Abstract
Human adenovirus (HAdV) causes infections predominantly in early childhood and the tissue tropism of specific HAdV species determines the clinical manifestation, including infections of the gastrointestinal tract, respiratory tract, and keratoconjunctivitis. Why HAdV shows such a tropism has not yet been fully elucidated, but in the intestine different mechanisms for virus entry or resistence to immune modulatory factors have been described. Recently identified antiviral strategies by interferons provide evidence about the repression of E1A and maybe even promote HAdV persistence. The presence of HAdV in a persistent status in the gut is of importance in the setting of pediatric stem cell transplant recipients where HAdV detection in stool usually preceds clinical signs and severe infections are related to mortality. The reactivation of persistent intestinal HAdV infections in these patients needs further investigation also with regard to successful therapy options. In addition, several newly identified recombinant HAdV types have been isolated from stool samples, thus raising the question of possible recombination events in the gut. In this review, intestinal HAdV infections are discussed in relation to the tissue tropism, persistence, recombination, and new in-vitro models to enhance the knowledge about virus–host interactions and support the development of new treatment approaches.
Highlights
The best-documented sites of human adenovirus (HAdV) replication and infectious virus production are the intestine, the lower airway tract, and the eyes where the virus can cause a variety of clinical manifestations ranging from mild to severe diseases [1]
The mechanisms for HAdV persistence and reactivation are unknown, antiviral mechanisms mediated by the innate immune system [11,12] might play a role in the maintenance of virus persistence [13]
This could be a possible regulation for HAdV persistence in T lymphocytes but, so far, there is no evidence for this
Summary
The best-documented sites of human adenovirus (HAdV) replication and infectious virus production are the intestine, the lower airway tract, and the eyes where the virus can cause a variety of clinical manifestations ranging from mild to severe diseases [1]. An interferon mediated repression of virus progeny production is described for epithelial cells [14] This could be a possible regulation for HAdV persistence in T lymphocytes but, so far, there is no evidence for this. Interferons promote the binding of E2F/Rb family proteins in the E1A enhancer region blocking the recruitment of the cellular GA-binding protein (GABP) transcription factor, which is necessary to initiate E1A expression This mechanism was observed in cells with an established persistent HAdV infection and the blocked virus replication could be reverted by withdrawal of IFN-γ [14]. One might speculate that the enhanced infection of the gut epithelium under immunosuppression, as it was found in pediatric HSCT-recipients [2], could be the result of increased virus replication and progeny production in intestinal lymphocytes by repressed cytokine secretion. The underlying mechanism in the intestine is so far unknown, but both immune cells and epithelial cells, capable of antigen presentation, are present in the gut
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