Abstract
Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins—a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development.
Highlights
The Adenoviridae family contains more than 100 types of human adenoviruses (HAdVs), which are classified into seven species (A to G) based on serum neutralization and genome sequence analyses [1,2]
Assuming that the short fiber knob (SFK) of enteric HAdVs contributes to cell attachment, we first characterized the nature of HAdV-F40 SFK
Despite being a leading cause of diarrhea and diarrheaassociated mortality in young children, no cellular attachment factors have been identified for the short fibers (SF) of enteric HAdVs
Summary
The Adenoviridae family contains more than 100 types of human adenoviruses (HAdVs), which are classified into seven species (A to G) based on serum neutralization and genome sequence analyses [1,2]. HAdVF40 and -F41 are the only members of species F and are referred to as enteric human adenoviruses. They cause gastrointestinal infections primarily in children below five years of age [4,5]. The protruding fiber is needed for initial attachment to host cell receptors [8,9], followed by secondary binding of the penton base to integrins leading to internalization of the virus into the cells [10,11,12]. Sulfated glycosaminoglycans (GAGs) can act as decoy receptors for sialic acid-binding HAdV-D37, where binding of the virus to GAGs prevent efficient infection [22].
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