Virus entry into host cells is a complex process that is largely regulated by access to specific cellular receptors. Human adenoviruses (HAdVs) and many other viruses use
cell adhesion molecules such as the coxsackievirus and
adenovirus receptor (CAR) for attachment to and entry into target cells. These molecules are rarely expressed on the apical side of polarized epithelial cells, which raises the question of how adenoviruses-and other viruses that engage
cell adhesion molecules-enter polarized cells from the apical side to initiate
infection. We have previously shown that species C HAdVs utilize
lactoferrin-a common innate immune component secreted to respiratory mucosa-for
infection via unknown mechanisms. Using a series of biochemical, cellular, and molecular biology approaches, we mapped this effect to the proteolytically cleavable, positively charged, N-terminal 49 residues of human
lactoferrin (hLF) known as human
lactoferricin (hLfcin).
Lactoferricin (Lfcin) binds to the hexon
protein on the viral capsid and anchors the virus to an unknown receptor structure of target cells, resulting in
infection. These findings suggest that HAdVs use distinct cell entry mechanisms at different stages of
infection. To initiate
infection, entry is likely to occur at the apical side of polarized epithelial cells, largely by means of hLF and hLfcin bridging HAdV capsids via hexons to as-yet-unknown receptors; when
infection is established, progeny virions released from the basolateral side enter neighboring cells by means of hLF/hLfcin and CAR in parallel.IMPORTANCE Many viruses enter target cells using
cell adhesion molecules as receptors. Paradoxically, these molecules are abundant on the lateral and basolateral side of intact, polarized, epithelial target cells, but absent on the apical side that must be penetrated by incoming viruses to initiate
infection. Our study provides a model whereby viruses use different mechanisms to infect polarized epithelial cells depending on which side of the cell-apical or lateral/basolateral-is attacked. This study may also be useful to understand the biology of other viruses that use
cell adhesion molecules as receptors.