An Increase in Epithelial Cell Apoptosis Is Associated with Chronic Intestinal Nematode Infection

Cliffe, Laura J.; Potten, Christopher S; Booth, Catherine; Grencis, Richard K.

doi:10.1128/iai.01375-06

Cited by 51 publications

(39 citation statements)

References 56 publications

(57 reference statements)

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“…Even though ST has been shown to induce apoptosis in enterocytes (43,64), the increased mitotic events and Paneth cell numbers appear to reflect rather an increased turnover rate of the small-intestinal epithelium (26). This is in agreement with Cliffe et al, who reported on crypt hyperplasia accompanied by increased apoptosis of enterocytes in chronic infection of mice with the nematode Trichuris muris (13).…”

Section: Discussionsupporting

confidence: 82%

Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

et al. 2012

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Paneth cells residing at the base of the small intestinal crypts contribute to the mucosal intestinal first line defense by secreting granules filled with antimicrobial polypeptides including lysozyme. These cells derive from the columnar intestinal stem cell located at position 0 and the transit amplifying cell located at position ؉4 in the crypts. We have previously shown that Salmonella enterica serovar Typhimurium (ST), a leading cause of gastrointestinal infections in humans, effects an overall reduction of lysozyme in the small intestine. To extend this work, we examined small-intestinal tissue sections at various time points after ST infection to quantify and localize expression of lysozyme and assess Paneth cell abundance, apoptosis, and the expression of Paneth cell differentiation markers. In response to infection with ST, the intestinal Paneth cell-specific lysozyme content, the number of lysozyme-positive Paneth cells, and the number of granules per Paneth cell decreased. However, this was accompanied by increases in the total number of Paneth cells and the frequency of mitotic events in crypts, by increased staining for the proliferation marker PCNA, primarily at the crypt side walls where the transit amplifying cell resides and not at the crypt base, and by apoptotic events in villi. Furthermore, we found a time-dependent upregulation of first ␤-catenin, followed by EphB3, and lastly Sox9 in response to ST, which was not observed after infection with a Salmonella pathogenicity island 1 mutant deficient in type III secretion. Our data strongly suggest that, in response to ST infection, a Paneth cell differentiation program is initiated that leads to an expansion of the Paneth cell population and that the transit amplifying cell is likely the main progenitor responder. Infection-induced expansion of the Paneth cell population may represent an acute intestinal inflammatory response similar to neutrophilia in systemic infection. Innate mucosal immunity represents the first line of defense against infection by preventing microbes from crossing the gut lining and invading the bloodstream. Paneth cells, located at the base of small intestinal crypts, contribute to the mucosal defense mechanism in the small intestine through the secretion of granules filled with antimicrobial (poly)peptides such as lysozyme, phospholipase A2, defensins (called cryptdins in mice), and RegIII␥ (12,42,44,51). Lysozyme is a bimodal polypeptide of approximately 14 kDa that hydrolyzes peptidoglycan (20) and also directly disrupts membranes, similar to antimicrobial peptides (29). In mice, two lysozyme genes are transcribed (27): one in myeloid cells (M lysozyme) and one in epithelial cells, in particular Paneth cells (P lysozyme). These two lysozymes share 92% homology but differ in their net charge with P lysozyme being more positively charged than M lysozyme (37).In the small intestine, the intestinal stem cell located in the crypts gives rise to Paneth cells, as well as enterocytes, goblet cells, and enteroendocrine cells (55...

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Section: Discussionsupporting

confidence: 82%

Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

et al. 2012

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“…Total RNA from epithelial cells was isolated with the use of the previously described method 27 . cDNA was generated with the use of an IMPROM-RT kit (Promega) and Absolute QPCR SYBR Green (ABgene Epsom, Surrey, United Kingdom) was used for quantitative PCR.…”

Section: Supplementary Methodsmentioning

confidence: 99%

Mucin Gene Deficiency in Mice Impairs Host Resistance to an Enteric Parasitic Infection

et al. 2010

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Background & AimsHyperplasia of mucin-secreting intestinal goblet cells accompanies a number of enteric infections, including infections by nematode parasites. Nevertheless, the precise role of mucins in host defense in nematode infection is not known. We investigated the role of the mucin (Muc2) in worm expulsion and host immunity in a model of nematode infection.MethodsResistant (BALB/c, C57BL/6), susceptible (AKR), and Muc2-deficient mouse strains were infected with the nematode, Trichuris muris, and worm expulsion, energy status of the whipworms, changes in mucus/mucins, and inflammatory and immune responses were investigated after infection.ResultsThe increase in Muc2 production, observed exclusively in resistant mice, correlated with worm expulsion. Moreover, expulsion of the worms from the intestine was significantly delayed in the Muc2-deficient mice. Although a marked impairment in the development of periodic acid Schiff (PAS)–stained intestinal goblet cells was observed in Muc2-deficient mice, as infection progressed a significant increase in the number of PAS-positive goblet cells was observed in these mice. Surprisingly, an increase in Muc5ac, a mucin normally expressed in the airways and stomach, was observed after infection of only the resistant animals. Overall, the mucus barrier in the resistant mice was less permeable than that of susceptible mice. Furthermore, the worms isolated from the resistant mice had a lower energy status.ConclusionsMucins are an important component of innate defense in enteric infection; this is the first demonstration of the important functional contribution of mucins to host protection from nematode infection.

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“…Trichuris muris is a natural counterpart nematode that dwells in the large intestine of mice (2,3). This parasite is very similar to the human parasite, and its larvae also embed in the epithelium of the cecum, causing alterations in the homeostasis of the epithelium as well as epithelial cell hyperplasia (3,4). Different strains of mice respond to T. muris infection differently depending on the type of immune response mounted.…”

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confidence: 99%

Lactobacillus rhamnosus Ingestion Promotes Innate Host Defense in an Enteric Parasitic Infection

McClemens

Kim

Wang

et al. 2013

Clin Vaccine Immunol

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Enteric parasite infections around the world are a huge economic burden and decrease the quality of life for many people. The use of beneficial bacteria has attracted attention for their potential therapeutic applications in various diseases. However, the effects of beneficial bacteria in enteric parasitic infections remain largely unexplored. We investigated the effects of ingestion of Lactobacillus rhamnosus (JB-1) in a model of enteric nematode (Trichuris muris) infection. C57BL/6 (resistant to infection), AKR (susceptible to infection), interleukin 10 (IL-10) knockout (KO), and mucin Muc2 KO mice were infected with T. muris and treated orally with probiotic JB-1 or medium. The mice were sacrificed on various days postinfection to examine goblet cells, epithelial cell proliferation, cytokines, and worm burdens. Treatment with JB-1 significantly enhanced worm expulsion in resistant C57BL/6 mice, and this was associated with increases in IL-10 levels, goblet cell numbers, and epithelial cell proliferation. Beneficial effects of JB-1 were absent in IL-10 KO and resistant mice treated with ␥-irradiated bacteria. Live JB-1 treatment also expedited worm expulsion in Muc2 KO mice and, more importantly, in AKR mice (susceptible to infection). Injection of IL-10 directly into the colonic tissue of uninfected mice induced goblet cell hyperplasia. These findings demonstrate that JB-1 modulates goblet cell biology and promotes parasite expulsion via an IL-10-mediated pathway and provide novel insights into probiotic effects on innate defense in nematode infection.

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An Increase in Epithelial Cell Apoptosis Is Associated with Chronic Intestinal Nematode Infection

Cited by 51 publications

References 56 publications

Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

Mucin Gene Deficiency in Mice Impairs Host Resistance to an Enteric Parasitic Infection

Lactobacillus rhamnosus Ingestion Promotes Innate Host Defense in an Enteric Parasitic Infection

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