Journal of Virology, April 2001, p. 3501-3508, Vol. 75, No. 8
Center for Infectious Disease and Vaccine Research,
University of Massachusetts Medical School, Worcester,
Massachusetts1; Department of
Virology2 and Department of
Immunology,3 Armed Forces Research Institute
of Medical Sciences, Bangkok, Thailand; and Department of Virus
Diseases, Walter Reed Army Institute of Research, Silver Spring,
Maryland4
Received 28 August 2000/Accepted 8 January 2001
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- Dendritic cells (DCs) are bone
marrow-derived cells that form a system of professional
antigen-presenting cells and are an important component of the innate
immune response. They are comprised of at least three distinct
subpopulations, one in the lymphoid/plasmacytoid lineage and two in the
myeloid lineage (1, 20, 26). Myeloid DCs are found in most
nonlymphoid organs including the epidermis (Langerhans cells), dermis,
gastrointestinal and respiratory mucosa, and the interstitia of
vascular organs (37). Following the uptake and processing
of antigen in the periphery, immature myeloid DCs differentiate to an
activated/mature state and migrate to the T-cell-rich areas of lymphoid
organs. Activated DCs are the unique stimulators of primary T-cell
responses and potent stimulators of memory responses, and they produce
an array of cytokines and chemokines (26, 44, 50, 55).
Thus, DCs are critical in the initiation of antimicrobial immunity, and
they provide a crucial step in the development of adaptive immunity.
Dengue is an emerging arboviral disease where the adaptive immune
response plays a significant role in determining the severity of
clinical illness. The dengue viruses are a group of four antigenically related mosquito-borne flaviviruses that produce a spectrum of clinical
illness and significant morbidity throughout the tropics (30,
35). Dengue hemorrhagic fever (DHF) and dengue shock syndrome
(DSS) represent the most severe and potentially life-threatening manifestations of a dengue viral infection. DHF/DSS is characterized by
the rapid onset of plasma leakage and coagulopathy near the time of
defervescence and viremia resolution. The most significant risk factor
for the development of DHF/DSS is acquisition of a second, heterotypic
dengue virus infection (3, 11, 13). During this second
dengue virus infection, it is postulated that the preexisting,
cross-reactive, adaptive immune response leads to excessive cytokine
production, complement activation, and the release of other phlogistic
factors which produce DHF/DSS. Both the humoral and cellular components
of adaptive immunity have been implicated in this process (12,
40). The principal target of dengue virus infection has been
presumed to be blood monocytes and tissue macrophages (14,
46). However, myeloid DCs residing in the epidermis (Langerhans
cells) and dermis are the predominant cells of the innate immune system
that dengue virus encounters following the bite of an infected
mosquito. A recent study demonstrated the permissiveness of immature
myeloid DCs to dengue virus infection but did not address the effect of
viral infection on the DCs (53). In this study, we further
investigated the interaction between dengue virus and myeloid DCs.
Immature myeloid DCs were generated from plastic-adherent peripheral
blood mononuclear cells (PBMC) and were considered representative of
myeloid interstitial DCs (1). Viral replication, DC
maturation and activation, and cytokine production were examined in the
hope of understanding the factors that guide formation of antiviral
adaptive immunity, and, under certain conditions, increase the risk of
developing severe disease.
Generation of DCs.
Immature myeloid DCs were generated from
PBMC using previously described techniques (38, 39, 44).
Peripheral blood was collected in heparinized tubes from healthy adult
volunteers. PBMC were isolated on Histopaque gradients (Sigma Chemical
Co., St. Louis, Mo.), washed two times with RPMI 1640 medium (Gibco BRL, Gaithersburg, Md.), and incubated with neuraminidase-treated sheep
red blood cells for 1 h on ice. Erythrocyte rosette-negative cells were collected and isolated using Histopaque gradient
centrifugation. The T-cell-depleted, erythrocyte rosette-negative cells
were cultured (3 × 106 cells/well) for 1 h in
24-well plates at 37°C in a CO2 incubator with RPMI 1640 and 10% heat-inactivated fetal calf serum (FCS; Gibco BRL).
Nonadherent cells were removed, and medium was replaced with the
addition of human recombinant interleukin-4 (rIL-4; 500 U/ml; Endogen
Inc., Woburn, Mass.) and human recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF; 800 U/ml; Endogen). Fresh medium
and cytokines (rIL-4 plus rGM-CSF) were replaced every 2 to 3 days.
After 7 days, the loosely adherent DCs were collected by vigorous
pipetting. The cells obtained expressed typical myeloid DC markers,
being CD3 Dengue virus infection of DCs.
Dengue type 2 virus strain
16681 (DEN-2 16681) was grown and propagated in the mosquito cell line
C6/36. The titers of virus stocks were determined by limiting dilution
plaque assay on LLC-MK2 cells (41). In some experiments,
virus was inactivated by UV irradiation from a germicidal lamp (60 min)
or heat treatment (65°C for 30 min); the absence of viable virus was
confirmed by plaque assay.
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.8.3501-3508.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Human Dendritic Cells Are Activated by Dengue Virus Infection:
Enhancement by Gamma Interferon and Implications for Disease
Pathogenesis
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
) and alpha interferon (IFN-). 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-
, 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- 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.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
, CD14, CD16,
CD20, CD56, CD40+,
HLA-DR+, and CD1a+. They had an immature DC
phenotype, being CD83, and comprised 80 to 85% of the
cell population. The remaining cells were predominantly B lymphocytes
and were not infected following dengue virus exposure (data not shown).
; Endogen) was added to one well with
DEN-2-infected DCs at a final concentration of 100 U/ml. At 48 h,
DCs were collected by vigorous pipetting and aliquoted into tubes for
fluorescence-activated cell sorting (FACS) immunostaining; viable DCs
were counted by trypan blue staining. Cell-free supernatants were
collected, aliquoted, and stored at 
70°C. The supernatant virus
titers were determined by plaque assay on LLC-MK2 cells as previously
noted. Cytokine levels were also determined in the supernatants by
enzyme-linked immunosorbent assay (ELISA).
Antibodies for flow cytometry. The following monoclonal antibodies (MAbs) were purchased from Pharmingen (San Diego, Calif.): fluorescein isothiocyanate (FITC)-conjugated mouse anti-human CD3, anti-human CD14, anti-human CD20, and isotype control (immunoglobulin G1 [IgG1]) MAbs; phycoerythrin-conjugated mouse anti-human HLA-DR, anti-human HLA-ABC, anti-human CD83, anti-human CD86, anti-human CD40, anti-human CD16, anti-human CD56, and isotype control (IgG1) MAbs; and CyChrome-conjugated mouse anti-human CD1a MAb. Phycoerythin-conjugated mouse anti-human CD80 (IgG1) MAb was purchased from Immunotech (Marseille, France). Mouse polyclonal anti-DEN-2 antibody (Ab) was purified from hyperimmune mouse ascitic fluid (AFRIMS, Bangkok, Thailand) and directly conjugated to FITC (FITC isomer I; Sigma).
Immunostaining and flow cytometry analysis. DCs were resuspended in staining buffer (phosphate-buffered saline, 1% heat-inactivated FCS, 0.09% sodium azide) and aliquoted at 1.5 × 105 cells/tube. After washing twice, cells were incubated for 30 min at 4°C with fluorescent MAbs to cell surface antigens (10 µl/tube). Cells were then fixed and permeabilized with Cytofix/Cytoperm according to the recommendations of the manufacturer (Pharmingen). Intracellular staining for dengue virus was accomplished by incubation with the FITC-conjugated anti-DEN-2 Ab (1 µg/tube) at 4°C for 30 min. After being washed twice, cells were resuspended in 0.3 ml of staining buffer prior to FACS analysis. Samples were analyzed using a FACScan flow cytometer (Becton Dickinson) and the CellQuest software package. In all experiments, three-color staining was simultaneously performed for (i) intracellular dengue virus, (ii) cell surface expression of CD83, costimulatory molecules, or HLA antigens, and (iii) surface CD1a expression. All analyses were performed on the CD1a+ cell population gate; a minimum of 50,000 events was acquired.
Determination of antiflavivirus antibody. The presence of antiflavivirus antibody was determined in the sera of all donors. Neutralizing Ab titers to dengue virus serotypes 1 to 4 and Japanese encephalitis virus were measured by a plaque reduction neutralization assay (41). The 50% plaque reduction neutralization titer was used for comparisons; a titer of >1:10 was considered evidence of prior exposure.
ELISAs for TNF- and IFN-.
ELISA plates (Immulon 1;
Dynex Technologies, Chantilly, Va.) were coated overnight at room
temperature with the appropriate Ab (for TNF-, mouse anti-human
TNF- MAb 2TNF-H34A [2.0 µg/ml]; for IFN-, sheep polyclonal
anti-human IFN- Ab [0.5 µg/ml]) (Endogen), each at 100 µl/well. Plates were incubated with 4% bovine serum albumin (200 µl/well; Sigma) in phosphate-buffered saline for 1 h at room
temperature; 50-µl aliquots of each sample were then added to each
well. Samples were incubated at room temperature for 1 h, and
standard dilutions for the appropriate cytokines (human rTNF-
[Endogen] and human rIFN-A [Biosource International, Camarillo,
Calif.]) were also evaluated. All samples and standard dilutions were
assayed in duplicate. Biotinylated detecting Ab (for TNF-, mouse
anti-human TNF- MAb 2TNF-H33 [0.25 µg/ml]; for IFN-, mouse
anti-human IFN- MAb 7N41 [0.75 µg/ml]) (Endogen) was added to
the plate (50 µl/well) and incubated for 1 h at room temperature. This was followed by a 30-min incubation with
streptavidin-peroxidase (poly-HRP Streptavidin [Endogen]; 1:20,000
dilution, 100 µl/well). Peroxidase substrate solution (Kirkegaard & Perry Laboratories Inc., Gaithersburg, Md.) was added, and the optical
density was read in an ELISA reader (Spectra Max 340; Molecular
Devices) at a wavelength of 450 nm.
ELISA for IL-12 p70 and IL-10. IL-12 p70 and IL-10 levels in the cell-free culture supernatants were measured using a commercial ELISA kit (Quantikine; R&D Systems, Minneapolis, Minn.) according to the manufacturer's instructions. All samples and standard dilutions were assayed in duplicate.
Statistics. All values are presented as mean ± standard error of the mean. Statistical significance of differences after infection or treatment of groups was calculated using the paired-samples Student t test for normally distributed variables or the Wilcoxon signed ranks test for nonparametric variables. Statistical significance of differences between two independent groups was calculated using the Student t test for normally distributed variables or the Mann-Whitney U test for nonparametric variables. Correlational analysis was performed using the Pearson statistical test. The statistical software package SPSS version 10.0 was used for all statistical analyses.
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Dengue virus productively infects immature myeloid DCs, and
infection is decreased the presence of IFN-.
Immature myeloid
DCs were infected with a laboratory-adapted strain of dengue virus,
DEN-2 16681, in the absence or presence of rIFN-. At 48 h,
cells were stained for surface CD1a expression and intracellular DEN-2
virus; the percentage of DEN-2-infected CD1a+ DCs was
quantitated by flow cytometry. The intracellular location of virus in
DCs was confirmed by immunofluorescence microscopy; adsorption
with heat-killed DEN-2 16681 or UV-inactivated virus did not
result in staining with the anti-DEN-2 Ab (data not shown). DCs were
>95% viable by trypan blue staining. In the absence of IFN-, the
percentage of DEN-2-infected CD1a+ DCs at 48 h was
65% ± 7% (range, 40 to 81%), and the log10 virus titer
(PFU per milliliter) in the cell-free supernatants was 6.16 ± 0.18 (range, 5.70 to 6.83) (n = 6). The supernatant
log10 virus titer (PFU per milliliter) correlated with the
percentage of DEN-2-infected DCs (Pearson correlation coefficient = 0.86, P = 0.03). When rIFN- was added after virus
adsorption, the percentage of DEN-2-infected CD1a+ DCs at
48 h decreased to 52% ± 10% (range, 24 to 76%) (P = 0.02). The supernatant log10 virus titer (PFU per
milliliter) also decreased to 5.38 ± 0.44 (range, 3.88 to 6.35),
although this decrease did not achieve statistical significance
(P = 0.06) (Fig. 1).
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0.95, P = 0.004). ADE of dengue virus infection in myeloid DCs was unable to be demonstrated in a previous study (53). The data show that dengue virus
can infect and replicate in immature myeloid DCs. IFN- decreases the
permissiveness of myeloid DCs to dengue virus infection.
IFN- enhances the activation of dengue virus-infected DCs.
DC maturation and activation is characterized by upregulation of the
costimulatory molecules CD40, CD80, CD86 (43, 44, 54),
increased cell surface expression of HLA classes I and II (43,
54), and upregulation of the specific DC marker CD83 (54,
56). Immature myeloid DCs were infected with DEN-2 16681 or
DEN-2 16681 plus rIFN- (100 U/ml) or were mock infected. At 48 h, the cell surface expression of CD83, CD40, CD80, CD86,
HLA class I, and HLA class II was assessed by flow cytometry in three groups: mock-infected (control) CD1a+ DCs (Fig.
2A), DEN-2-infected CD1a+ DCs
following virus adsorption (Fig. 2B), and uninfected (bystander) CD1a+ DCs following virus adsorption (Fig. 2C). Significant
increases in the cell surface expression of CD83, CD40, CD80, CD86, and HLA classes I and II were seen in the DEN-2-infected and uninfected (bystander) DCs compared to the mock-infected controls (Fig. 2; Table
1). In control experiments, exposure of
immature myeloid DCs to UV-inactivated dengue virus did not induce
maturation or activation as determined by CD83, CD80, and CD86
expression (data not shown).
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overcame this suppression and increased expression of
costimulatory and HLA molecules on the cell surface of the DEN-2-infected DCs (Table 1). Mean surface levels of CD80, CD86, and
HLA class I in the DEN-2-infected DCs with IFN- approached or
exceeded the levels seen in the uninfected (bystander) DCs without
IFN-.
LPS and Mycoplasma are potent inducers of DC maturation and
activation (5, 6, 42, 52). LPS concentrations in the virus
stock and culture supernatants of the dengue virus exposed DCs were <5
pg/ml. The virus stock, C6/36 cell line, and DC culture supernatants
did not contain Mycoplasma, as determined by a nucleic acid
hybridization assay. Thus, DC maturation and activation were not due to
LPS or Mycoplasma contamination. The data demonstrate that
both directly infected and uninfected myeloid DCs undergo maturation
and activation after exposure to live dengue virus. The degree of
maturation and activation appears to be less in the virus infected DCs
than in the adjacent, uninfected DCs. Activation of dengue
virus-infected DCs can be enhanced by the addition of IFN-.
Dengue virus induces TNF- and IFN- production from myeloid
DCs.
Elevated TNF- and IFN- levels have been detected
in the sera of dengue virus-infected persons. We measured dengue
virus-induced production of TNF- and IFN- from myeloid DCs.
Immature myeloid DCs were infected with DEN-2 16681 or mock infected.
Cell-free supernatants were collected at 48 h and assayed for
TNF- and IFN- by ELISA. TNF- levels increased from 54 ± 7 pg/ml in the mock-infected DCs to 743 ± 174 pg/ml in the dengue
virus-exposed DCs (P = 0.01) (Fig.
3A). IFN- levels increased from
16 ± 5 U/ml in the mock-infected DCs to 101 ± 17 U/ml in
the dengue virus-exposed DCs (P = 0.009) (Fig. 3B). In
control experiments, exposure of DCs to UV-inactivated dengue virus did
not induce production of TNF- or IFN- (for TNF-, mock
infection, 92 ± 29 pg/ml; for UV-inactivated virus exposure,
56 ± 40, n = 2, P = 0.2; for IFN-, mock infection and UV-inactivated virus exposure, <4 U/ml,
n = 2). The data indicate that replicating dengue
virus induces significant TNF- and IFN- release from myeloid DCs.
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Dengue virus induces IL-12 p70 secretion from myeloid DCs in the
presence of IFN- and does not induce IL-10 secretion.
Myeloid
DCs have been shown to be a major source of the IL-12 that is necessary
for generation of a type 1 T-cell response and cell-mediated immunity
(CMI) (5). IL-10 is the predominant type 2 cytokine that
downregulates IL-12 production and CMI (7). We measured
dengue virus-induced production of the biologically active heterodimer,
IL-12 p70, and IL-10 from myeloid DCs. Immature myeloid DCs were
infected with DEN-2 16681 or DEN-2 16681 plus rIFN- (100 U/ml) or
were mock infected. Cell-free supernatants were collected at 48 h
and assayed for IL-12 p70 and IL-10 by ELISA. Production of IL-12 p70
was low following dengue virus infection. IL-12 p70 concentrations were
1.1 ± 0.1 pg/ml in the mock-infected DCs and 10.2 ± 5.5 pg/ml in the dengue virus-exposed DCs (P = 0.2) (Fig.
4A). IL-12 p70 remained unchanged and at
the level of detection (1.0 pg/ml) following exposure to UV-inactivated dengue virus.
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, IL-12 p70 levels increased from
4.2 ± 1.0 pg/ml in the mock-infected DCs to 48.7 ± 22.3 pg/ml in the dengue virus-exposed DCs, though this did not reach statistical significance (P = 0.07) (Fig. 4B). The
level of IL-12 p70 induced by dengue virus in the presence of IFN-
was greater than in the absence of IFN- (48.7 ± 22.3 pg/ml and
10.2 ± 5.5 pg/ml, respectively, P = 0.03).
Dengue virus infection did not induce significant IL-10 release from
immature myeloid DCs and was not affected by the addition of IFN-
(mock-infected DCs, 37.5 ± 4.5 pg/ml; dengue virus-exposed DCs, 42.5 ± 3.8 pg/ml; dengue virus-exposed DCs plus IFN-
[100 U/ml], 46.4 ± 4.9, P = 0.3) (Fig.
5).
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can augment dengue virus-induced IL-12 p70 release.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Although dengue virus infection of myeloid DCs has been previously
reported (53), this study is the first to describe the effects of dengue virus infection on the DCs. The results of this study
provide evidence that exposure of immature myeloid DCs to dengue virus
leads to productive infection with DC maturation and activation.
Activation of the dengue virus-infected myeloid DCs
appears blunted compared to the surrounding, uninfected DCs. While
dengue virus infection of myeloid DCs results in production of TNF-
and IFN-, secretion of IL-12 p70 is low. Addition of IFN-
enhances the activation of dengue virus-infected myeloid DCs and
enhances virus-induced IL-12 p70 release.
We have demonstrated that immature human myeloid DCs are
permissive to dengue virus infection and replication, though wide variability to infection was seen among the blood-derived DCs from six
individuals. The addition of IFN- (100 U/ml) immediately following
exposure to dengue virus enhanced activation of the virus-infected DCs
yet decreased the percentage of infected myeloid DCs and virus
production. This is consistent with a recent report that found
immature, but not mature or activated, myeloid DCs to be permissive to
infection with dengue virus (53). Others have also
demonstrated a decreased permissiveness to viral infection in activated
DCs but have found the phenomenon to be stimulus dependent (4,
36). IFN- (100 U/ml) also decreased dengue virus replication
in human peripheral blood monocytes (48). Virus
replication and production in immature CD1a+ DCs, and their
location in the epidermis and dermis, suggest that myeloid DCs are an
important early target for dengue virus infection in vivo. Dengue virus
infection of human skin CD1a+ DCs has been recently
demonstrated ex vivo (53).
When exposed to live dengue virus, immature myeloid DCs underwent
maturation, as characterized by the upregulation of CD83 and surface
activation markers and the secretion of cytokines. Measles virus,
influenza virus, and a variety of other microbial pathogens and
products are also inducers of DC maturation (4, 37, 45).
The effects of dengue virus infection on the maturation and activation
of myeloid DCs appear to be pleiotropic. Dengue virus infection of
immature myeloid DCs induced significant release of TNF- and
IFN-, low levels of IL-12 p70 release, and no appreciable IL-10
release. Whether cytokines were produced solely by the virus-infected DCs or additionally by the adjacent uninfected DCs could not be determined; however, a productive viral infection was required. TNF-
and IFN- production have also been demonstrated following dengue
virus infection of human monocytes or monocytic cell lines (18,
21). TNF- and IFN- can drive maturation of both the virus-infected DCs and the adjacent uninfected DCs, resulting in an
increase in the cell surface expression of CD83, HLA classes I and II,
and costimulatory molecules (28, 34, 44, 54). The lower
mean levels of HLA class I and CD80/CD86 on the surface of the dengue
virus-infected DCs compared to the adjacent uninfected DCs suggest that
dengue virus may exert a small inhibitory effect on the cytokine
mediated upregulation of these cell surface molecules. Flavivirus-induced upregulation of class I major histocompatibility complex and CD80 expression has been previously described (19, 27, 33, 47). Depending on the cell culture system used, this
upregulation has been found to be either cytokine dependent (47) or cytokine independent (33). In dengue
virus infection of myeloid DCs, it appears that a cytokine-mediated
effect dominates the expression of HLA class I and CD80/CD86 on the
cell surface. Whether the upregulation of these T-cell stimulatory
molecules is also counteracted by a direct viral effect will require
further study.
Dengue virus-induced IL-12 p70 release from myeloid DCs was low but was
enhanced by IFN-. Similar findings have been seen among other
virus-exposed myeloid DCs. Adenovirus infection of peripheral
blood-derived myeloid DCs produced incomplete maturation and failed to
induce IL-12 p70 release (36). IFN- has been shown to
inhibit the production of IL-12 p70 from DCs and may contribute to a
suppression of IL-12 release during viral infection (29).
IL-12 production from myeloid DCs activated by measles virus requires
coculture with lymphocytes or other CD40 ligand (CD40L)-bearing cells
(8). The engagement of CD40 on DCs by CD40L-bearing T
cells requires IFN- in order to produce IL-12 p70 (16,
49). Thus, for several viral pathogens, there appears to be a
pattern whereby IFN- is an important second signal for the
secretion of bioactive IL-12 from DCs. In dengue virus-infected DCs,
IFN- also increases expression of the molecules involved in
stimulating the antigen-specific T-cell response. This
two-signal process may represent a regulatory mechanism for
modulating potentially harmful type 1 T-cell activation early in the
immune response.
These data have relevant implications for the pathogenesis of dengue
virus-induced disease. Early in a primary infection, dengue
virus-infected DCs would be weakly activated and would not produce
significant amounts of IL-12 p70, as there is a paucity of IFN- and
dengue virus-reactive T cells (bearing CD40L) in the local
microenvironment. With continued viral replication and stimulation of
the innate immune response, there is eventual production of IFN-
with T- and B-cell activation. Viremia is cleared; CMI and humoral
immunity develop without an early, anamnestic burst of type 1 cytokines. In this setting, the risk of proceeding to DHF/DSS is low.
During a heterotypic, second dengue virus infection, cross-reactive
memory T cells would be activated in response to dengue virus-infected
DCs. These T cells are a source of early IFN- and CD40L in the DC
microenvironment, leading to greater DC activation, greater T-cell
stimulatory capacity, a burst of IL-12 p70 release, increases in
TNF- (2) and IFN- (51) secretion, and
potential dysregulation of the type 1 cytokine response. Viremia is
cleared, yet the cascade of events initiated by an early, poorly
controlled type 1 cytokine response likely contributes to the
pathogenesis of DHF/DSS. Plasma levels of IFN-, TNF-, and soluble
TNF- receptors have been found to be elevated in DHF/DSS compared to
dengue fever (10, 17).
We have postulated that the relative presence or absence of IFN- in
the local microenvironment surrounding dengue virus-infected DCs is a
key determinant of disease manifestation and severity. In our
experiments, DCs were exposed to 100 U of rIFN- per ml. Although in
vivo concentrations of IFN- in lymph nodes containing dengue
virus-infected DCs are unknown, there is evidence to suggest that 100 U/ml is within an achievable range. Dengue virus-immune CD4+ T cells have produced 10 to 280 U of IFN- per ml in
response to dengue virus antigens, and serum levels of IFN- in
dengue virus-infected patients and dengue virus vaccine recipients have reached 50 U/ml. A critical question that remains is what other factors
modulate the appearance of early IFN-, DC activation, and IL-12 p70
production. Dengue virus-stimulated natural killer (NK) cells are a
potential source of early IFN- in both primary and secondary
infections. The percent of circulating activated NK cells was found to
be greater in children who developed DHF compared to dengue fever
(9). Activated platelets may provide an alternative source
of CD40L. The number of DCs infected (viral load), differences in virus
strains, and polymorphisms in the transcriptional promoters of IL-12
(p40 and p35) and IFN- are potential modulators of the early type 1 cytokine response to dengue virus infection in vivo.
The data presented here underscore the multifaceted role of DCs in viral infection. Immature myeloid DCs are an early target of dengue virus infection and a source of virus replication and production. At the same time, they play a critical role in the development of both protective and pathogenic aspects of antiviral immunity. Further studies to delineate the interaction between dengue virus and DCs should provide new opportunities for vaccination strategies and therapeutic interventions in this emerging arboviral disease.
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ACKNOWLEDGMENTS |
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We thank Khun Naowayubol Nutkumhang and Khun Somsak Imlap for performing the virus titration plaque assays, Khun Napaporn Lutthiwongsakorn for performing the plaque reduction neutralization assays, Khun Kosol Yongvanitchit for FACS analysis, and Khun Utaiwon Kum-arb for assistance with DC preparation. We thank Ananda Nisalak for overall supervision of the diagnostic virology laboratory at AFRIMS and Alan Rothman and Sharone Green for assistance with manuscript preparation.
This work was supported by the National Institutes of Health (grant NIH-P01AI34533) and the U.S. Army Medical Research and Materiel Command.
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FOOTNOTES |
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* Corresponding author. Mailing address: USAMC-AFRIMS, Department of Virology, APO AP 96546. Phone: 66-2-644-4674. Fax: 66-2-644-4760. E-mail: dlibraty{at}mozart.inet.co.th or libratydh{at}thai.amedd.army.mil.
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Journal of Virology, April 2001, p. 3501-3508, Vol. 75, No. 8
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.8.3501-3508.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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