Broad sialic acid usage amongst species D human adenovirus

Area of Science:

• Virology
• Structural Biology
• Infectious Diseases

Background:

• Human adenoviruses (HAdV) are common pathogens, with Species D (HAdV-D) linked to gastrointestinal infections and epidemic keratoconjunctivitis (EKC).
• The precise mechanisms of HAdV-D cell entry remain poorly understood.
• Sialic acid (SA) has been implicated as a potential cellular receptor for EKC-causing HAdV-D strains.

Purpose of the Study:

• To investigate the role of sialic acid (SA) in the cell infection mechanisms of Human Adenovirus Species D (HAdV-D).
• To elucidate the structural basis of HAdV-D fiber-knob protein interactions with SA.
• To assess the contribution of SA and the coxsackie and adenovirus receptor (CAR) to HAdV-D infectivity.

Main Methods:

• Determined apo state crystal structures of seven HAdV-D fiber-knob proteins.
• Obtained crystal structures of HAdV-D25, D29, D30, and D53 fiber-knob proteins in complex with sialic acid (SA).
• Assessed infectivity of HAdV-C5 vectors displaying HAdV-D fiber-knobs after cell surface SA removal and evaluated CAR engagement.

Main Results:

• Provided high-resolution crystal structures for seven previously uncharacterized HAdV-D fiber-knob proteins.
• Revealed structural complexes of HAdV-D25, D29, D30, and D53 fiber-knobs with SA, detailing binding interactions.
• Demonstrated that reducing cell surface SA significantly decreased the infectivity of HAdV-C5 vectors pseudotyped with HAdV-D fiber-knobs.
• Observed variable dependence on both SA and the coxsackie and adenovirus receptor (CAR) for HAdV-D infectivity.

Conclusions:

• Many HAdV-D strains engage sialic acid (SA) as a key factor in their cell entry pathway.
• Structural data provides a basis for understanding SA-mediated HAdV-D tropism.
• Variable usage of SA and CAR highlights the diversity within HAdV-D and is crucial for developing targeted antivirals and engineered viral vectors.