Human pDCs preferentially sense enveloped hepatitis A virions

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Hepatitis A virus (HAV) is unique among picornaviruses, acquiring a host membrane envelope upon release.
• This envelopment protects HAV from neutralizing antibodies and aids liver dissemination.
• Acute HAV infections typically show weak type I interferon (IFN) responses, raising questions about immune sensing.

Purpose of the Study:

• To investigate if plasmacytoid dendritic cells (pDCs) can detect enveloped HAV (eHAV).
• To understand the mechanism and requirements for pDC activation by HAV.
• To determine the role of pDCs in the early stages of HAV infection in vivo.

Main Methods:

• Co-culture of human pDCs with HAV-infected cells or culture supernatants.
• Analysis of IFN-α production by pDCs using TLR7 signaling pathway.
• Isopycnic and rate-zonal gradient centrifugation to identify pDC-activating material.
• Assessment of eHAV uptake by pDCs via phosphatidylserine receptors.
• In vivo studies in chimpanzees monitoring pDC recruitment to the liver and IFN-stimulated gene expression.

Main Results:

• Concentrated nonenveloped HAV did not activate isolated pDCs.
• pDCs produced significant IFN-α when co-cultured with infected cells or exposed to supernatants, mediated by TLR7.
• eHAV, not exosomes, was identified as the inducer of pDC activation.
• pDC activation occurred independently of viral replication and involved eHAV uptake facilitated by phosphatidylserine receptors.
• In chimpanzees, pDCs transiently infiltrated the liver early in infection, preceding peak IFN-stimulated gene expression.

Conclusions:

• Enveloped HAV (eHAV) facilitates early, albeit limited, detection by pDCs through TLR7 signaling.
• Membrane envelopment of HAV serves a dual role: immune evasion and specific immune cell activation.
• pDCs are recruited to the liver early in HAV infection, suggesting a role in initial immune surveillance.