Human Dendritic Cells Are Activated by Dengue Virus Infection: Enhancement by Gamma Interferon and Implications for Disease Pathogenesis

ABSTRACT The ability of dendritic cells (DCs) to shape the adaptive immune response to viral infection is mediated largely by their maturation and activation state as determined by the surface expression of HLA molecules, costimulatory molecules, and cytokine production. Dengue is an emerging arboviral disease where the severity of illness is influenced by the adaptive immune response to the virus. In this report, we have demonstrated that dengue virus infects and replicates in immature human myeloid DCs. Exposure to live dengue virus led to maturation and activation of both the infected and surrounding, uninfected DCs and stimulated production of tumor necrosis factor alpha (TNF-α) and alpha interferon (IFN-α). Activation of the dengue virus-infected DCs was blunted compared to the surrounding, uninfected DCs, and dengue virus infection induced low-level release of interleukin-12 p70 (IL-12 p70), a key cytokine in the development of cell-mediated immunity (CMI). Upon the addition of IFN-γ, there was enhanced activation of dengue virus-infected DCs and enhanced dengue virus-induced IL-12 p70 release. The data suggest a model whereby DCs are the early, primary target of dengue virus in natural infection and the vigor of CMI is modulated by the relative presence or absence of IFN-γ in the microenvironment surrounding the virus-infected DCs. These findings are relevant to understanding the pathogenesis of dengue hemorrhagic fever and the design of new vaccination and therapeutic strategies.

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Altered immune response of immature dendritic cells following dengue virus infection in the presence of specific antibodies

Journal of General Virology ◽

10.1099/jgv.0.000491 ◽

2016 ◽

Vol 97 (7) ◽

pp. 1584-1591 ◽

Cited By ~ 2

Author(s):

Silvia Torres ◽

Jacky Flipse ◽

Vinit C. Upasani ◽

Heidi van der Ende-Metselaar ◽

Silvio Urcuqui-Inchima ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Virus Infection ◽

Dengue Virus ◽

Dengue Virus Infection ◽

Specific Antibodies ◽

Immature Dendritic Cells ◽

Altered Immune Response

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Central role of dendritic cells in shaping the adaptive immune response during respiratory syncytial virus infection

Future Virology ◽

10.2217/fvl.11.62 ◽

2011 ◽

Vol 6 (8) ◽

pp. 963-973 ◽

Cited By ~ 21

Author(s):

Daniel S McDermott ◽

Kayla A Weiss ◽

Cory J Knudson ◽

Steven M Varga

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Respiratory Syncytial Virus ◽

Virus Infection ◽

Respiratory Syncytial Virus Infection ◽

Adaptive Immune Response ◽

Adaptive Immune ◽

Syncytial Virus

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TNF- -dependent maturation of local dendritic cells is critical for activating the adaptive immune response to virus infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.211423598 ◽

2001 ◽

Vol 98 (21) ◽

pp. 12162-12167 ◽

Cited By ~ 126

Author(s):

J. M. Trevejo ◽

M. W. Marino ◽

N. Philpott ◽

R. Josien ◽

E. C. Richards ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Virus Infection ◽

Adaptive Immune Response ◽

Adaptive Immune

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Dendritic Cell Precursors Are Permissive to Dengue Virus and Human Immunodeficiency Virus Infection

Journal of Virology ◽

10.1128/jvi.79.12.7291-7299.2005 ◽

2005 ◽

Vol 79 (12) ◽

pp. 7291-7299 ◽

Cited By ~ 34

Author(s):

Wing-Hong Kwan ◽

Anna-Marija Helt ◽

Concepción Marañón ◽

Jean-Baptiste Barbaroux ◽

Anne Hosmalin ◽

...

Keyword(s):

Immune Response ◽

Human Immunodeficiency Virus ◽

Virus Infection ◽

Dengue Virus ◽

Blood Monocytes ◽

Dengue Virus Infection ◽

Differentiation Potential ◽

Antiviral Immune Response ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT CD14+ interstitial cells reside beneath the epidermis of skin and mucosal tissue and may therefore play an important role in viral infections and the shaping of an antiviral immune response. However, in contrast to dendritic cells (DC) or blood monocytes, these antigen-presenting cells (APC) have not been well studied. We have previously described long-lived CD14+ cells generated from CD34+ hematopoietic progenitors, which may represent model cells for interstitial CD14+ APC. Here, we show that these cells carry DC-SIGN and differentiate into immature DC in the presence of granulocyte-macrophage colony-stimulating factor. We have compared the CD14+ cells and the DC derived from these cells with respect to dengue virus and human immunodeficiency virus type 1 (HIV-1) infection. Both cell types are permissive to dengue virus infection, but the CD14+ cells secrete the anti-inflammatory cytokine interleukin 10 and no tumor necrosis factor alpha. Regarding HIV, the CD14+ cells are permissive to HIV-1, release higher p24 levels than the derived DC, and more efficiently activate HIV Pol-specific CD8+ memory T cells. The CD14+ DC precursors infected with either virus retain their DC differentiation potential. The results suggest that interstitial CD14+ APC may contribute to HIV-1 and dengue virus infection and the shaping of an antiviral immune response.

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Evolution of the innate and adaptive immune response in women with acute Zika virus infection

Nature Microbiology ◽

10.1038/s41564-019-0618-z ◽

2019 ◽

Vol 5 (1) ◽

pp. 76-83 ◽

Cited By ~ 3

Author(s):

Pierre Tonnerre ◽

Juliana G. Melgaço ◽

Almudena Torres-Cornejo ◽

Marcelo A. Pinto ◽

Constanze Yue ◽

...

Keyword(s):

Immune Response ◽

Virus Infection ◽

Zika Virus ◽

Adaptive Immune Response ◽

Adaptive Immune ◽

Zika Virus Infection

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Dengue Virus-Infected Dendritic Cells, but Not Monocytes, Activate Natural Killer Cells through a Contact-Dependent Mechanism Involving Adhesion Molecules

mBio ◽

10.1128/mbio.00741-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 25

Author(s):

Vivian Vasconcelos Costa ◽

Weijian Ye ◽

Qingfeng Chen ◽

Mauro Martins Teixeira ◽

Peter Preiser ◽

...

Keyword(s):

Dendritic Cells ◽

Virus Infection ◽

Dengue Virus ◽

Nk Cells ◽

Adhesion Molecules ◽

Cell Activation ◽

Nk Cell ◽

Denv Infection ◽

Ifn Γ

ABSTRACT Natural killer (NK) cells play a protective role against dengue virus (DENV) infection, but the cellular and molecular mechanisms are not fully understood. Using an optimized humanized mouse model, we show that human NK cells, through the secretion of gamma interferon (IFN-γ), are critical in the early defense against DENV infection. Depletion of NK cells or neutralization of IFN-γ leads to increased viremia and more severe thrombocytopenia and liver damage in humanized mice. In vitro studies using autologous human NK cells show that DENV-infected monocyte-derived dendritic cells (MDDCs), but not monocytes, activate NK cells in a contact-dependent manner, resulting in upregulation of CD69 and CD25 and secretion of IFN-γ. Blocking adhesion molecules (LFA-1, DNAM-1, CD2, and 2β4) on NK cells abolishes NK cell activation, IFN-γ secretion, and the control of DENV replication. NK cells activated by infected MDDCs also inhibit DENV infection in monocytes. These findings show the essential role of human NK cells in protection against acute DENV infection in vivo, identify adhesion molecules and dendritic cells required for NK cell activation, and delineate the sequence of events for NK cell activation and protection against DENV infection. IMPORTANCE Dengue is a mosquito-transmitted viral disease with a range of symptoms, from mild fever to life-threatening dengue hemorrhagic fever. The diverse disease manifestation is thought to result from a complex interplay between viral and host factors. Using mice engrafted with a human immune system, we show that human NK cells inhibit virus infection through secretion of the cytokine gamma interferon and reduce disease pathogenesis, including depletion of platelets and liver damage. During a natural infection, DENV initially infects dendritic cells in the skin. We find that NK cells interact with infected dendritic cells through physical contact mediated by adhesion molecules and become activated before they can control virus infection. These results show a critical role of human NK cells in controlling DENV infection in vivo and reveal the sequence of molecular and cellular events that activate NK cells to control dengue virus infection. IMPORTANCE Dengue is a mosquito-transmitted viral disease with a range of symptoms, from mild fever to life-threatening dengue hemorrhagic fever. The diverse disease manifestation is thought to result from a complex interplay between viral and host factors. Using mice engrafted with a human immune system, we show that human NK cells inhibit virus infection through secretion of the cytokine gamma interferon and reduce disease pathogenesis, including depletion of platelets and liver damage. During a natural infection, DENV initially infects dendritic cells in the skin. We find that NK cells interact with infected dendritic cells through physical contact mediated by adhesion molecules and become activated before they can control virus infection. These results show a critical role of human NK cells in controlling DENV infection in vivo and reveal the sequence of molecular and cellular events that activate NK cells to control dengue virus infection.

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Stimulation of Innate and Adaptive Immunity by Using Filamentous Bacteriophage fd Targeted to DEC-205

Journal of Immunology Research ◽

10.1155/2015/585078 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Luciana D’Apice ◽

Valerio Costa ◽

Rossella Sartorius ◽

Maria Trovato ◽

Marianna Aprile ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Adaptive Immune Response ◽

Antibody Fragment ◽

Antigenic Determinants ◽

Rna Seq ◽

Single Chain ◽

Single Chain Antibody ◽

Filamentous Bacteriophage ◽

Adaptive Immune

The filamentous bacteriophage fd, codisplaying antigenic determinants and a single chain antibody fragment directed against the dendritic cell receptor DEC-205, is a promising vaccine candidate for its safety and its ability to elicit innate and adaptive immune response in absence of adjuvants. By using a system vaccinology approach based on RNA-Sequencing (RNA-Seq) analysis, we describe a relevant gene modulation in dendritic cells pulsed with anti-DEC-205 bacteriophages fd. RNA-Seq data analysis indicates that the bacteriophage fd virions are sensed as a pathogen by dendritic cells; they activate the danger receptors that trigger an innate immune response and thus confer a strong adjuvanticity that is needed to obtain a long-lasting adaptive immune response.

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Current Understanding of the Pathogenesis of Dengue Virus Infection

Current Microbiology ◽

10.1007/s00284-020-02284-w ◽

2020 ◽

Author(s):

Puneet Bhatt ◽

Sasidharan Pillai Sabeena ◽

Muralidhar Varma ◽

Govindakarnavar Arunkumar

Keyword(s):

Immune Response ◽

T Cells ◽

Virus Infection ◽

Dengue Virus ◽

Genetic Factors ◽

Host Immune Response ◽

Severe Dengue ◽

Ns1 Protein ◽

Dengue Virus Infection ◽

Antibody Dependent Enhancement

AbstractThe pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response. Host factors such as antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity as well as genetic factors are major determinants of disease susceptibility. NS1 protein and anti-DENV NS1 antibodies were believed to be responsible for pathogenesis of severe dengue. The cytokine response of cross-reactive CD4+ T cells might be altered by the sequential infection with different DENV serotypes, leading to further elevation of pro-inflammatory cytokines contributing a detrimental immune response. Fcγ receptor-mediated antibody-dependent enhancement (ADE) results in release of cytokines from immune cells leading to vascular endothelial cell dysfunction and increased vascular permeability. Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) suppressing host immune response are viral determinants of disease severity. Dengue infection can lead to the generation of autoantibodies against DENV NS1antigen, DENV prM, and E proteins, which can cross-react with several self-antigens such as plasminogen, integrin, and platelet cells. Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. This review article highlights the various factors responsible for the pathogenesis of dengue and also highlights the recent advances in the field related to biomarkers which can be used in future for predicting severe disease outcome.

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Polyphenol Effects on Splenic Cytokine Response in Post-Weaning Contactin 1-Overexpressing Transgenic Mice

Molecules ◽

10.3390/molecules24122205 ◽

2019 ◽

Vol 24 (12) ◽

pp. 2205 ◽

Cited By ~ 1

Author(s):

Thea Magrone ◽

Anna Spagnoletta ◽

Antonella Bizzoca ◽

Matteo Antonio Russo ◽

Emilio Jirillo ◽

...

Keyword(s):

Immune Response ◽

Adaptive Immune Response ◽

Immune Development ◽

Adaptive Immune ◽

Tnf Α ◽

Pregnant Mice ◽

Ifn Γ ◽

Delayed Maturation ◽

Red Grape ◽

Necrosis Factor

Background: In mice, postnatal immune development has previously been investigated, and evidence of a delayed maturation of the adaptive immune response has been detected. Methods: In this study, the effects of red grape polyphenol oral administration on the murine immune response were explored using pregnant mice (TAG/F3 transgenic and wild type (wt) mice) as the animal model. The study was performed during pregnancy as well as during lactation until postnatal day 8. Suckling pups from polyphenol-administered dams as well as day 30 post-weaning pups (dietary-administered with polyphenols) were used. Polyphenol effects were evaluated, measuring splenic cytokine secretion. Results: Phorbol myristate acetate-activated splenocytes underwent the highest cytokine production at day 30 in both wt and TAG/F3 mice. In the latter, release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α was found to be higher than in the wt counterpart. In this context, polyphenols exerted modulating activities on day 30 TAG/F3 mice, inducing release of interleukin (IL)-10 in hetero mice while abrogating release of IL-2, IFN-γ, TNF-α, IL-6, and IL-4 in homo and hetero mice. Conclusion: Polyphenols are able to prevent the development of an inflammatory/allergic profile in postnatal TAG/F3 mice.

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