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Studying Cryptosporidium Infection in 3D Tissue-derived Human Organoid Culture Systems by Microinjection
Published on: September 14, 2019
Cryptosporidium infection causes undernutrition and, conversely, weanling undernutrition intensifies infection
Bruna P Coutinho1, Reinaldo B Oriá, Carlos M G Vieira
1Center for Blobal Health, School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Insights
Early malnutrition in mice intensifies Cryptosporidium parvum infections, leading to severe intestinal damage and increased parasite shedding. Conversely, Cryptosporidium infection can cause undernutrition, highlighting a detrimental cycle in early life development.
Area of Science:
- Pediatric Infectious Diseases
- Gastroenterology
- Nutritional Immunology
Background:
- Cryptosporidium parvum is a major cause of diarrheal disease in young children globally, particularly in developing nations.
- Early life malnutrition is a significant public health concern, potentially impacting immune development and susceptibility to infections.
- The interplay between early-life malnutrition and the severity of Cryptosporidium parvum infections remains incompletely understood.
Purpose of the Study:
- To investigate the impact of early postnatal malnutrition on the severity of Cryptosporidium parvum infection in a murine model.
- To assess how Cryptosporidium parvum infection influences intestinal adaptation and growth in undernourished suckling mice.
Main Methods:
- Suckling mice were subjected to controlled periods of undernutrition mimicking early postnatal malnutrition.
- Mice were inoculated with Cryptosporidium parvum oocysts, and infection severity was monitored via oocyst shedding.
- Intestinal tissues were analyzed for histological changes, inflammatory markers (TNF-alpha, IFN-gamma), and gene expression.
Main Results:
- Combined malnutrition and Cryptosporidium infection resulted in the poorest growth outcomes and additive negative effects on body weight and intestinal villi.
- Undernourished infected mice exhibited significantly higher oocyst shedding and increased intestinal inflammatory responses (TNF-alpha, IFN-gamma) compared to nourished infected mice.
- Malnutrition exacerbated intestinal mucosal damage, characterized by hyperplastic crypts and heightened inflammatory responses in infected mice.
Conclusions:
- Early postnatal malnutrition intensifies Cryptosporidium parvum infection, leading to increased parasite load and more severe intestinal damage.
- Cryptosporidium parvum infection can contribute to undernutrition, creating a vicious cycle with detrimental effects on host health.
- These findings underscore the critical importance of nutritional status in modulating susceptibility and response to enteric pathogens during early development.
Abstract:
Cryptosporidium parvum is a leading pathogen in children in developing countries. To investigate whether early postnatal malnutrition leads to heavier C. parvum infections, we assessed intestinal adaptation and parasite load in suckling mice during the first 2 wk of life, analogous to the first postnatal yr in humans. Undernutrition was induced by daily C57BL6J pup separation from lactating dams. Half of the pups were separated daily, for 4 hr on day 4, 8 hr on day 5, and for 12 hr from day 6 until day 14. On day 6, each pup received an oral inoculum of 10(5) to 10(7) parasites in 10-25 microl of PBS. Littermate controls received PBS alone. Stools were assessed from days 8, 11, and 14 for oocyst counts. Mice were killed on day 14, 8 days postinoculation, at the peak of the infection. Ileal and colon segments were obtained for histology, real-time and reverse transcriptase PCR, and immunoassays. Villus and crypt lengths and cross-sectional areas were also measured. Undernourished and nourished mice infected with excysted 10(6) or 10(7) oocysts exhibited the poorest growth outcomes compared with their uninfected controls. Nourished 10(6)-infected mice had comparable weight decrements to uninfected undernourished mice. Body weight and villi were additively affected by malnutrition and cryptosporidiosis. Hyperplastic crypts and heavier inflammatory responses were found in the ilea of infected malnourished mice. Undernourished infected mice exhibited greater oocyst shedding, TNF-alpha and IFN-gamma intestinal levels, and mRNA expression compared to nourished mice infected with either 10(5) or 10(6) oocysts. Taken together, these findings show that Cryptosporidium infection can cause undernutrition and, conversely, that weanling undernutrition intensifies infection and mucosal damage.
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