Understanding the Central Nervous System Symptoms of Rotavirus: A Qualitative Review

Abstract

This qualitative review on rotavirus infection and its complications in the central nervous system (CNS) aims to understand the gut-brain mechanisms that give rise to CNS driven symptoms such as vomiting, fever, feelings of sickness, convulsions, encephalitis, and encephalopathy. There is substantial evidence to indicate the involvement of the gut-brain axis in symptoms such as vomiting and diarrhea. The underlying mechanisms are, however, not rotavirus specific, they represent evolutionarily conserved survival mechanisms for protection against pathogen entry and invasion. The reviewed studies show that rotavirus can exert effects on the CNS trough nervous gut-brain communication, via the release of mediators, such as the rotavirus enterotoxin NSP4, which stimulates neighboring enterochromaffin cells in the intestine to release serotonin and activate both enteric neurons and vagal afferents to the brain. Another route to CNS effects is presented through systemic spread via lymphatic pathways, and there are indications that rotavirus RNA can, in some cases where the blood brain barrier is weakened, enter the brain and have direct CNS effects. CNS effects can also be induced indirectly as a consequence of systemic elevation of toxins, cytokines, and/or other messenger molecules. Nevertheless, there is still no definitive or consistent evidence for the underlying mechanisms of rotavirus-induced CNS complications and more in-depth studies are required in the future.

Keywords: central nervous system; disease symptoms; enteric nervous system; gastroenteritis; gut–brain communication; rotavirus.

Figure 1

Schematic representation of possible routes by which rotavirus infection can affect the brain to give rise to central nervous system (CNS)-associated symptoms. From very early on, infection-induced released mediators like rotavirus enterotoxin nonstructural protein 4 and serotonin can activate nerves (I) that propagate the signal to the brain. In hosts suffering from malnutrition, immunosuppression, or immunodeficiency, virus/-antigen/-RNA may enter the bloodstream and/or the lymphatic system, and together with dysfunction in the blood brain barrier there is a possibility that they directly enter the brain (II) to cause less prevalent symptoms like encephalitis or encephalopathy. However, evidence that rotavirus enters the brain is lacking. Finally, infection-induced systemic elevation of rotavirus-antigens or -RNA, toxins, cytokines, and/or other messenger molecules may indirectly (III) affect the brain. Routes are not exclusive and could overlap or occur at different timepoint in the same host. Hour glasses represent time lapse post infection. Less common symptoms represented by smaller arrows and text.