Welcome to the ICOPA 2022 Online Program

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The intestinal Protozoan parasite Giardia sp. interacts with the intestinal surface, causing epithelial alterations, mucus layer disruptions, and gut microbiota dysbiosis. These effects occur at the site of infection and beyond. Giardia infection is a common cause of diarrheal disease, and may lead to post-infectious complications, including Irritable Bowel Syndrome. However, giardiasis can also occur in the absence of symptoms, and it appears to protect children against diarrhea in countries with poor sanitation. Here we present our recent findings generated from human tissues and human gut microbiota, as well as live rodent models. The various genotypes of Giardia isolates have different metabolomic profiles that may contribute to distinct pathophysiological effects. Our recent studies also demonstrated that the parasite directly disrupts human microbiota biofilms and induces the release of invasive bacterial pathobionts from these commensal communities. We discovered that Giardia trophozoites release extra-cellular vesicles that are able to affect proliferation and motility in commensal bacteria. Giardia cysteine proteases cleave the mucus lining of the gut, hence facilitating bacterial translocation. Our findings also demonstrate that high fat versus low fat diets may facilitate pathogenic factors in giardiasis, offering further support to the hypothesis that diet also plays a role in symptom variability. Together, these observations shed new light on the biology of infections in the gastrointestinal tract and underscore the multifactorial basis of clinical presentation variability in giardiasis. The findings point to new research directions in our attempts at the developing novel strategies to control enteric disease.

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Metronidazole (MTZ) is a clinically important antimicrobial agent that is active against both bacterial and protozoan anaerobic and microaerophilic organisms. A recent and dramatic increase in the number of MTZ resistant bacteria and protozoa is of great concern since there are few alternative drugs with a similarly broad activity spectrum. To identify key factors and mechanisms underlying MTZ resistance in the protozoan parasite Giardia intestinalis we characterized two in vitro selected, metronidazole resistant parasite lines, as well as one revertant, by analyzing fitness aspects associated with increased drug resistance, as well as changes in their genomes, transcriptomes and proteomes. We also conducted meta-analyses using already existing omicsdata from additional MTZ resistant G. intestinalis isolates. The combined data suggest that in vitro generated MTZ resistance has a substantial fitness cost to the parasite, which may partly explain why resistance is not widespread despite decades of heavy use. Mechanistically, MTZ resistance in Giardia is multifactorial and associated with complex changes, yet a core set of pathways involving reduced expression of drug-activating oxidoreductases, changed plasma membrane composition and increased intracellular oxygen levels are central to MTZ resistance in both Giardia and bacteria.

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Giardia duodenalis causes infection in humans and companion livestock and wild species. Control of clinical giardiasis relies on the use of chemotherapeutic drugs. However therapeutic failures are increasing due to secondary drug effects, suboptimal dosing in deworming campaigns and emergence of parasites resistant to used drugs. Thus there is a need to search for new agents to optimize giardiasis chemotherapy.

The completion of the Giardia genome project and the use of biochemical, molecular and bioinformatics tools allowed finding ligands/inhibitors for some tens of potential drug targets in this parasite. Further, the synthesis of second generation nitroimidazoles and benzimidazoles along with high-throughput technologies have allowed screening libraries of repurposed drugs or drugs from other collections increasing the arsenal of anti-giardial compounds to some hundreds with activity against metronidazole or albendazole-resistant Giardia. Cysteine-modifying agents such as omeprazole, disulfiram, allicin and auranofin outstand due to their pleiotropic activity based on the extensive repertoire of thiol-containing proteins and the microaerophilic metabolism of this parasite. At the clinical level the use of monotherapy with prolonged dosage and drug combinations have shed promising outcomes in pediatric and adult giardiasis patients who show failure with conventional drugs.

There is a robust group of promising agents of novel or repurposed use that require evaluation at clinical levels and be included as first- or second-line treatments. Also development of Machine Learning technologies and nanotechnology resources may allow drug discovery and increase efficacy of existing or repurposed drugs for giardiasis.

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Giardia duodenalis is a widespread protozoan parasite causing the commonest parasitic diarrheal disease-affecting humans. Although G. duodenalis infections in humans are largely asymptomatic, they often result in severe and chronic diseases and can cause post-infectious sequelae. The armamentarium of currently approved drugs for symptomatic giardiasis is still limited and restricted to compounds with a broad antimicrobial activity, often associated with severe side effect and to increasing cases of treatment-refractory giardiasis, particularly with nitroimidazoles. This scenario is alarming and poses further challenges for an effective management of giardiasis.

Aim of this lecture is to provide an overview of the current knowledge concerning alternative non-pharmacological approaches that are under development as new promising treatment for giardiasis. Alteration of the intestinal microbiota has been observed in patients with giardiasis and microbiota composition is likely responsible of failure of Giardia infection in rodents model. Modulation of the gut microbiome by the use of probiotics (microbial cell preparations or components of microbial cells) is getting attention. Probiotics (bacteria and yeasts), alone or in support to drug treatment, promote shortening/reduction of the gastrointestinal illness as well as counteract intestinal damages caused by G. duodenalis. Pre-clinical evidence suggest that probiotics can act directly against the parasite and/or promote protective response in the gut. In addition, parasite endosymbiotic viruses such as the Giardia-specific Giardiavirus possess, can have a significant impact on the parasite growth and survival. The exploitation of parasite-specific viruses as biological weapon against parasitic diseases is getting momentum In the near future Giardiavirus might offer a drug-free, cutting-edge, safe and target-specific therapy for giardiasis.