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Annual mortality rates due to infectious diarrhea are about 2.2 million; children are the most vulnerable age group to severe gastroenteritis, representing group A rotaviruses as the main cause of disease. One of the main factors of rotavirus pathogenesis is the NSP4 protein, which has been characterized as a viral toxin involved in triggering several cellular responses leading to diarrhea. Furthermore, the rotavirus protein NSP1 has been associated with interferon production inhibition by inducing the degradation of interferon regulatory factors IRF3, IRF5, and IRF7. On the other hand, probiotics such as Bifidobacterium and Lactobacillus species in combination with prebiotics such as inulin, HMO, scGOS, lcFOS have been associated with improved generalized antiviral response and anti-rotavirus effect by the reduction of rotavirus infectivity and viral shedding, decreased expression of NSP4 and increased levels of specific anti-rotavirus IgAs. Moreover, these probiotics and prebiotics have been related to shorter duration and severity of rotavirus diarrhea, to the prevention of infection and reduced incidence of reinfections. In this review we will discuss in detail about the rotavirus pathogenesis and immunity, and how probiotics such as Lactobacillus and Bifidobacterium species in combination with prebiotics have been associated with the prevention or modulation of rotavirus severe gastroenteritis. Keywords Rotavirus · Pathogenesis · Probiotics · Prebiotics

The NSP4 protein is a multifunctional protein that plays a role in the morphogenesis and pathogenesis of the rotavirus. Although NSP4 is considered an enterotoxin, the relationship between gastroenteritis severity and amino acid variations in NSP4 of the human rotavirus remains unclear. In this study, we analyzed the sequence diversity of NSP4 and the severity of gastroenteritis of children with moderate to severe gastroenteritis. The rotavirus-infected children were hospitalized before the rotavirus vaccine program in Mexico. All children had diarrhea within 14 days, 44 (88%) were vomiting and 35 (70%) had fevers. The severity analysis showed that 13 (26%) cases had mild gastroenteritis, 23 (46%) moderate gastroenteritis and 14 (28%) severe. NSP4 phylogenetic analysis showed three clusters within the genotype E1. Sequence analysis revealed similar mutations inside each cluster, and an uncommon variation in residue 144 was found in five of the Mexican NSP4 sequences. Most of the amino acid variations were located in the VP4 and VP6 binding site domains, with no relationship to different grades of gastroenteritis. This finding indicates that severe gastroenteritis caused by the rotavirus appears to be related to diverse viral or cellular factors instead of NSP4 activity as a unique pathogenic factor.

De los virus que provocan gastroenteritis, rotavirus es el principal agente causal de diarreas severas provocando la muerte de cerca 440,000 niños por año a nivel mundial. Algunos estudios señalan a las proteínas VP4, VP7 y NSP4 como factores de patogenicidad; VP4 y VP7 se involucran en procesos de ingreso del virus a la célula y en la producción de anticuerpos de neutralización; NSP4 es la única proteína descrita como enterotoxina, la cual, mediante un incremento en Ca2+ desencadena los procesos diarreicos. Hasta el momento, no se conocen los mecanismos por los cuales rotavirus puede causar una gastroenteritis severa. Por lo que el objetivo del presente trabajo es determinar si existe una correlación entre el polimorfismo de los genes que codifican para VP4, VP7 y NSP4 con los casos severos de diarrea. Se analizaron 123 muestras de heces de niños menores de 5 años colectadas de Octubre de 2004 a Marzo de 2005. La presencia del RNA característico de rotavirus se determinó a través de electroforesis en un sistema continuo. Posteriormente el RNA se sometió a RT-PCR para determinar los genotipos VP4, VP7 y NSP4. Los productos de PCR fueron desnaturalizados y sometidos a un sistema de SSCP para detectar el polimorfismo intragenotípico de las cepas de estudio y someter a una población representativa a secuencia de nucleótidos. Los resultados muestran que 64 (52%) de las cepas presentaron el modelo de migración característico de rotavirus. Con respecto a VP7 y VP4 el genotipo que predominó fue G1P[8] (34%), para NSP4 el genotipo Wa (65%) fue el que más se presentó. Por otro lado, las variaciones intragenotípicas detectadas en los genes que codifican para VP4 y VP7 mostraron tres modelos de migración y no se detectó una asociación con la severidad de la gastroenteritis. Por su parte, para NSP4, se detectaron 5 modelos de variación intragenotípica, mismos que se correlacionaron con el grado de deshidratación (P<0.05). Los análisis de secuencia de los modelo indicó variacion