A newborn mouse Cryptosporidium parvum infection model: its application to the study of therapeutic and prophylactic measures for controlling cryptosporidiosis in ruminants

Martı́n-Gomez, S.; Álvarez-Sánchez, M.A.; Rojo-Vázquez, F.A.

doi:10.1007/s00436-005-0055-1

Cited by 10 publications

(6 citation statements)

References 32 publications

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“…The efficacy of pyrvinium, in comparison to that of paromomycin, was tested in a neonatal mouse model (20). Oocyst shedding by C. parvum-infected mice, as one indicator of drug efficacy, was quantified by IFA on distal colonic fecal smears made at the time of necropsy.…”

Section: Resultsmentioning

confidence: 99%

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Efficacy of Pyrvinium Pamoate against Cryptosporidium parvum Infection In Vitro and in a Neonatal Mouse Model

Downey¹,

Chong

Graczyk

et al. 2008

Antimicrob Agents Chemother

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No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients.Here we investigated the nonabsorbed anthelmintic drug pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 M paromomycin or 27 M chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of pyrvinium pamoate in vivo. Beginning 3 days after infection, pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a >90% reduction in infection intensity in pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.Cryptosporidium is an important apicomplexan protozoan pathogen that contributes significantly to diarrheal disease in both humans and animals throughout the world (9, 10, 21). In immunocompetent hosts, infections are generally restricted to the intestinal epithelium, causing an acute, self-limiting gastroenteritis. However, in AIDS patients and other immunocompromised individuals, infection can result in life-threatening, chronic diarrhea and may spread to extraintestinal locations (16,26). Although the efficacies of numerous antimicrobial agents against Cryptosporidium infection have been tested using animal and cell culture models, there is currently no reliably effective therapeutic for the treatment of chronic cryptosporidiosis in immunocompromised patients (30).Recently, nitazoxanide (NTZ), a nitrothiazole benzamide, was approved by the FDA for the treatment of cryptosporidiosis in immunocompetent adults and children aged Ͼ1 year (2). However, while clinical studies are ongoing, the efficacy of NTZ for the treatment of Cryptosporidium infection in immunocompromised patients has not yet been demonstrated (1). A 50% inhibitory concentration (IC 50 ) of 3.8 M has been reported for NTZ in cell culture (12). In a neonatal mouse model, oral administration of NTZ at 150 mg/kg of body weight reduced oocyst output to less than 5% of that seen in controls (6); however, NTZ at 100 or 200 mg/kg was ineffective at reducing parasite burdens in a SCID mouse model (24).Prior to the FDA approval of NTZ as an anti-Cryptosporidium therapeutic, the glycoside antibiotic paromomyc...

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Section: Resultsmentioning

confidence: 99%

“…Vehicle control mice received an equal volume of water. All mice were euthanized by cervical dislocation on day 9 postinfection, the time at which levels of oocyst shedding peak in infected neonatal mice, according to one study (20). To quantify oocyst shedding, fecal smears were made from 2 to 3 l of stool removed from the distal colon.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Pyrvinium Pamoate against Cryptosporidium parvum Infection In Vitro and in a Neonatal Mouse Model

Downey¹,

Chong

Graczyk

et al. 2008

Antimicrob Agents Chemother

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“…Two litters, which were born from mothers immunised intranasally with SA35/40 with LT, were infected with 10 5 oocysts and then sacrificed five [28] and nine days post-infection (p.i. ), respectively [29]. Another litter born from an intranasally immunised mother was infected with 5 × 10 3 oocysts and sacrificed at nine days p.i.…”

Section: Methodsmentioning

confidence: 99%

Delivery of SA35 and SA40 peptides in mice enhances humoral and cellular immune responses and confers protection against Cryptosporidium parvum infection

et al. 2019

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Background Cryptosporidium parvum is a major cause of diarrhea in children and ruminants at the earliest stages of life. Maternal antibodies represent the main shield of neonate mammals for most of the infections. Two recombinant antigens (SA35 and SA40), portions of two C. parvum proteins, were tested for their ability to induce immune responses in adult mice and for protection on neonate BALB/c mice born from females immunised by mucosal delivery of both peptides. Methods Adult BALB/c mice were intraperitoneally immunised with SA35 and SA40, separately or mixed, and their immune response was characterised. Furthermore, BALB/c pregnant mice were immunised by mucosal delivery with an SA35/40 mix, before and during pregnancy. Soon after birth, their offspring were infected with two doses (1 × 10 5 and 5 × 10 3 ) of C. parvum oocysts and the parasitic burden was determined at 5 and 9 days post-infection. Results Intraperitoneal immunisation with SA35 and SA40 induced specific IgG and IgG1 in serum, specific IgA in the intestinal mucosa, increase of CD3+/CD4+ and CD30+ cells in splenocytes, which produced IFN-γ. Neonates born from immunised mice and infected with 1 × 10 5 oocysts showed a significant reduction of oocysts and intestinal forms (23 and 42%, respectively). A reduction of all parasitic forms (96%; P < 0.05) was observed when neonates were infected with 5 × 10 3 oocysts. Conclusions SA35 and SA40 peptides induce specific humoral and cell-mediated immune responses to C. parvum in adult mice. Moreover, mucosal administration of the SA35/40 mix in pregnant mice reduces C. parvum burden in their litters.

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“…The detection of IgM antibodies can be useful for the diagnosis of acute cryptosporidiosis, while the detection of IgG antibodies can be effective in detecting past infection and its endemicity . Accordingly, the presence of antibodies to Cryptosporidia in the newborn mice correlates positively with the degree of their intestine purification from oocysts …”

Section: Introductionmentioning

confidence: 99%

“…newborn mice correlates positively with the degree of their intestine purification from oocysts. 8 Studies of the protective immune responses of the host against cryptosporidiosis include investigation of the adaptive cellular immunity and, in particular, require knowledge on the presence of CD4+ T cells. AIDS patients with low CD4+ T cell counts are highly susceptible to cryptosporidiosis which is accompanied by high rates of morbidity and mortality; however, after antiretroviral therapy, the partial recovery of CD4+ T cells can be observed.…”

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confidence: 99%

Natural killer cell activity irreversibly decreases after Cryptosporidium gastroenteritis in neonatal mice

Filatova

Knyazev

Skarlato

et al. 2018

Parasite Immunology

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Cryptosporidiosis causes persistent diarrhoea in infants, immunocompromised patients and elderly persons. Long-term consequences of the disease include increased risk of malignancy, cardiomyopathy and gastrointestinal inflammation. This study aimed to investigate prolonged effects of cryptosporidiosis on innate immunity and growth in neonatal C3HA mice. The disease was challenged by Cryptosporidium parvum oocyst inoculation into 7-day-old animals. The mice whose intestine smears contained 3-5 or 6 and more oocysts per microscopic field at the day 5 after infection were considered as mildly or severely infected, correspondingly. To determine natural killer cell (NK) activity, we applied H-uridine cytotoxic assay to the animals at 5-68 days after infection using K562 cells as targets. At severe infection, there was a statistically significant 1.5-2.0 fold decline of body mass, spleen mass and spleen cellularity that persisted in animals of all ages. Accordingly, NK cytotoxicity showed even more drastic drop reaching 2.7-3.0 folds that was statistically significant in all animals. At mild infection, the discovered effects were less pronounced and reached significance only in some age groups. Thus, our study provides evidence that NK cells show long-term cytotoxic activity decrease following Cryptosporidium infection in neonatal mice, particularly in severe disease.

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A newborn mouse Cryptosporidium parvum infection model: its application to the study of therapeutic and prophylactic measures for controlling cryptosporidiosis in ruminants

Cited by 10 publications

References 32 publications

Efficacy of Pyrvinium Pamoate against Cryptosporidium parvum Infection In Vitro and in a Neonatal Mouse Model

Efficacy of Pyrvinium Pamoate against Cryptosporidium parvum Infection In Vitro and in a Neonatal Mouse Model

Delivery of SA35 and SA40 peptides in mice enhances humoral and cellular immune responses and confers protection against Cryptosporidium parvum infection

Natural killer cell activity irreversibly decreases after Cryptosporidium gastroenteritis in neonatal mice

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