Replication And Pathogenesis

Rotavirus was not maintained in artificial culture until it was realized that proteolytic cleavage of VP4 was required for full infectivity. Thus culture in a variety of cells including MA104 is achieved by including trypsin in the culture medium. Some rotavirus strains attach to their cellular receptor (acetylated sialic acid) via VP5*. However, recent work has shown that sulfated sialyl lipid inhibits rotavirus attachment to MA104 cells in vitro and prevents rotavirus infection in mice. Following attachment, some rotaviruses enter host cells by receptor-mediated endocytosis, but others, particularly following trypsin pretreatment, enter directly by membrane perme-abilization. Uncoating of rotavirus to release dsRNA is facilitated by low intracytoplasmic [Ca2+]. Virus replication takes place entirely in the cytoplasm. The majority of VP and NSP are synthesized on cytoplasmic ribosomes but the glycoproteins, VP7 and NSP4, are synthesized on the rough endoplasmic reticulum. Subviral particles assemble in cytoplasmic viroplasms and then, facilitated by NSP4, bud through the endoplasmic reticulum transiently acquiring a membrane. The lipid is gradually replaced by a thin protein layer which becomes the outer capsid as the virion matures. The progeny virions are then released by cell lysis.

During the peak of rotavirus replication, infants excrete up to 1011 virus particles per milliliter of stool. The infective dose is of the order of 102 virus particles. Rotavirus infects the mature villous enterocytes of the small intestine. It cannot infect immature crypt cells or colonic enterocytes. In addition to acetylated sialic acid and sulfated sialyl lipids, some human rotaviruses bind to integrins. Four mechanisms have been suggested for rotavirus-induced diarrhea.[3,4] First, within 12-24 hr following infection small intestinal brush border disac-charidase enzyme levels fall to less than one-third of normal. This is a result of rotaviral inhibition of transport of disaccharidases to the microvillar membranes. Dietary

Fig. 1 Negative stain electron micrograph of rotavirus.

Thus the rate of dying of villous enterocytes exceeds the rate of production of new enterocytes in the crypts. This results in blunting of the villi and subsequent loss of surface area for absorption of fluid, electrolytes, and nutrients. Finally, there is some evidence that rotavirus affects the intestinal neuroendocrine axis which may also contribute to diarrhea. There are suggestions that NSP4 might be involved in each of the above mechanisms.[6]

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