Rhadinovirus host entry by co-operative infection

Area of Science:

• Virology
• Immunology
• Respiratory Medicine

Background:

• Rhadinoviruses cause chronic infections with significant health and economic impacts.
• Respiratory transmission and lung pathology are common features of several rhadinoviruses.

Purpose of the Study:

• To elucidate the mechanism of rhadinovirus lung infection using Murid Herpesvirus-4 (MuHV-4) as a model.
• To investigate the initial cellular targets and entry pathways of MuHV-4 in the lung.

Main Methods:

• In situ analysis of MuHV-4 infection in lung tissues.
• Ex vivo infection assays using alveolar macrophages and type 1 alveolar epithelial cells (AECs).
• Inhibition studies using antibodies targeting cell binding and membrane fusion.

Main Results:

• MuHV-4 primarily targets alveolar macrophages for host entry, not epithelial cells or B cells.
• Alveolar macrophages lack heparan, a key rhadinovirus binding molecule, and are infected poorly ex vivo.
• Virions initially bind to heparan-positive AECs, are then acquired by macrophages, which subsequently licenses AEC infection, demonstrating a co-operative entry mechanism.

Conclusions:

• Rhadinovirus lung entry is a co-operative process involving sequential interactions between AECs and macrophages.
• This mechanism expands the known viral tropism beyond cells readily infected in vitro.
• Neutralization strategies must target downstream events like membrane fusion to effectively block MuHV-4 entry.