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Review
. 2009 Jan;25(1):36-43.
doi: 10.1097/MOG.0b013e328317c897.

Rotavirus Vaccines and Pathogenesis: 2008

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Free PMC article
Review

Rotavirus Vaccines and Pathogenesis: 2008

Joseph M Hyser et al. Curr Opin Gastroenterol. .
Free PMC article

Abstract

Purpose of review: Rotaviruses cause life-threatening gastroenteritis in children throughout the world. The burden of disease has resulted in the development of two live, attenuated vaccines that are now licensed in many countries. This review summarizes new data on these vaccines, their effectiveness, and remaining challenges including new data on the rotavirus enterotoxin, a potential antiviral target.

Recent findings: Live attenuated rotavirus vaccines are used to protect infants against severe rotavirus-induced gastroenteritis and, RotaTeq, a pentavalent bovine-based vaccine, and, Rotarix, a monovalent human rotavirus, are now currently licensed in many countries. Initial results of the licensed RotaTeq vaccine have been promising in the USA and results of immunogenicity and efficacy in developing countries are expected soon. However, universal vaccine implementation is challenging due to age limitations on administration of these vaccines. Chronic rotavirus infections in immunocompromised children may remain a problem and require the development of new treatments including antiviral drugs. Increasing data on the mechanisms of action of the rotavirus enterotoxin highlight this pleiotropic protein as a good target as well as a unique calcium agonist.

Summary: Rotavirus is now a commonly occurring vaccine-preventable disease among children in developed countries and hopefully this also will soon be true for developing countries. Future studies will determine whether other methods of prevention, such as nonreplicating vaccines and antiviral drugs, will be needed to treat disease in immunocompromised children.

Figures

Figure 1
Figure 1
Structure and Proteins of Rotavirus. Panel A. The eleven segments of genomic double-stranded RNA are shown separated after electrophoresis on a polyacrylamide gel. Each numbered gene segment codes for at least one protein that is either a virion protein (VP) or a nonstructural (NSP) protein. The gene coding assignments are shown for the simian agent SA11. Panel B. This image shows the structure of rotavirus particles as determined by image reconstruction after cryo electron microscopy. The three concentric protein shells are seen in the cutaway and the proteins are color-coded. Different types of particles can be observed in stool samples named triple-layered particles, double-layered particles and core particles and the proteins in each type of particle are shown. Modified from [2]
Figure 2
Figure 2. Classification of iNSP4 and eNSP4 Functions
A. Upon RV infection, intracellular NSP4 (iNSP4) is synthesized in the endoplasmic reticulum (ER) as a transmembrane glycoprotein. iNSP4 induces a phospholipase C (PLC)-independent calcium leakage from the ER by an unknown mechanism and results in a sustained elevation in the intracellular calcium concentration (↑[Ca2+]i). ER-bound iNSP4 also binds VP6 on immature DLPs, facilitates (1) the budding of DLPs through the ER membrane and (2) the acquisition of the outer capsid proteins VP4 and VP7. iNSP4 that traffics to the plasma membrane is cleaved by a protease, generating the rotavirus enterotoxin, extracellular NSP4 (eNSP4). B. eNSP4 binds to integrins α1β1 or α2β1 on neighboring cells, triggering the activation of phosphoinositide-3 kinase (PI3K) and PLC. While the consequences of PI3K activation are under investigation, NSP4-induced activation of PLC leads to the production of inositol 1,4,5-trisphosphate (IP3) and IP3 receptor (IP3R)-mediated calcium release. The calcium activates chloride secretion that is independent of the CFTR channel. Chloride secretion is age-dependent, occurring in neonatal, but not adult, mice and leads to diarrhea.

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