Doctoral thesis: Sugar - friend or enemy at virus infection?

6 September 2019

Adenovirus interact with different types of glycans ("sugars"), which can either serve as functional receptors that are utilized for infection or as decoy receptors that prevent infection. These findings have been used to develop novel drugs for the treatment of severe infections of the eye. This is shown by Naresh Chandra in his doctoral thesis in virology that he will defend 20 September.

Epidemic keratoconjunctivitis (EKC) is a severe ocular disease for which no antiviral drugs are available. Globally, there are 20-30 million estimated cases of EKC reported every year. EKC-causing adenovirus type 37 (AdV-37) binds to sialic acid (SA) and glycosaminoglycans (GAGs), which are two different types of glycans.

The outcome of these interactions has not been fully understood. Naresh Chandra demonstrates in his thesis that SA-containing glycans serve as functional cellular receptors for AdV-37 and other EKC-causing AdVs, resulting in infection of corneal cells. He also shows that GAGs function as decoy receptors for these viruses. These decoys bind to incoming viruses and prevent them from binding to functional SA-containing receptors. Naresh also demonstrates that Suramin, a GAG-mimetic and an approved drug, prevents AdV-37 from infecting corneal cells.

This is the first study reporting that virus binding to cell-surface decoy receptors constitutes a target for the development of attachment inhibitors. Suramin can also be used as antiviral against other EKC-causing AdVs and GAG-binding viruses, adds Naresh. In addition, Naresh also demonstrates that unrelated AdV-3 does not bind to SA and cannot infect corneal cells, which adds insight into the molecular mechanisms that determine the tropism (cell-specificity) of different types of AdVs.

Approximately, 300 million individuals suffer from obesity, causing severe health complications. Several epidemiological studies highlighted a link between infection with another AdV type i.e., AdV-36 and obesity. Naresh Chandra and his colleagues find that AdV-36 relies on rare SA-containing glycans for attachment to cell-surface. Interestingly, analyses revealed that AdV-36 preferentially bind to SAs, containing two acetyl groups, whereas AdV-37 binds to SA with one acetyl group.

Structural analyses unveiled the preference of AdV-36 binding to two acetyl group containing SA. Interestingly, two acetyl group containing SA is not produced by humans, but are produced by e.g., cattle, and can be metabolized by humans and potentially be used as receptors by AdV-36. This is probably an important mechanism whereby AdV-36 infect human and cause obesity, Naresh says. Additional studies are needed to understand the impact of AdV-36-interaction with two acetyl group containing SA and the potential impact on human obesity.

In summary, this study provides insights into multiple roles of glycans in AdV infection cycle. This will be helpful (i) to develop glycan/glycan-mimetic-based drugs for the treatment of infections caused by glycan-binding AdV and (ii) to understand the unique pathogenicity profile and biology of AdV-36, causing obesity, a significant threat to global health.

This study was conducted using multiple, cell-based and biochemical methods, including virus-binding assays, fluorescent-based infection assays, flow cytometry, immunohistochemistry, surface plasmon resonance, and glycan array.

Naresh Chandra comes from the northern Himalayan state of India and has a Master degree in Biotechnology from Indian Institute of Technology, Roorkee, India. India. After his doctorate degree, Naresh is will pursue his career in Pharma Industry. Apart from this Naresh is interested in Social Entrepreneurship.

Read the doctoral thesis

About the public defence of the doctoral thesis
Naresh Chandra, Deopartment of Clinical Microbiology, defends on friday 20 September 9.00 o'clock his doctoral thesis Glycobiology of human adenovirus infections: implications for tropism and treatment. Faculty opponent Gunnel Halldén, Barts Cancer Institute, Queen Mary University of London, London, UK. Principal supervisor Niklas Arnberg. Place: E04, Building 6F, University Hospital, Umeå.

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