Research Highlights

Proteoglycans: A sweet treat for adenovirus attachment

HSPGs function as co-receptors for growth factors and their receptor tyrosine kinases, which are present either on the same cell or on adjacent cells. Figure taken from Nature 446, 1030–1037 (26 April 2007).

Adenoviruses are best known for causing respiratory illnesses and some specific serotypes also cause gastroenteritis and conjunctivitis. Adenoviruses are known to hijack host proteins, and many adenoviral serotypes, such as Ad35, use the regulatory complement protein CD46 for attachment. A few other serotypes, including Ad3, employ an unidentified receptor to establish infection. Several types of viruses and parasites have evolved to co-opt host HSPGs, such as fibronectin, to mediate pathogenesis. HSPGs are comprised of core proteins and repeating sulfated disaccharides of glucuronic acid and N-acetylglucosamine, which mediate cell migration. Now, in a study published in PLoS Pathogens, Tuve et al. identify HSPG as a co-receptor for two medically relevant adenovirus serotypes, Ad3 and Ad35.

Adenoviral attachment to host cells is partially mediated by a knob domain located on fibers that project from the outer protein capsid of the virus. Tuve et al. failed to detect any membrane proteins that interact with the Ad3 knob domain, so instead they looked at carbohydrates. The authors found that abrogating HSPG expression on cells significantly reduced Ad3 knob adherence, with Ad35 adherence also showing inhibition, though to a lesser degree. Further analysis by Western blot confirmed that the Ad3 knob specifically binds to HSPGs with low affinity, while Ad35 binds to CD46 with high affinity in a manner inhibited by HSPG. Thus, HSPGs may be involved in adenovirus attachment to host cells.

Tuve et al. collaborated with the Consortium for Functional Glycomics to screen for other potential carbohydrate binding partners of the Ad3 and Ad35 knob domains using a glycan array. Both serotypes, but particularly Ad3, bound to the most highly sulfated glycan of the 320 glycans on the array. Combined with studies using HS-deficient cells, Tuve et al. concluded that Ad3 requires the highly sulfated regions of HSPG to bind to host cells.

Although this study showed that the Ad3 and Ad35 knob domains interact with HSPG, these proteoglycans are not an absolute requirement for whole viral particle attachment. Thus, in contrast to other serotypes, the Ad3 knob protein is not the adenoviral ligand for the major host receptor. Instead, the Ad3 knob appears to bind HSPG as an initial co-receptor, increasing direct contact with host cells and giving other viral factors a better chance at binding the unknown receptor. HSPG plays a more minor role in Ad35 infection, acting as an alternative low-affinity receptor when the preferred receptor, CD46, is unavailable.

This study provides valuable information about the infectious mechanism of adenoviruses that will aid the development of new therapeutics and further the potential for the use of adenoviruses in gene therapy.

Author: Heather Buschman