 seems able to < > along with K56-2 cells in the swarming colony. ImportancePseudomonas aeruginosa and Burkholderia cenocepacia are important opportunistic pathogens often found together in the airways of persons with cystic fibrosis. Laboratory co-culture of both species often ends with one taking over the other. We used a surface motility assay to study the social interactions between population of these bacterial species. Under our conditions, B. cenocepacia cannot swarm without supplementation of the wetting agent produced by P. aeruginosa. In a mixed colony of both species, an aflagellated mutant of P. aeruginosa provides the necessary wetting agent to B. cenocepacia, allowing both bacteria to swarm and colonize a surface. We highlight this peculiar interaction where both bacteria set aside their antagonistic tendencies to cooperate.

microbiology↗