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Infections
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Cryptosporidium parvum is a gut parasite of cattle that can be transmitted to humans via contaminated water. In non-immunocompromised people it causes self-limiting diarrhoea. However, in immunocompromised patients, chronic cholera-like diarrhoea results, with malabsorption. C. parvum infects the small and large bowel mucosae, the parasites residing in large numbers just within the enterocyte surface membrane; small intestinal villi are blunted and there is an enteritis.
Gastrointestinal and liver infections
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Many of the organisms responsible for persistent diarrhoea are sensitive to antimicrobial chemotherapeutic agents and, for many, there is randomized controlled trial evidence that their use reduces the severity and duration of the illness (Table 6.9). Cryptosporidium parvum continues to be resistant to the majority of antimicrobial agents, although paromomycin has been shown to have some efficacy in an open study.100 Recent evidence suggests that high-dose albendazole or the emerging agent, nitazoxanide, may also have a role in the treatment of C. parvum infection.101 The microsporidia have variable sensitivity to antibiotics; albendazole is effective in treating Encephalitozoon intestinalis but not Entero-cytozoon bieneusi infection,102, 103 although the latter may, in some cases, be suppressed by this agent. Other antibiotics that have been shown in small uncontrolled studies to suppress infection include atovaquone,104 furazolidone,105 furazolidone-albendazole combination106 and thalidomide.107Cyclospora cayeta-nensis infection responds promptly and predictably to trimethoprim-sulphamethoxazole.108
Waterborne and water-washed disease *
Published in Jamie Bartram, Rachel Baum, Peter A. Coclanis, David M. Gute, David Kay, Stéphanie McFadyen, Katherine Pond, William Robertson, Michael J. Rouse, Routledge Handbook of Water and Health, 2015
Examples of highly infectious faecal–oral pathogens that have a high probability of causing infection and possibly illness from a very low dose (as few as one ingested microorganism) are the human noroviruses and rotaviruses. For these viruses the 50 per cent infectious doses (doses for which the probability of infection are about 50:50 or 50 per cent based on human volunteer studies) are perhaps one or a few virus particles (Ward et al., 1986; Teunis et al., 2008). Other faecal–oral microorganisms with relatively high infectivity (high probability of infection at relatively low doses) are some strains of the protozoan parasite Cryptosporidium parvum and some enteric bacteria that cause dysentery, such as Shigella species and enterohemorrhagic strains of Escherichia coli, for which 50 per cent infectious doses are in the range of 10–100 microorganisms. In contrast, some other faecal–oral pathogens are relatively low in infectivity, such as certain species of Salmonella bacteria, for which the 50 per cent infectious doses for different species are >1000 microorganisms based on human volunteer studies (Teunis et al., 1996; Haas et al., 1999). However, compilation of data from careful and timely epidemiological investigations of foodborne and waterborne outbreaks suggest that some species and strains of Salmonella are infectious and have the potential to cause disease at relatively low doses of between 10 and 100 microorganisms (Food and Drug Administration, 2012).
Treatment of cryptosporidiosis: nitazoxanide yes, but we can do better
Published in Expert Review of Anti-infective Therapy, 2023
Maria A. Caravedo, A. Clinton White
Cryptosporidiosis is caused by members of the genus Cryptosporidium, which are intracellular protozoans that cause enteric disease worldwide [1] While there are over 40 species, including a wide range that can infect people, most human disease is caused by Cryptosporidium hominis and Cryptosporidium parvum [2] It was initially recognized as a public health problem in populations with T-cell dysfunction, such as patients with HIV/AIDS, severe combined immunodeficiency, and malnourished children, in whom cryptosporidiosis can have a prolonged and severe course, leading to high mortality. During the past decades, the number of cases in AIDS patients has dramatically decreased. However, cryptosporidiosis has emerged as an increasing problem in patients with iatrogenic immunosuppression including solid and stem cells transplantation and CAR-T therapy [3–5] In addition, a number of defects of the innate immune response are emerging as risk factors for cryptosporidiosis in children with congenital immunodeficiencies including defects of CD40 ligand (also termed hyper IgM syndrome), IL-21 receptor alterations, and dedicator of cytokinesis 8 (DOCK8) defects [6–8]
Phenotypic screening techniques for Cryptosporidium drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Melissa S. Love, Case W. McNamara
The first cell-based high-throughput screening assay for Cryptosporidium parvum was reported in 2013 by Bessoff et al. [62]. The authors built upon previous techniques and married them together to create a 384-well imaging-based assay. In brief, C. parvum oocysts were excysted and added to HCT-8 cells and treated over a 48-hour period before being fixed and imaged to determine parasite growth inhibition. Cell-based imaging assays often rely on antibodies for labeling specific cell types or features, but commercially available antibodies against Cryptosporidium have been severely limited; the authors of this study creatively took advantage of a lectin that binds to the N-acetyl-D-glucosamine (GlcNAc) present on the surface of Cryptosporidium and selectively labels the parasites but not the host cells [63,64]. Though not trivial and requiring specialized imaging equipment, microplate washing and dispensing capabilities, the assay is reproducible and allows for the concomitant assessment of both parasite and host cell growth. The authors developed this assay to screen the NIH Clinical Collections (727 FDA-approved drugs or drug-like compounds) and the MMV Open Access Malaria Box (400 compounds), which namely resulted in the identification of itavastatin, a cholesterol-lowering medication that inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase, a rate-limiting enzyme in the mevalonate pathway, and MMV665917, an antimalarial compound with unknown mechanism of action [47,65].
Repurposing existing drugs: identification of irreversible IMPDH inhibitors by high-throughput screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Albertus Eka Yudistira Sarwono, Shinya Mitsuhashi, Mohammad Hazzaz Bin Kabir, Kengo Shigetomi, Tadashi Okada, Fumina Ohsaka, Satoko Otsuguro, Katsumi Maenaka, Makoto Igarashi, Kentaro Kato, Makoto Ubukata
Inhibition of Cryptosporidium parvum IMPDH (CpIMPDH) of the pathogenic protozoa C. parvum has been proposed as an antiprotozoal therapeutic strategy against the infection. The enzyme plays an important role in the streamline salvage purine nucleotide biosynthesis of the protozoa. Therefore, inhibition of the enzyme resulted in a detrimental effect to the protozoan growth. In human, IMPDH has two isoenzymes, type I and type II. Generally, human IMPDH type I (hIMPDH I) is a ubiquitous enzyme and expressed by various tissues in low level, while hIMPDH II is expressed in a rapidly multiplying cells. Inhibition of hIMPDH II, in particular, has been sought after, due to its role as a chemotherapeutic target for various purposes, such as anticancer, immunosuppressive, and antiviral therapy1–8. Therefore, this study was aimed to discover novel inhibitors for CpIMPDH and hIMPDH II, representatives of microbial and mammalian IMPDH, respectively.