Cryptosporidium Infection Causes Undernutrition and, Conversely, Weanling Undernutrition Intensifies Infection

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 μl 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-α and IFN-γ 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.Cryptosporidiosis, first described by Tyzzer (1907) in the gastric glands of infected mice (Tzipori and Ward, 2002), has emerged as an increasingly recognized public health threat. Cryptosporidium spp. have been identified in watery diarrhea of patients with HIV and other immunocompromised patients and in large human outbreaks of diarrhea in both developed and developing parts of the world (Harp, 2003;Ramirez et al., 2004;Houpt et al., 2005). Furthermore, the long-term impact of cryptosporidial infection has been increasingly recognized in impoverished settings around the world (Checkley et al., 1997;Guerrant, 1997;Checkley et al., 1998 protozoan is adapted to survive and spread in the environment (Dillingham et al., 2002;Karanis et al., 2007).Crowded households with inadequate sanitation further aggravate the likelihood of the infection spreading from person to person (Newman et al., 1999;Caccio and Pozio, 2006). The lack of adequate treatment or prevention for high-risk groups for this chlorine-resistant food-and waterborne protozoan adds to the difficulties controlling cryptosporidial infections (Smith and Corcoran, 2004).Impoverished household environments and water contamination tremendously increase the risk of exposure to waterborne pathogen...

Persistent G. lamblia impairs growth in a murine malnutrition model

“…Although growth failure was present in nourished mice, the effect was modest and delayed relative to the more profound decrement seen in the setting of malnutrition. Counter to other enteric infections in malnutrition (32)(33)(34), this compounded effect cannot be explained by a higher burden of infection in the malnourished mice. Intriguingly, another investigation also demonstrated a relatively decreased burden of G. lamblia trophozoites in the small bowel following severe PD in mice (44).…”

“…More recently, Shukla et al showed growth impairment in BALB/c mice infected with axenic trophozoites, although infection did not worsen the growth impact of PD compared with controls (30). We have previously demonstrated that malnutrition using a low-protein (LP) diet worsens growth after infection with enteroaggregative E. coli and Cryptosporidium in both neonatal and weaned murine models (31)(32)(33)(34). We have seen from these studies that malnutrition leads to heavier infection and increased proinflammatory signaling, while infection leads to further weight faltering, thus replicating a "vicious cycle" of malnutrition and intestinal infection (31)(32)(33)(34).…”

Acid-base disorders in calves with chronic diarrhea

“…The cryptosporidial colonization of the small and large intestine results in destruction of enterocytes. Contrary to isolated bacterial or viral infections, mixed infections with C. parvum are associated with shortening of intestinal villi and persistent severe disorders of digestion and absorption (Coutinho et al 2008, Ok et al 2009). …”

“…While the diarrhea of neonatal calves is usually associated with bacterial (E. coli) or rotaviruses and coronaviruses infections, Cryptosporidium spp. seems to be the most common cause of diarrhea in older, 3-week-old animals (Coutinho et al 2008, Foster and Smith 2009, Ok et al 2009). Clinical signs of diarrhea include loose watery stools, lack of appetite and abdominal pain.…”

The Global Burden of Pediatric Cryptosporidium Infections

“…In vitro and animal studies suggest a role between infection and inflammation causing deranged immune signaling leading to enteropathy and poor growth [17][18][19]. These models, which need further validation in human studies, demonstrate that specific nutrient deprivation has a profound impact on the character and intensity of inflammation [19,20], such as an apparent bias away from Th1-type primary immune responses (Bartelt, unpublished) similar to what has been shown in malnourished children in Haiti with cryptosporidiosis [21].…”