Adenoviruses Use Lactoferrin as a Bridge for CAR-Independent Binding to and Infection of Epithelial Cells

Abstract

Most adenoviruses bind to the coxsackie-and adenovirus receptor (CAR). Surprisingly, CAR is not expressed apically on polarized cells and is thus not easily available to viruses. Consequently, alternative mechanisms for entry of coxsackievirus and adenovirus into cells have been suggested. We have found that tear fluid promotes adenovirus infection, and we have identified human lactoferrin (HLf) as the tear fluid component responsible for this effect. HLf alone was found to promote binding of adenovirus to epithelial cells in a dose-dependent manner and also infection of epithelial cells by adenovirus. HLf was also found to promote gene delivery from an adenovirus-based vector. The mechanism takes place at the binding stage and functions independently of CAR. Thus, we have identified a novel binding mechanism whereby adenovirus hijacks HLf, a component of the innate immune system, and uses it as a bridge for attachment to host cells.

Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus–adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN

“…The relevance for DC-SIGN-Lf-mediated enhancement of Ad5 infection in humans therefore remains unknown, but other soluble proteins equipped with high-mannose N-linked glycans may play a role in promoting rAd5 infection of APCs expressing lectin receptors such as DC-SIGN. The previously reported modest effects of BLf compared with HLf for enhancing Ad5 infection of epithelial cells may be explained by a lack of or low expression of receptors with binding affinity to the high-mannose carbohydrate residues on BLf (Johansson et al, 2007). Due to the wide tropism of Ad5, the virus probably utilizes various cell-surface proteins depending on the target cell type.…”

“…Therefore, it seems likely that other soluble components and/or cell-surface receptors are involved in promoting Ad5 binding and infection. As Lf was recently shown to facilitate attachment of Ad5 to epithelial cells by serving as a bridge between the virus and the target cell surface (Johansson et al, 2007), we investigated the effect of Lf on infection of APCs. Lf is present in mucosal tissues and in most bodily fluids, such as milk, tear fluid, saliva, nasal secretions and vaginal mucus, and at low concentration in serum (Masson et al, 1966;Weinberg, 2001).…”

“…As mentioned earlier, it was reported recently that the iron-binding protein Lf can promote infection of Ad5 in epithelial cells where CAR is not accessible (Johansson et al, 2007). We therefore investigated whether Lf influenced and/or promoted infection of rAd5 in human APCs.…”

“…As opposed to the fiber knob, the hexon of Ad5 was shown to be able to directly bind the coagulation factor X and mediate Ad5 infection of the liver (Waddington et al, 2008). Moreover, lactoferrin (Lf), an iron-binding protein present at mucosal sites and in many bodily fluids, was shown to facilitate binding of Ad5 to human epithelial cells and enhance infection via a CAR-independent manner using a yet undefined receptor (Johansson et al, 2007). Interestingly, Lf is mainly known for its immunomodulatory properties, which enhance anti-microbial and anti-inflammatory responses (Legrand et al, 2005).…”

“…However, CAR is naturally expressed in tight junctions between cells and therefore has limited accessibility on the apical cell surface (Cohen et al, 2001). As a likely consequence of this, CAR has been shown to play a minor role in Ad5 infection of epithelial cells (Johansson et al, 2007), hepatocytes (Smith et al, 2003), fibroblasts (Hidaka et al, 1999;Leopold et al, 2006) and antigen-presenting cells (APCs) such as dendritic cells (DCs) (Cheng et al, 2007;Lore et al, 2007;Rozis et al, 2005;Tillman et al, 1999). Thus, CAR-independent infection pathways used by Ad5 have been proposed.…”