Human pDCs preferentially sense enveloped hepatitis A virions

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

doi:10.1172/jci77527

Cited by 84 publications

(95 citation statements)

References 47 publications

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“…Interestingly, however, the enveloped form of HAV is more prone to capture by pDCs (59). Thus, while eluding neutralizing antibodies, eHAV may be more prone to recognition by innate immune sensors (59). This finding supports the notion that human pDCs have adapted to detect potentially pathogenic virus infections by internalizing exosome-like vesicles carrying infectious HCV genomes (36,40,43).…”

Section: Do Other Enveloped Viruses Shuttle Genomes In Evs?supporting

confidence: 56%

“…Similarly, HCV RNA-containing EVs were recognized, albeit significantly less readily, by neutralizing antibodies (36). Interestingly, however, the enveloped form of HAV is more prone to capture by pDCs (59). Thus, while eluding neutralizing antibodies, eHAV may be more prone to recognition by innate immune sensors (59).…”

Section: Do Other Enveloped Viruses Shuttle Genomes In Evs?mentioning

confidence: 99%

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Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Dongen

Masoumi

Witwer

et al. 2016

Microbiol Mol Biol Rev

232

193

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SUMMARYExtracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, being involved in a wide array of key biological processes. Eukaryotic cells, and also bacteria, actively release heterogeneous subtypes of EVs into the extracellular space, where their contents reflect their (sub)cellular origin and the physiologic state of the parent cell. Within the past 20 years, presumed subtypes of EVs have been given a rather confusing diversity of names, including exosomes, microvesicles, ectosomes, microparticles, virosomes, virus-like particles, and oncosomes, and these names are variously defined by biogenesis, physical characteristics, or function. The latter category, functions, in particular the transmission of biological signals between cellsin vivoand how EVs control biological processes, has garnered much interest. EVs have pathophysiological properties in cancer, neurodegenerative disorders, infectious disease, and cardiovascular disease, highlighting possibilities not only for minimally invasive diagnostic applications but also for therapeutic interventions, like macromolecular drug delivery. Yet, in order to pursue therapies involving EVs and delivering their cargo, a better grasp of EV targeting is needed. Here, we review recent progress in understanding the molecular mechanisms underpinning EV uptake by receptor-ligand interactions with recipient cells, highlighting once again the overlap of EVs and viruses. Despite their highly heterogeneous nature, EVs require common viral entry pathways, and an unanticipated specificity for cargo delivery is being revealed. We discuss the challenges ahead in delineating specific roles for EV-associated ligands and cellular receptors.

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Section: Do Other Enveloped Viruses Shuttle Genomes In Evs?supporting

confidence: 56%

Section: Do Other Enveloped Viruses Shuttle Genomes In Evs?mentioning

confidence: 99%

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Dongen

Masoumi

Witwer

et al. 2016

Microbiol Mol Biol Rev

232

193

View full text Add to dashboard Cite

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“…Importantly, the immunostimulatory RNA can be carried from infected cells to the pDCs by noncanonical and/or noninfectious viral particles. Notably, for evolutionarily distant viruses, including hepatitis C virus (HCV), LCMV, and hepatitis A virus (HAV), infected cells secrete exosome-like vesicles containing viral elements that efficiently trigger pDC IFN production (11)(12)(13). HCV-infected cells produce these vesicles via the cellular exosomal pathway and without the requirement of viral structural proteins (12).…”

Section: Pdc Activation By Cell-cell Contact With Virus-infected Cellsmentioning

confidence: 99%

Cell-Cell Sensing of Viral Infection by Plasmacytoid Dendritic Cells

Webster

Assil

Dreux

2016

J Virol

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All cells possess signaling pathways designed to trigger antiviral responses, notably characterized by type I interferon (IFN) production, upon recognition of invading viruses. Especially, host sensors recognize viral nucleic acids. Nonetheless, virtually all viruses have evolved potent strategies that preclude host responses within the infected cells. The plasmacytoid dendritic cell (pDC) is an immune cell type known as a robust type I IFN producer in response to viral infection. Evidence suggests that such functionality of the pDCs participates in viral clearance. Nonetheless, their contribution, which is likely complex and varies depending on the pathogen, is still enigmatic for many viruses. pDCs are not permissive to most viral infections, and consistently, recent examples suggest that pDCs respond to immunostimulatory viral RNA transferred via noninfectious and/or noncanonical viral/cellular carriers. Therefore, the pDC response likely bypasses innate signaling blockages induced by virus within infected cells. Importantly, the requirement for cell-cell contact is increasingly recognized as a hallmark of the pDC-mediated antiviral state, triggered by evolutionarily divergent RNA viruses. The innate immune response represents the first line of defense against many pathogens. This response is initiated by the recognition of pathogen-associated molecular patterns (PAMPs) by cellular pathogen recognition receptors (PRRs), including Tolllike receptors (TLRs). This leads to the production of antiviral molecules, including interferons (IFNs), a broad range of interferon-stimulated genes (ISGs), and inflammatory cytokines. This first line of host response suppresses viral spread and jump-starts the adaptive immune response.Dendritic cells (DCs) serve as unique immune sentinels, surveying tissues, sensing infection and inflammation, sampling potential antigens, integrating these peripheral cues, and instructing both the innate and the adaptive immune system accordingly. Through this array of specialized functions, DCs orchestrate powerful pathogen-directed immunity and are pivotal in the regulation of viral pathogenesis. Different DC subsets respond in unique and specialized fashions to orchestrate antiviral responses. Among these, plasmacytoid dendritic cells (pDCs) are key players in the early antiviral responses, notably by their ability to produce a large amount of type I IFN (IFN-␣ and IFN-␤) (i.e., 1,000-fold more than other cell types) and type III IFN (IFN-/interleukin-28 [IL-28]/IL-29) (reviewed in reference 1). Their response is rapid and triggered mainly by the endosomal sensors TLR7 and TLR9, which recognize viral nucleic acids (RNA and DNA, respectively).The type I IFN response induced by pDCs is thought to be a key part of their role in the resolution of viral infections (1), especially at the acute phase. Direct evidence is still limited in human studies; nevertheless, an association between the resolution of viral infections and pDC functionality has been reported for certain viruses. For example, pD...

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“…Nevertheless HCV, an enveloped RNA virus, can be recognized by sensory plasmacytoid dendritic cells (pDCs) (3). More recently, Hepatitis A virus, a nonenveloped RNA virus, was shown to hijack a host membrane, presumably to escape neutralizing antibodies while facilitating sensing by pDCs (4). How DNA viruses, and in particular latent herpes viruses, are recognized by the innate immune system and whether this causes or protects from pathogenesis remains unclear (5).…”

mentioning

confidence: 99%

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Baglio¹,

Eijndhoven²,

Koppers-Lalić

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

144

145

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Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viraland exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand-off and may promote inflammatory disease.exosomes | EBV-EBER1 | innate sensing | dendritic cells | skin inflammation

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Human pDCs preferentially sense enveloped hepatitis A virions

Cited by 84 publications

References 47 publications

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Cell-Cell Sensing of Viral Infection by Plasmacytoid Dendritic Cells

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

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