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Human pDCs preferentially sense enveloped hepatitis A virions
Zongdi Feng, … , Christopher M. Walker, Stanley M. Lemon
Zongdi Feng, … , Christopher M. Walker, Stanley M. Lemon
Published November 21, 2014
Citation Information: J Clin Invest. 2015;125(1):169-176. https://doi.org/10.1172/JCI77527.
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Research Article Virology

Human pDCs preferentially sense enveloped hepatitis A virions

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Abstract

Unlike other picornaviruses, hepatitis A virus (HAV) is cloaked in host membranes when released from cells, providing protection from neutralizing antibodies and facilitating spread in the liver. Acute HAV infection is typified by minimal type I IFN responses; therefore, we questioned whether plasmacytoid dendritic cells (pDCs), which produce IFN when activated, are capable of sensing enveloped virions (eHAV). Although concentrated nonenveloped virus failed to activate freshly isolated human pDCs, these cells produced substantial amounts of IFN-α via TLR7 signaling when cocultured with infected cells. pDCs required either close contact with infected cells or exposure to concentrated culture supernatants for IFN-α production. In isopycnic and rate-zonal gradients, pDC-activating material cosedimented with eHAV but not membrane-bound acetylcholinesterase, suggesting that eHAV, and not viral RNA exosomes, is responsible for IFN-α induction. pDC activation did not require virus replication and was associated with efficient eHAV uptake, which was facilitated by phosphatidylserine receptors on pDCs. In chimpanzees, pDCs were transiently recruited to the liver early in infection, during or shortly before maximal intrahepatic IFN-stimulated gene expression, but disappeared prior to inflammation onset. Our data reveal that, while membrane envelopment protects HAV against neutralizing antibody, it also facilitates an early but limited detection of HAV infection by pDCs.

Authors

Zongdi Feng, You Li, Kevin L. McKnight, Lucinda Hensley, Robert E. Lanford, Christopher M. Walker, Stanley M. Lemon

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Figure 4

pDCs are transiently recruited to the livers of HAV-infected chimpanzees.

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pDCs are transiently recruited to the livers of HAV-infected chimpanzees...
(A) Serum IFN-α and changes in intrahepatic ISG15 and IFIT1 mRNA abundance are shown together with levels of intrahepatic HAV RNA in a chimpanzee, 4x0293, experimentally infected with HAV. The ISG15 response and virologic events have been described previously (12). Sections of archived liver specimens collected from chimpanzee 4x0293 at indicated times prior to and after intravenous challenge with HAV were stained with rabbit polyclonal antibody to human BDCA2. (B) Serum IFN-α and ISG15 and IFIT1 mRNA and ALT activities and intrahepatic HAV RNA in chimpanzee 4x0395 that was similarly infected with HAV (12). Sections of archived liver biopsies from 4x0395 were stained with murine monoclonal antibody 15B to human BDCA2. Scale bars: 200 μm.

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