Role of TLR1, TLR2 and TLR6 in the modulation of intestinal inflammation and Candida albicans elimination

Toll-like receptors (TLRs) are the major pattern recognition receptors that mediate sensing of a wide range of microorganisms. TLR2 forms heterodimers with either TLR1 or TLR6, broadening its ligand diversity against pathogens. TLR1, TLR2 and TLR6 have been implicated in the recognition of Candida albicans, an opportunistic fungal pathogen that colonizes the gastrointestinal tract. In this study, we explored whether the deficiency in TLR1, TLR2 or TLR6 impacts C. albicans colonization and inflammation-associated colonic injury in the dextran sulfate sodium (DSS)-induced colitis in mice. DSS treatment and C. albicans challenge induced greater weight loss, worse clinical signs of inflammation, higher histopathologic scores, and increased mortality rates in TLR1(-/-) and TLR2(-/-) mice when compared to TLR6(-/-) and wild-type mice. The number of C. albicans colonies in the stomach, colon and feces was decreased in TLR6(-/-) mice as compared to TLR2(-/-), TLR1(-/-) and wild-type mice. Interestingly, the population of E. coli in colonic luminal contents, intestinal permeability to FITC-dextran and cytokine expression were significantly increased in TLR1(-/-) and TLR2(-/-) mice, while they were decreased in TLR6(-/-) mice. In contrast to TLR6, both TLR1 and TLR2 deficiencies increased intestinal inflammation, and the overgrowth of C. albicans and E. coli populations in the colitis model, suggesting the involvement of TLR1 and TLR2 in epithelial homeostasis, and a role of TLR6 in increasing intestinal inflammation in response to pathogen-sensing

How Gut Bacterial Dysbiosis Can Promote Candida albicans Overgrowth during Colonic Inflammation

Candida albicans is a commensal opportunistic yeast, which is capable of colonising many segments of the human digestive tract. Excessive C. albicans overgrowth in the gut is associated with multiple risk factors such as immunosuppression, antibiotic treatment associated with changes to the gut microbiota and digestive mucosa that support C. albicans translocation across the digestive intestinal barrier and haematogenous dissemination, leading to invasive fungal infections. The C. albicans cell wall contains mannoproteins, β-glucans, and chitin, which are known to trigger a wide range of host cell activities and to circulate in the blood during fungal infection. This review describes the role of C. albicans in colonic inflammation and how various receptors are involved in the immune defence against C. albicans with a special focus on the role of mannose-binding lectin (MBL) and TLRs in intestinal homeostasis and C. albicans sensing. This review highlights gut microbiota dysbiosis during colonic inflammation in a dextran sulphate sodium (DSS)-induced colitis murine model and the effect of fungal glycan fractions, in particular β-glucans and chitin, on the modification of the gut microbiota, as well as how these glycans modulate the immuno-inflammatory response of the host

Could Intravenous Immunoglobulin Collected from Recovered Coronavirus Patients Protect against COVID-19 and Strengthen the Immune System of New Patients?

The emergence of the novel coronavirus in Wuhan, China, which causes severe respiratory tract infections in humans (COVID-19), has become a global health concern. Most coronaviruses infect animals but can evolve into strains that cross the species barrier and infect humans. At the present, there is no single specific vaccine or efficient antiviral therapy against COVID-19. Recently, we showed that intravenous immunoglobulin (IVIg) treatment reduces inflammation of intestinal epithelial cells and eliminates overgrowth of the opportunistic human fungal pathogen Candida albicans in the murine gut. Immunotherapy with IVIg could be employed to neutralize COVID-19. However, the efficacy of IVIg would be better if the immune IgG antibodies were collected from patients who have recovered from COVID-19 in the same city, or the surrounding area, in order to increase the chance of neutralizing the virus. These immune IgG antibodies will be specific against COVID-19 by boosting the immune response in newly infected patients. Different procedures may be used to remove or inactivate any possible pathogens from the plasma of recovered coronavirus patient derived immune IgG, including solvent/detergent, 60 °C heat-treatment, and nanofiltration. Overall, immunotherapy with immune IgG antibodies combined with antiviral drugs may be an alternative treatment against COVID-19 until stronger options such as vaccines are available

In Vivo Imaging of Bioluminescent Escherichia coli in a Cutaneous Wound Infection Model for Evaluation of an Antibiotic Therapy

A rapid, continuous method for noninvasively monitoring the effectiveness of several antibacterial agents in real time by using a model of wound infection was developed. This study was divided into three steps: (i) construction of a plasmid to transform Escherichia coli into a bioluminescent variant, (ii) study of the bioluminescent E. coli in vitro as a function of temperature and pH, and (iii) determination of the MIC and the minimal bactericidal concentration of sulfamethoxazole-trimethoprim (SMX-TMP). Finally, the efficacy of SMX-TMP was monitored in vivo in a cutaneous wound model (hairless rat) infected with this bioluminescent bacterium by using a bioluminescence imaging system. E. coli was transformed by electroporation with a shuttle vector (pRB474) containing the firefly (Photinus pyralis) luciferase gene, resulting in a bioluminescent phenotype. It was found that pH 5.0 was optimal for incorporation of the susbstrate d-luciferin for the luciferase reaction. In vitro, when the agar dilution method, standard turbidity assays, and the bioluminescence imaging system were used, E. coli(pRB474) proved to be susceptible to SMX-TMP. In vivo, at 4 h, SMX-TMP treatment was already efficient compared to no treatment (P = 0.034). At 48 h, no bioluminescence was detected in the wound, demonstrating the susceptibility of E. coli to SMX-TMP. In conclusion, this study points out the advantage of using bioluminescence imaging to evaluate the effects of antibiotics for the treatment of acute infections in vivo in a nondestructive and noninvasive manner

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

International audienceInvasive fungal infections represent an expanding threat to public health. During the past decade, a paradigm shift of candidiasis from Candida albicans to non-albicans Candida species has fundamentally increased with the advent of Candida auris. C. auris was identified in 2009 and is now recognized as an emerging species of concern and underscores the urgent need for novel drug development strategies. In this review, we discuss the genomic epidemiology and the main virulence factors of C. auris. We also focus on the different new strategies and results obtained during the past decade in the field of antifungal design against this emerging C. auris pathogen yeast, based on a medicinal chemist point of view. Critical analyses of chemical features and physicochemical descriptors will be carried out along with the description of reported strategies

H89 Treatment Reduces Intestinal Inflammation and Candida albicans Overgrowth in Mice

International audienceDeregulation of the dynamic crosstalk between the gut microbiota, intestinal epithelial cells, and immune cells is critically involved in the development of inflammatory bowel disease and the overgrowth of opportunistic pathogens, including the human opportunistic fungus Candida albicans. In the present study, we assessed the effect of N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), a protein kinase A inhibitor, on the migration of macrophages to C. albicans through dextran sulphate sodium (DSS)-challenged Caco-2 cells. We also investigated the impact of H89 on intestinal inflammation and C. albicans clearance from the gut, and determined the diversity of the gut microbiota in a murine model of DSS-induced colitis. H89 reduced the migration of macrophages to C. albicans through DSS-challenged Caco-2 cells. In addition, H89 decreased C. albicans viability and diminished the expression of pro-inflammatory cytokines and innate immune receptors in macrophages and colonic epithelial Caco-2 cells. In mice with DSS-induced colitis, H89 attenuated the clinical and histological scores of inflammation and promoted the elimination of C. albicans from the gut. H89 administration to mice decreased the overgrowth of Escherichia coli and Enterococcus faecalis populations while Lactobacillus johnsonii populations increased significantly. Overall, H89 reduced intestinal inflammation and promoted the elimination of C. albicans from the gut

Role of Bacteria-Derived Exopolysaccharides in Inflammatory Bowel Disease with a Special Focus on Cyanobacterial Exopolysaccharides

International audienceInstances of inflammatory bowel disease (IBD), a chronic inflammatory condition of the gastrointestinal tract, are rapidly increasing in western and newly industrialized countries. Exopolysaccharides (EPSs) are one of the strategies to enhance the gut microbiota and modulate the immune-inflammatory response deregulation in IBD patients. EPSs are produced by commensal bacteria such as Lactobacillus and Bifidobacterium. Additionally, Cyanobacteria species are promising sources of novel EPS and have potential pharmaceutical and therapeutic applications. The presence of uronic acids and sulphate groups in Cyanobacterial EPSs is an important factor that gives EPSs an anionic charge that is not seen in other prokaryotic species. This feature may impact their physico-chemical characteristics and biological properties. Additionally, Cyanobacterial EPSs have a wide range of biotechnological applications that include use as thickeners, stabilizers, and gelling agents in the food and pharmaceutical sectors. The present review focuses on the role of EPSs in IBD, with a special focus on EPSs derived from Cyanobacteria. This review also covers the biological properties of Cyanobacterial EPS in immuno-inflammatory responses and against pathogens as well as its role in biotechnological applications. Overall, Cyanobacterial EPSs have therapeutic potential against IBD due to their anti-inflammatory and immunoregulatory properties that can reduce inflammation and regulate the immune response and restore the gut microbiota of patients

Antifungal Properties of Hydrazine-Based Compounds against <i>Candida albicans</i>

Candida albicans, an opportunistic yeast, is the most common cause of fungal infection. In the past decade, there has been an increase in C. albicans resistance to existing antifungal drugs, which has necessitated the development of new antifungal agents. In the present study, screening 60 compounds from the JUNIA chemical library enabled us to explore an additional 11 hybrid compounds that contain pyrrolidinone rings and hydrazine moieties for their potential antifungal activities. This chemical series was identified with fair to excellent antifungal activities. Among this series, three molecules (Hyd.H, Hyd.OCH3, and Hyd.Cl) significantly reduced C. albicans viability, with rapid fungicidal activity. In addition, these three compounds exhibited significant antifungal activity against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. Hyd.H, Hyd.OCH3, and Hyd.Cl did not show any cytotoxicity against human cancer cell lines up to a concentration of 50 µg/mL and decreased Candida biofilm formation, with a significant reduction of 60% biofilm formation with Hyd.OCH3. In an infection model of Caenorhabditis elegans with C. albicans, hydrazine-based compounds significantly reduced nematode mortality. Overall, fungicidal activity was observed for Hyd.H, Hyd.OCH3, and Hyd.Cl against C. albicans, and these compounds protected C. elegans from C. albicans infection

Regulation of Innate Immune Response to Candida albicans Infections by αMβ2-Pra1p Interaction▿

Candida albicans is a common opportunistic fungal pathogen and is the leading cause of invasive fungal diseases in immunocompromised individuals. The induction of cell-mediated immunity to C. albicans is one of the main tasks of cells of the innate immune system, and in vitro evidence suggests that integrin αMβ2 (CR3, Mac-1, and CD11b/CD18) is the principal leukocyte receptor involved in recognition of the fungus. Using αMβ2-KO mice and mutated strains of C. albicans in two models of murine candidiasis, we demonstrate that neutrophils derived from mice deficient in αMβ2 have a reduced ability to kill C. albicans and that the deficient mice themselves exhibit increased susceptibility to fungal infection. Disruption of the PRA1 gene of C. albicans, the primary ligand for αMβ2, protects the fungus against leukocyte killing in vitro and in vivo, impedes the innate immune response to the infection, and increases fungal virulence and organ invasion in vivo. Thus, recognition of pH-regulated antigen 1 protein (Pra1p) by αMβ2 plays a pivotal role in determining fungal virulence and host response and protection against C. albicans infection