Human Plasmacytoid Dendritic Cells Sense Lymphocytic Choriomeningitis Virus-Infected Cells
            <i>In Vitro</i>

Wieland, Stefan; Takahashi, Ken; Boyd, Bryan; Whitten-Bauer, Christina; Ngo, Nhi; Torre, Juan Carlos de la; Chisari, Francis V.

doi:10.1128/jvi.01714-13

Cited by 37 publications

(48 citation statements)

References 41 publications

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“…Recent studies showed that pDC sense hepatitis C virus (HCV)-or lymphocytic choriomeningitis virus (LCMV)-infected cells (59,60), and viral transmission by cell-to-cell contacts are more potent inducers of IFN than infection by cell-free viral particles (61,62). We confirmed and extended these data to HIV-1 transfer from primary pDC to CD4 T lymphocytes.…”

supporting

confidence: 77%

Broadly Neutralizing Antibody VRC01 Prevents HIV-1 Transmission from Plasmacytoid Dendritic Cells to CD4 T Lymphocytes

Lederle

Laumond

et al. 2014

J Virol

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supporting

confidence: 77%

Broadly Neutralizing Antibody VRC01 Prevents HIV-1 Transmission from Plasmacytoid Dendritic Cells to CD4 T Lymphocytes

Lederle

Laumond

et al. 2014

J Virol

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“…HCV-infected cells produce these vesicles via the cellular exosomal pathway and without the requirement of viral structural proteins (12). This process is presumably similar for LCMV (13). While HAV was originally classified as a nonenveloped virus, recent work demonstrated that viral capsids containing HAV genomes can acquire cell membranes via the exosomal pathway and are thus identified as an enveloped form of HAV (eHAV) (14).…”

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

confidence: 99%

“…Nonetheless, on the downside, this vesicular form of HAV is also an efficient PAMP carrier for the activation of the pDC response (11). For these various viruses, the exosomal transfer of the immunostimulatory RNA to pDC commonly requires cellcell contact with infected cells (11)(12)(13). Importantly, we recently illustrated that the cell-cell sensing of infected cells by pDC might involve other types of PAMP carriers.…”

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

confidence: 99%

“…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%

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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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“…Alternatively, the K465V and G467K mutations may interfere with virus cell entry, despite these mutations being located within the CD of GP2. Interestingly, human pDCs are refractory to rCl-13 WT infection when infected ex vivo (62), suggesting the existence of a yet-unidentified cell entry pathway required for infection of pDCs in vivo that could be affected by K465V and G467K mutations. Published data support a very strong correlation between high affinity for ␣DG of the LCMV GP and the virus's ability to persist.…”

Section: Discussionmentioning

confidence: 99%

Residues K465 and G467 within the Cytoplasmic Domain of GP2 Play a Critical Role in the Persistence of Lymphocytic Choriomeningitis Virus in Mice

Iwasaki

Cubitt

et al. 2016

J Virol

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Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever disease in humans and pose serious public health concerns in their regions of endemicity. Moreover, mounting evidence indicates that the worldwide-distributed prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), is a neglected human pathogen of clinical significance. We have documented that a recombinant LCMV containing the glycoprotein (GPC) gene of LASV within the backbone of the immunosuppressive clone 13 (Cl-13) variant of the Armstrong strain of LCMV (rCl-13/LASV-GPC) exhibited Cl-13-like growth properties in cultured cells, but in contrast to Cl-13, rCl-13/LASV-GPC was unable to establish persistence in immunocompetent adult mice, which prevented its use for some in vivo experiments. Recently, V459K and K461G mutations within the GP2 cytoplasmic domain (CD) of rCl-13/LASV-GPC were shown to increase rCl-13/LASV-GPC infectivity in mice. Here, we generated rCl-13(GPC/VGKS) by introducing the corresponding revertant mutations K465V and G467K within GP2 of rCl-13 and we show that rCl-13(GPC/VGKS) was unable to persist in mice. K465V and G467K mutations did not affect GPC processing, virus RNA replication, or gene expression. In addition, rCl-13(GPC/VGKS) grew to high titers in cultured cell lines and in immunodeficient mice. Further analysis revealed that rCl-13(GPC/VGKS) infected fewer splenic plasmacytoid dendritic cells than rCl-13, yet the two viruses induced similar type I interferon responses in mice. Our findings have identified novel viral determinants of Cl-13 persistence and also revealed that virus GPC-host interactions yet to be elucidated critically contribute to Cl-13 persistence. IMPORTANCEThe prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), provides investigators with a superb experimental model system to investigate virus-host interactions. The Armstrong strain (ARM) of LCMV causes an acute infection, whereas its derivative, clone 13 (Cl-13), causes a persistent infection. Mutations F260L and K1079Q within GP1 and L polymerase, respectively, have been shown to play critical roles in Cl-13's ability to persist in mice. However, there is an overall lack of knowledge about other viral determinants required for Cl-13's persistence. Here, we report that mutations K465V and G467K within the cytoplasmic domain of Cl-13 GP2 resulted in a virus, rCl-13(GPC/VGKS), that failed to persist in mice despite exhibiting Cl-13 wild-type-like fitness in cultured cells and immunocompromised mice. This finding has uncovered novel viral determinants of viral persistence, and a detailed characterization of rCl-13(GPC/VGKS) can provide novel insights into the mechanisms underlying persistent viral infection.A renaviruses are enveloped viruses with a bisegmented negative-strand RNA genome (1). Each genome segment, L and S, uses an ambisense coding strategy to direct the synthesis of two proteins in opposite orientations, separated by a noncoding intergenic region (IGR) (1). The S RNA encodes the viral nucleop...

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Human Plasmacytoid Dendritic Cells Sense Lymphocytic Choriomeningitis Virus-Infected Cells In Vitro

Cited by 37 publications

References 41 publications

Broadly Neutralizing Antibody VRC01 Prevents HIV-1 Transmission from Plasmacytoid Dendritic Cells to CD4 T Lymphocytes

Broadly Neutralizing Antibody VRC01 Prevents HIV-1 Transmission from Plasmacytoid Dendritic Cells to CD4 T Lymphocytes

Cell-Cell Sensing of Viral Infection by Plasmacytoid Dendritic Cells

Residues K465 and G467 within the Cytoplasmic Domain of GP2 Play a Critical Role in the Persistence of Lymphocytic Choriomeningitis Virus in Mice

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