Age-Dependent TLR3 Expression of the Intestinal Epithelium Contributes to Rotavirus Susceptibility

Pott, Johanna; Stockinger, Silvia; Torow, Natalia; Smoczek, Anna; Lindner, Cornelia; McInerney, Gerald M.; Bäckhed, Fredrik; Baumann, Ulrich; Pabst, Oliver; Bleich, André; Hornef, Mathias W.

doi:10.1371/journal.ppat.1002670

Cited by 153 publications

(169 citation statements)

References 40 publications

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“…We could confirm the low transcriptional activity of TLR3 in whole organ intestinal samples of neonatal mice, which was not upregulated after pIC treatment either (Supplementary Figure S2 online). In contrast, it was previously shown that intestinal immune cells, such as macrophages, are not affected by this downregulation (28). Intestinal permeability (breastfed: n = 5, formula only, formula + pIC, and formula + LPS each n = 4).…”

Section: Discussionmentioning

confidence: 79%

“…injection of pIC (30 µg/g body weight (BW)) into adult mice induces mucosal injury in a TLR3-dependent manner and proposed a TLR3 dependency in the pathogenesis of viral gastrointestinal infections. In contrast, Pott et al (28) showed a reduced expression of TLR3 in the intestinal epithelium of neonatal mice as well as pediatric human small intestinal biopsies compared with adults. We could confirm the low transcriptional activity of TLR3 in whole organ intestinal samples of neonatal mice, which was not upregulated after pIC treatment either (Supplementary Figure S2 online).…”

Section: Discussionmentioning

confidence: 86%

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The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

Ginzel

Klemann

et al. 2015

Pediatr Res

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Background: Necrotizing enterocolitis (NEC) is a lifethreatening gastrointestinal disease in premature infants with high mortality and morbidity with uncertain pathogenesis. Recent research focused on the role of intraluminal bacteria and lipopolysaccharide (LPS). However, an additional role of viral agents in the pathogenesis of NEC has recently been postulated. We assessed the role of polyinosinic:polycytidylic acid (pIC) mimicking viral dsRNA in contributing to the development of NEC in neonatal mice. Methods: Four-d-old C57BL/6J pups were stressed by asphyxia and hypothermia twice daily. Animals were either fed by formula only (FO), formula containing LPS or pIC. After 72 h, mice were euthanized, intestines harvested, and the severity of NEC was assessed. results: Breastfed mice showed no evidence of NEC. Very mild NEC-like lesions were observed in mice fed by FO. Supplementation of LPS or pIC to the formula led to increased intestinal tissue damage and inflammation compared with FO in a similar manner. conclusion: Our study demonstrates the ability of viral factors to induce NEC in neonatal mice even in the absence of LPS. Furthermore, we present a new mouse model of pIC-induced NEC which may be used to obtain further mechanistic insights in the pathogenesis of this disease.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 86%

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

Ginzel

Klemann

et al. 2015

Pediatr Res

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“…Adult mice deficient in TLR--3 or the adaptor molecule had significantly higher viral shedding and decreased epithelial expression of proinflammatory and antiviral genes as compared to wild--type animals. In contrast, neonatal mice with the same deficiencies did not display these features, but increase of TLR--3 expression was observed over time and may be related to the age--dependent susceptibility to rotavirus infection 38 .…”

Section: Inflammatory Response To Rotavirus Infectionmentioning

confidence: 87%

“…Moreover, TLR--3 has been associated with rotavirus susceptibility, viral shedding and histological damage upregulation of epithelial TLR3 expression during infancy might contribute to the age--dependent susceptibility to rotavirus infection 38 . Adult mice deficient in TLR--3 or the adaptor molecule had significantly higher viral shedding and decreased epithelial expression of proinflammatory and antiviral genes as compared to wild--type animals.…”

Section: Inflammatory Response To Rotavirus Infectionmentioning

confidence: 99%

Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Hagbom¹

2015

Linköping University Medical Dissertations

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Rotavirus infections cause diarrhea and vomiting that can lead to severe dehydration. Despite extensive tissue damage and cell death, the inflammatory response is very limited. The focus of this thesis was to study pathophysiological mechanisms behind diarrhea and vomiting during rotavirus infection and also to investigate the mechanism behind the limited inflammatory response. An important discovery in this thesis was that rotavirus infection and the rotavirus toxin NSP4 stimulate release of the neurotransmitter serotonin from intestinal sensory enterochromaffin cells, in vitro and ex vivo. Interestingly, serotonin is known to be a mediator of both diarrhea and vomiting. Moreover, mice pups infected with rotavirus responded with central nervous system (CNS) activation in brain structures associated with vomiting, thus indicating a cross-talk between the gut and brain in rotavirus disease. Our finding that rotavirus infection activates the CNS led us to address the hypothesis that rotavirus infection not only activates the vagus nerve to stimulate vomiting, but also suppresses the inflammatory response via the cholinergic anti-inflammatory pathway, both of which are mediated by activated vagal afferent nerve signals into the brain stem. We found that mice lacking an intact vagus nerve, and mice lacking the α7 nicotine acetylcholine receptor (nAChR), being involved in cytokine suppression from macrophages, responded with a higher inflammatory response. Moreover, stimulated cytokine release from macrophages, by the rotavirus toxin NSP4, could be attenuated by nicotine, an agonist of the α7 nAChR. Thus, it seems most reasonable that the cholinergic anti-inflammatory pathway contributes to the limited inflammatory response during rotavirus infection. Moreover, rotavirus-infected mice displayed increased intestinal motility at the onset of diarrhea, which was not associated with increased intestinal permeability. The increased motility and diarrhea in infant mice could be attenuated by drugs acting on the enteric nervous system, indicating the importance and contribution of nerves in the rotavirus mediated disease. In conclusion, this thesis provides further insight into the pathophysiology of diarrhea and describe for the first time how rotavirus and host cross-talk to induce the vomiting reflex and limit inflammation. Results from these studies strongly support our hypothesis that serotonin and activation of the enteric nervous system and CNS contributes to diarrhea, vomiting and suppression of the inflammatory response in rotavirus disease

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“…Rotaviruses are also important causes of diarrhea in animals and can manifest in 65 different disease severity depending on the age of the animals (Ciarlet et al, 2002; Neog et al, 66 2011;Pott et al, 2012;Riepenhoff et al, 1982). Although pigs of all ages are susceptible to 67 rotavirus infection, neonatal and even post-weaned piglets are frequently infected (Bohl et al, 68 1982;Lecce 1978).…”

mentioning

confidence: 99%

Molecular characterization of porcine rotavirus C in pigs with gastroenteritis in Thailand, 2011 – 2016

Tuanthap

Phupolphan

Luengyosluechakul

et al. 2018

Preprint

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Swine are economically important food animals, but highly contagious enteric viruses can affect entire swine herds and contribute significantly to piglet morbidity and mortality. The most frequent viruses associated with pig gastroenteritis have been reported as porcine epidemic diarrhea virus (PEDV) and rotavirus. Rotavirus is an important cause of diarrhea in piglets and pigs worldwide, and group A and C types are those that pig herds are mostly affected by. In Thailand, studies on rotavirus group A (RVA) have been reported continuously, whereas information on group C is still limited. In this study, we aimed to identify rotavirus group C (RVC) from the feces and intestinal contents of pigs affected with diarrhea. Seven hundred and sixty-nine samples were collected from swine herds located in difference provinces throughout Thailand. The specimens were tested using virus-specific RT-PCR to detect the gene encoding RVC capsid protein VP7 and VP4.Sequencing analyses showed that 6.6% (51/769) of samples were positive for RVC, one third of which tested as single positive for RVC (34/51). Co-infections with the most frequent enteric viruses, RVA and PEDV were also analyzed. Co-infections of RVA/RVC accounted for 21.6% (11/51) of samples and of PEDV/RVC for 7.8% (4/51) of samples, while three samples (5.9%) tested positive for all three viruses. Infections were not associated with seasonality, since the virus was detected throughout the year. RVC was detected in pigs up to 8 weeks old. Analysis of the partial VP7 gene sequences was suggestive that the predominant genotype was G1, which was closely related to the Swine are economically important food animals, but highly contagious enteric viruses 33 can affect entire swine herds and contribute significantly to piglet morbidity and mortality. The 34 most frequent viruses associated with pig gastroenteritis have been reported as porcine epidemic 35 diarrhea virus (PEDV) and rotavirus. Rotavirus is an important cause of diarrhea in piglets and 36 pigs worldwide, and group A and C types are those that pig herds are mostly affected by. In 37 Thailand, studies on rotavirus group A (RVA) have been reported continuously, whereas 38 information on group C is still limited. In this study, we aimed to identify rotavirus group C 39 (RVC) from the feces and intestinal contents of pigs affected with diarrhea. Seven hundred and 40 sixty-nine samples were collected from swine herds located in difference provinces throughout 41 Thailand. The specimens were tested using virus-specific RT-PCR to detect the gene encoding 42 RVC capsid protein VP7 and VP4. Sequencing analyses showed that 6.6% (51/769) of samples 43 were positive for RVC, one third of which tested as single positive for RVC (34/51). Co-44 infections with the most frequent enteric viruses, RVA and PEDV were also analyzed. Co-45 infections of RVA/RVC accounted for 21.6% (11/51) of samples and of PEDV/RVC for 7.8% 46 (4/51) of samples, while three samples (5.9%) tested positive for all three viruses. Infections 47 were not...

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Age-Dependent TLR3 Expression of the Intestinal Epithelium Contributes to Rotavirus Susceptibility

Cited by 153 publications

References 40 publications

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

Rotavirus Disease Mechanisms Diarrhea, Vomiting and Inflammation : How and Why

Molecular characterization of porcine rotavirus C in pigs with gastroenteritis in Thailand, 2011 – 2016

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