Enteroviruses Detected in Intestinal Specimens from Children with Advanced Ileocecal Crohn’s Disease

Enteroviruses have been detected in specimens taken from all the children in a small cohort with advanced ileocecal Crohn’s disease (ICD), while no enteroviruses were detected in specimens from normal children or from children with colon obstructions not related to Crohn's disease (CD).

Advanced ileocecal Crohn’s disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 (nucleotide-binding oligomerization domain-containing protein 2) mutations. Homozygosity for a mutation in NOD2 increases the risk of the disease by a factor of 20 to 40. NOD2 encodes an intracellular protein that contains two caspase-recruitment domains, a nucleotide-binding domain, and 10 leucine-rich sequence repeats in the C-terminal region.

In addition to its relation to CD, recent findings have indicated a role for NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. Since the role of viruses in CD was unknown, a multidisciplinary team of Swedish investigators hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD.

The research team, which included pediatricians, pathologists, virologists, molecular biologists, cell biologists and geneticists, worked with resections and biopsy specimens from a group comprising nine children with advanced, stricturing ICD, six patients with volvulus (abnormal twisting of the intestine causing obstruction), and 15 CD patients. The investigators used immunohistochemistry and in situ hybridization to demonstrate the presence of HEV-B and of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus.

Results showed that all patients with ICD had disease-associated polymorphisms in NOD2 or ATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia.

The common presence of HEV-B in the mucosa and enteric nervous system of the ICD patients in this small cohort was a novel finding that the investigators considered warranting further investigation to analyze whether HEV-B had a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provided a possible route of entry for CBV into the enteric nervous system.

Senior author Dr. Alkwin Wanders, associate professor of medicine at Uppsala University (Sweden) said, "This unique composition [of researchers], with complementary clinical and scientific expertise, has been extremely fruitful for our studies. Enterovirus could be thought to be stored in nerve cells in the intestine and to spread to different parts of the intestine via nerve fibers. This would explain both the fact that the disease is periodic and the fact that it often affects multiple segments of the intestines."

The study was published in the June 27, 2013, online edition of the journal Clinical and Translational Gastroenterology.

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