Human Lactobacillus sp strain GG (Lactobacillus GG) administered during acute rotavirus diarrhea has been shown to promote clinical recovery. To elucidate the immune mechanisms behind such a favorable outcome, the ELISPOT (solid phase enzyme-linked immunospot) assay of Ig- and specific antibody-secreting cells among circulating lymphocytes was used, giving indirect evidence of the immunologic events in the gut. After rehydration, 39 children with acute rotavirus diarrhea, mean age 16 (SD 6) mo, randomly received either a Lactobacillus GG fermented milk product (study group) or a pasteurized yogurt (placebo group). The duration of diarrhea was significantly shorter in the study group than in the placebo group [mean 1.1 (SD 0.6) versus 2.5 (SD 1.4)d, p = 0.001]. Lactobacillus GG therapy was associated with a significantly enhanced nonspecific humoral response during the acute phase of the infection, reflected in the IgG, IgA, and IgM Ig-secreting cell numbers. At convalescence, 90% of the study group versus 46% of the placebo group had developed an IgA specific antibody-secreting cell response to rotavirus (p = 0.006). The results indicate that Lactobacillus GG promotes recovery from rotavirus diarrhea via augmentation of the local immune defense. Furthermore, specific IgA response to rotavirus is endorsed, which is possibly relevant in protection against reinfections.

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Enhancement of the circulating antibody secreting cell response in human diarrhea by a human Lactobacillus strain.

Rotaviruses are responsible for significant gastrointestinal disease, primarily in children <5 years of age and the young of other mammalian species. Each year rotaviruses cause approximately 111 million episodes of gastroenteritis in children, which result in 25 million visits to clinics, 2 million

Pathogenesis of Intestinal and Systemic Rotavirus Infection

Biliary atresia: Current concepts and research directions. Summary of a symposium

The effect of viable or heat inactivated human Lactobacillus casei strain GG on rotavirus immune responses in patients with rotavirus diarrhoea was assessed. Rotavirus serum IgA enzyme immunoassay antibody responses were higher in infants treated with viable L casei strain GG than in those treated with inactivated L casei strain GG. There was a significant difference at convalescence with rotavirus specific IgA secreting cells found in 10/12 infants receiving viable but only 2/13 infants receiving inactivated L casei strain GG. The results indicate that viable L casei strain GG stimulate rotavirus specific IgA antibody responses, theoretically significant in the prevention of reinfections.

https://adc.bmj.com/content/archdischild/72/1/51.full.pdf

Viable versus inactivated lactobacillus strain GG in acute rotavirus diarrhoea.

Neonatal cholestatic disorders are a group of hepatobiliary diseases occurring within the first 3 months of life. Bile flow is impaired, and patients have conjugated hyperbilirubinemia, acholic stools, and hepatomegaly. Overall, 1 in 2,500 live births is affected with a neonatal cholestatic disorder (1). The two most common causes of neonatal cholestasis are biliary atresia and idiopathic neonatal hepatitis, accounting for up to 50% to 70% of cases. Other causes include a variety of neonatal infections (viral, toxoplasmosis, syphilis, bacterial), metabolic and genetic diseases, progressive familial intrahepatic cholestatic disorders (PFIC), paucity of interlobular bile duct disorders (e.g., Alagille syndrome), choledochal cyst, ischemia–reperfusion injury, association with parenteral nutrition administration, and other conditions (Table 1). Despite clinical improvement after the portoenterostomy procedure, approximately 70% to 80% of children with biliary atresia will eventually require liver transplantation; thus, biliary atresia alone accounts for almost 50% of all liver transplants performed in children (1). It should be noted that $77 million is spent each year in the United States on liver transplantation for children and the ensuing hospitalizations (2). This sum of money covers 0.2% of total health care expenditures related to children, even though these children represent 0.0006% of the total pediatric population. Importantly, this disproportionate expenditure for liver transplantation in children could be cut in half if improved therapies for biliary atresia were developed that could abrogate or further delay the need for liver transplantation. Remarkably, little is known about the etiopathogenesis of biliary atresia; consequently, there has been slow progress in developing improved therapies or preventative strategies during the past decade. The purpose of this review is to summarize recent advances in the diagnosis and management of biliary atresia, examine the clinical outcome, describe the evolving theories of the etiology and pathogenesis of this disorder, and highlight gaps in our current knowledge.

Pathogenesis and outcome of biliary atresia : current concepts

Extrahepatic biliary atresia is a devastating disease occurring in 1 in 10,000 to 14,000 infants annually in the United States. We have recently described preliminary data suggesting an association of group C rotavirus with biliary atresia in two infants. However, a group C rotavirus animal model of biliary atresia is not presently available. On the other hand, some strains of the better-characterized and much more common group A rotaviruses produce hepatobiliary disease in infant mice. This disease shares many characteristics of the human infection. The present report describes extrahepatic biliary obstruction in immunocompetent BALB/c infant mice infected with a human or animal strain of group A rotavirus. Two-d-old BALB/c mice orally inoculated with hepatobiliary tropic rotavirus were shown to have active virus replication in the biliary tract and liver as early as 48 h postinoculation. At approximately 7 d postinoculation, between one fourth and one half of infant mice, depending on the virus strain, showed signs of inflammation and swelling in the bile ducts. The obstruction was complete in about one half of symptomatic animals. Although there was no obvious atresia as described in human infants, the obstruction was irreversible about 50% of the time, and the resulting fibrosis and bile ductular proliferation in the liver were strikingly similar to those seen in the liver of the human infant with biliary atresia.

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Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice.

The pathogenic profiles of two heterologous animal rotaviruses, rhesus rotavirus strain MMU 18006 and bovine rotavirus strain WC3, were evaluated in mice with severe combined immunodeficiency (SCID mice) and normal BALB/c mice. Control animals were inoculated with homologous murine strain EDIM 5099 or a tissue culture-adapted murine rotavirus. Heterologous infection with rhesus rotavirus resulted in hepatitis in 84% of SCID and 21% of BALB/c mice, with mortality rates of 27 and 0%, respectively. Surviving SCID animals developed chronic liver disease, while symptoms in BALB/c mice resolved in 2 to 4 weeks after onset. Histopathologic examination revealed a diffuse hepatitis with focal areas of parenchymal necrosis. Rotavirus was detected in liver tissue from 100% of 29 SCID and 85% (11 of 13) BALB/c animals tested by cell culture infectivity, immunofluorescence, or electron microscopy. No extramucosal spread of virus or hepatitis was observed after infection with heterologous bovine strain WC3 or homologous murine rotaviruses. This finding of a novel rotavirus-induced disease manifestation suggests altered tissue tropism in a heterologous host for a group of viruses previously shown to replicate exclusively in the gut mucosa. The implications of our observations suggest that in human vaccine trials utilizing heterologous rotavirus strains, special attention should be paid to children with immunodeficiency disorders, and screening for hepatic function should be included in vaccine protocols.

Extramucosal spread and development of hepatitis in immunodeficient and normal mice infected with rhesus rotavirus.

Rotaviruses are important pathogens causing severe diarrhoea in human infants and young animals. Available information on the pathogenic mechanisms of and the immune response to rotaviruses is reviewed here. Studies in our laboratory using the suckling mouse model have focused on elucidating the nature of interaction between the virus and the gut, and on the importance of T and B cell mediated immunity in protection and recovery from the disease. Our data suggest that the age dependence of mouse rotavirus (MRV) infection is related to the presence of virus-specific receptors on the enterocytes. The uptake of rotavirus antigens appears to be limited to the epithelium associated with Peyer's patches. The antigen is transported to local and regional lymph nodes. Recent studies have indicated that rotavirus infection also increases the uptake of other macromolecules in the intestine. Rotavirus-specific mucosal IgA response seems to be related to the location and magnitude of MRV antigen in the lymph follicles in different segments of the small intestine. Studies in mice with different types of immunodeficiency suggest that a specific immune response is required for complete resolution of virus infection. Several parameters of immunity to rotavirus infection have been examined and, similar to other reports, local immunity in the intestine appears to have the most important role in protection. It also has been observed that nutritional factors may be important in modifying disease. However, there are still many questions to be answered concerning the role of immunity in mediating the pathogenesis of rotavirus infection.

Ingrid Uhnoo

Papers

Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice.

Extramucosal spread and development of hepatitis in immunodeficient and normal mice infected with rhesus rotavirus.

Immunological aspects of interaction between rotavirus and the intestine in infancy.