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*
Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital;
Graduate Institute of Life Science;
Institute of Biology and Anatomy; and
Department of Parasitology and Tropical Medicine, National Defense Medical Center, Taiwan, Republic of China;
¶ School of Medical Technology, College of Medicine and Division of Infectious Disease, National Taiwan University, Taiwan, Republic of China; and
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Immunology Division, Cheng-Hsin Rehabilitation Medical Center, Taiwan, Republic of China.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IFN-, but not IL-6 and IL-12. Although DC underwent spontaneous
apoptosis in the absence of feeding cytokines, this process appeared to
be delayed after DV infection. Our observations provide important
information in understanding the pathogenesis of DV
infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After DV infection most patients are viremic in the early febrile
phase, and the viruses are quickly cleared from the blood after
defervescence (4). The activation of both humeral and
cellular immune responses is considered to be involved in virus
clearance; the former response is shown by detecting the increased
serum neutralizing Ab levels, and the latter is correlated with the
generation and activation of CD4+ and
CD8+ T lymphocytes that recognize
serotype-specific, Dengue serotype cross-reactive epitopes
(4, 5, 6, 7). The activation of T lymphocytes and other immune
effector cells then leads to increased levels of TNF-, soluble TNF
receptor (sTNFR/75), IL-8, IFN-
, and other mediators that may be
associated with the pathogenesis of increased vascular permeability, a
characteristic picture seen in DHF/DSS patients (8, 9, 10, 11).
Importantly, not only the activation of CD8+ T
lymphocytes but also the level of cytokines and the production of
viruses, compared with those in DF patients, are significantly higher
in DHF patients (7, 11, 12). Because both virus
replication in organs such as brain, skin, and lymph nodes and host
factors such as cytokines influence the pathogenesis of DV infection in
humans, the identification of the natural hosts for DV as well as the
subsequent consequences of the infected cells and their
interactions with T lymphocytes appear to be critical for effective
therapy of DV infection.
Dendritic cells (DC) are potent APCs that, after infection, migrate from peripheral tissues to the lymph nodes and activate CD4+ and CD8+ T lymphocytes (13, 14, 15, 16). By using mutational analysis, this migration step has been shown to be crucial for viral pathogenesis (17). The T lymphocyte stimulatory capacity is mediated through both the increased expression of B7-1 and B7-2 costimulatory molecules and the secretion of a variety of cytokines (16, 18). Reciprocally, DC may be activated or regulated by environmental factors, chemokines as well as cytokines (reviewed in Refs. 19, 20, 21). Furthermore, DC can efficiently help maintain the protective antiviral cytotoxic T cell memory (22). Because DC have been shown to bind and allow replications of many viruses (23, 24, 25, 26 ; reviewed in Refs. 27 and 28), we postulated that DC could be infected with DV and possibly play a role in the pathogenesis of DV infection through an increase in virus load and cell activation.
In the present study we show that DV could efficiently infect DC and
produce virus particles. After infection, DC were activated to secrete
TNF- and IFN- and were driven to undergo the maturation process.
Given that DC underwent spontaneous apoptosis in the absence of feeding
cytokines and that the infection of DC by DV resulted in accelerated
cell apoptosis in the early phase after infection, both cell maturation
and cytokine production could probably produce an anti-apoptotic
effect in the late phase of infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cell culture medium consisted of RPMI 1640 (Life Technologies, Gaithersburg, MD) supplemented with 10% FBS, 2 mM glutamine, and 1000 U/ml penicillin-streptomycin (Life Technologies, Gaithersburg, MD). Recombinant GM-CSF and IL-4 were purchased from R&D Systems (Minneapolis, MN). mAb to viral E protein was obtained from supernatants of hybridoma cells (HB46; American Type Culture Collection, Manassas, VA) and mAb to viral nonstructural protein 1 (NS1) with high specificity has been described previously (29). The fluorescence-labeled mAbs against cell surface molecules were purchased as follows: anti-B7-1, anti-HLA-DR, anti-CD3, anti-CD19, anti-CD14, and anti-CD56 from Becton Dickinson (Mountain View, CA); anti-B7-2 and anti-CD83 from PharMingen (San Diego, CA); and anti-CD11b from Dako (Carpinteria, CA). The isotype-matched control mAb for flow cytometric analysis was purchased from either PharMingen or Becton Dickinson. Unless otherwise indicated, the rest of the reagents were purchased from Sigma (St. Louis, MO).
Establishment of DC from human PBMC
The generation of DC from human PBMC was performed as described by Romani et al. (30). In brief, whole blood (20–50 ml) from healthy donors (>80 participants) was mixed with Ficoll-Hypaque, and after centrifugation the layer of mononuclear cells was collected. After lysis of RBC, the mononuclear cells were laid on petri dishes (Costar, Cambridge, MA) for 30–60 min at 37°C to remove nonadherent cells. After five washes with PBS, adherent cells were cultured in 3 ml of medium containing 800 U/ml GM-CSF and 500 U/ml IL-4. The culture medium was changed every other day with 300 µl of fresh medium containing 2400 U of GM-CSF and 1500 U of IL-4. The detached cells, the main population of CD1a+ cells (our unpublished observations), were used for experiments after culture for 7–10 days. During this period of time, the examination of cell type-specific markers in a gated population of established DC showed CD14 (0%), CD3 (0%), CD19 (1%), and CD56 (2%). Consistently, >95% of the cells in the gated region expressed CD1a.
Preparation of DV
The preparation of DV has been described previously (31). In brief, four serotypes of DV were propagated in C6/36 mosquito cells in half DMEM and half Mitsuhashi and Moramorosch insect medium containing 2% heat-inactivated FCS at 28°C for 7 days. The supernatants were collected and stored at -70°C until use. The virus titer was determined to be 4 x 106 to 3 x 107 PFU/ml by plaquing on baby hamster kidney (BHK) cells. The strains of four serotypes of DV used in this study were described previously or obtained as follows: DV1, Hawaii strain (American Type Culture Collection); DV2, New Guinea C strain (32); DV3, H87 strain (American Type Culture Collection); and DV4, H241 strain (American Type Culture Collection). Unless otherwise specified, DV2 New Guinea C strain was used as the source of DV to infect DC throughout this paper.
Infection of DC with DV
DC cultured for 7–10 days were infected with mock (C6/36 mosquito cell culture supernatants) or different DV serotypes at various multiplicities of infection (MOIs) for 4 h at 37°C as modified from the report by Hung et al. (31). Cells were then washed and cultured in six-well plates (Costar) with culture medium supplemented with or without cytokines as indicated in the figure legends. Cell density was maintained at 1 x 106/ml in 0.5–2 ml of the medium.
Measurement of virus titers
The supernatants from DV-infected DC were collected at various time points as indicated. The production of virus particles in supernatants was determined by titration on adherent BHK cells, permissive to four serotypes of DV. The numbers of plaques were counted and shown as PFU per milliliter. Virus titers <102 were taken as 102 for convenience.
Confocal microscope and electron microscope examinations
After infection, DC were collected at 24 and 48 h and fixed in 4% paraformaldehyde in 0.1 M PBS, pH 7.4, for 30 min. The DC cell suspensions were adhered to a polylysine-coated slide, permeabilized by incubating with 1% Triton X-100 for 5 min twice, and stained with anti-NS1 mAb (29), and then rabbit anti-mouse Ab conjugated with FITC (Jackson ImmunoResearch Laboratories, West Grove, PA) was added. After washing, the cells were stained with goat anti-CD1a polyclonal Ab (Santa Cruz Biotechnology, Santa Cruz, CA), followed by biotin-conjugated anti-sheep/goat mAb (Amersham Pharmacia, Piscataway, NJ), which was finally labeled with streptavidin-Cy3 (Amersham Pharmacia). For electron microscopy, DC cell pellets were collected and fixed in 2.5% glutaraldehyde and 0.1 M cacodylate buffer. After dehydrations with ethanol, the cells were embedded in eponate-12 as described previously (33), and examined under a transmission electron microscope (JEM 1230; JEOL, Peabody, MA).
Determination of cytokine production and cell surface molecule expression
Standard ELISAs were used to measure cytokine concentrations in
harvested supernatants as detailed in our previous work
(34). All determinants were performed in duplicate (IL-6
and IFN-) or triplicate (TNF- and IL-12) and expressed as the
mean ± SD. The detection limits for these cytokines are: TNF-,
5 pg/ml (R&D Systems); IFN-, 10 pg/ml (Endogen, Woburn, MA); IL-6, 3
pg/ml (R&D Systems); and IL-12, 7 pg/ml (R&D Systems). The expression
of cell surface molecules was determined by flow cytometric analysis
(35). Each histogram or density plot comprised at least
104 events.
Measurement of cellular apoptosis by flow cytometric analysis
The mock-treated or DV-infected DC, after washing with cold PBS, were pelleted and resuspended in binding buffer containing HEPES-buffered PBS supplemented with 2.5 mmol/l CaCl2. Then 10 µl of annexin V-FITC at a concentration of 10 µg/ml and 10 µl of propidium iodide (PI) at a concentration of 50 µg/ml were added to each sample and incubated for 15 min at room temperature. After washing, the cells were analyzed by a flow cytometer (Becton Dickinson). The annexin V+ and PI- population represents early apoptosis, and the late apoptotic or necrotic population is shown to be annexin V+ and PI+.
Nested RT-PCR
To determine the specificity of DV2, a nested RT/PCR method described by Lanciotti et al. (36) was exactly adapted. In brief, the viral RNA was isolated from the supernatants of DV-infected DC. After RT of RNA to cDNA, samples were subjected to PCR. The consensus primers 5'-TCAATATGCTGAAACGCGCGAGAAACCG-3' (D1 primer, genomic positions 134–161) and 5'-TTGCACCAACAGTCAATGTCTTCAGGTTC-3' (D2 primer, genomic positions 616–644) were used to amplify 511-bp DNA products (our unpublished observations). After the first-round amplification reaction with consensus primers, a second-round amplification reaction was conducted, except that the D2 primer was replaced with the DV2-specific primer 5'-CGCCACAAGGGCCATGAACAG-3' (genomic positions 232–252). The RT-PCR working conditions have been detailed previously (36). The final products were analyzed on a 4% agarose gel, stained with ethidium bromide, and visualized under UV light. After the second-round PCR, a 119-bp product specific for DV2 is detected.
Statistics
When necessary, the results were expressed as the mean ± SD. A paired (for comparison of cytokine production) or unpaired (for comparison of virus titers) Student’s t test was used to determine the difference, which was considered significant at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DC were propagated from culturing adherent human PBMC in the
presence of GM-CSF and IL-4. The detached cells were then removed at
different time points, stained with anti-CD1a or isotype-matched
control mAb, and analyzed in a flow cytometer. As shown in Fig. 1
A, after culture for >7
days, >95% of the gated monocyte-derived DC population expressed
CD1a. In contrast, the expression of CD14 was barely detectable after 7
days of culture (Fig. 1B). All of the following experiments
were performed using DC cultured for 7–10 days. At this time point, DC
routinely represented 65–95% of the total cell population. Such an
estimation is a conservative, low measure of the DC population, because
a significant number of unstained "cells" are acellular debris, as
characterized by their size and light scatter properties in flow
cytometric analysis.
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Because DC were established in the culture medium containing IL-4
and GM-CSF, we first investigated the effects of these cytokines on
virus production. After infection with DV2 New Guinea C strain at an
MOI of 1, DC were maintained in the culture medium with or without
cytokines. As shown in Fig. 2A, DC could provide efficient
replications of DV and yielded infectious virus particles in both
conditions. In the presence of cytokines, higher titers of virus
particles were produced. To minimize the effects of cytokines, the rest
of the experiments were conducted without supplementing the culture
medium with cytokines after DV infection. The specificity of the
productive infection of DV2 was subsequently confirmed with nested
RT-PCR that detects a 119-bp product specific for DV2 in the culture
supernatants (Fig. 2B). These results exclude the
possibility that the productive infection of DC by DV2 is because of
the contamination by other DV serotypes or other flaviviruses. The
infection of DC by DV was further investigated by staining both the
intracellular viral NS1 protein and the cell surface CD1a molecule and
then was analyzed under a confocal microscope. As illustrated in Fig. 2C, only DV-infected, but not mock-treated, DC coexpressed
CD1a and NS1 proteins. As predicted, CD1a was localized on the cell
surface, whereas NS1 was located in the cytosol (Fig. 2C,
lower panel, showing better contrast). In our preliminary
studies we also found that neither purified B lymphocytes nor T
lymphocytes, two major populations contaminating DC purity, could be
infected by DV (our unpublished observations). Therefore, these results
strongly suggest that DV could infect cultured human DC.
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To investigate the organelle of DC where DV resided, the infected
DC were examined under an electron microscope. As shown in Fig. 3a, after infection for
24 h DV particles were obvious in cystic vesicles, vacuoles, and
the endoplasmic reticulum. Fig. 3B clearly shows the
structures of the rough endoplasmic reticulum with virus particles
inside. This is consistent with the characters of flavivirus infection
(37). In addition, virus-induced hypertrophy and
proliferation of the rough endoplasmic reticulum as well as swollen
mitochondria were observed (Fig. 3, a and b). We
could not find similar pictures in mock-treated DC (our unpublished
observations). These findings may suggest a cell undergoing apoptosis,
although in this particular picture of EM, the nuclear condensation has
not developed yet (38) (Fig. 3a). However, we
did observe many DV-infected cells showing pictures of nuclear
condensation (our unpublished observation). Because mock-treated DC
also showed patterns of nuclear condensation, whether these findings in
DV-infected DC were due to DV infection or as were the result of a
spontaneous consequence in the absence of feeding cytokines was
not clear. When the cells were examined 48 h after infection,
bulky virus particles inside the vesicle were detected, and virus
release out of the cell membrane became evident (Fig. 3c).
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There are four serotypes of DV (DV1–4), and their infectivities
in DC were examined. As shown in Fig. 4, although the production of virus titers was different, four serotypes
of DV at an MOI of 1 could infect DC.
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After confirming the infection of DC by DV, the possible outcomes
of DC after infection were investigated. There are two stages in DC
development. In the immature stage, DC primarily phagocytose and
process Ag, whereas in the mature stage, DC function as the best Ag
presenters to T lymphocytes by up-regulating the expression of
costimulatory and HLA-DR molecules (16). We determined
whether DV infection of DC could enhance the expression of these cell
surface molecules. After mock infection or infection with DV at an MOI
of 1 for 48 h, cells were collected, and the gated DC population
was analyzed for cell surface molecule expression. As shown in Fig. 5, compared with mock-treated DC, DV
infection induced significant expression of B7-1, B7-2, CD11b, HLA-DR,
and CD83 on DC. Thus, DV infection of DC induced cellular
maturation.
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Aside from the expression of costimulatory molecules, DC also
initiate a potent immune response through the secreted cytokines. The
supernatants from mock-treated or DV-infected DC were collected at
48 h after infection and assayed for several cytokine
concentrations. As shown in Fig. 6A, the cultured DC
spontaneously produced a variety of cytokines, consistent with other
reports (39, 40). In the presence of DV infection, DC
produced higher levels of IFN- and TNF-, but not IL-12 and IL-6.
The production of IFN- was not detectable (our unpublished
observations). The induction of TNF- production could also be
observed in four serotypes of DV infection (Fig. 6B).
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In the absence of feeding cytokines, DC died through an apoptotic
pathway, similar to that observed in spontaneous apoptosis of monocytes
(41) (our unpublished observations). We found that
compared with mock treatment, DV infection resulted in a higher
percentage of cell death in the early phase of infection (see below).
Such an accelerated apoptotic mechanism appeared not to involve Fas/Fas
ligand interaction, because these two molecules were not induced on
DV-infected DC (our unpublished observations). It has been shown that
mature DC are more resistant than immature DC to vaccinia virus-induced
cell apoptosis; we determined whether this could also be observed in DV
infection (26, 42). Both mock-treated and DV-infected DC
cultured for longer periods of time in the absence of exogenous
cytokines were stained with annexin V-FITC and PI and examined with a
flow cytometer. As shown in Fig. 7, compared with mock-treated DC, DV infection induced more DC showing
annexin V+PI- and annexin
V+PI+ in the first 22
h. In contrast to mock-treated DC that died rapidly after 22 h,
the DV-infected DC were more resistant to apoptosis.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human PBMC cultured with recombinant IL-4 and GM-CSF were shown to
generate DC with the most efficient Ag-presenting function
(46). In the presence of DC maturation factor CD40 ligand,
these myeloid lineage DC become potent inducers of Th1 differentiation
(47). Using different techniques, we show that DC,
established from this well-appreciated condition, could provide DV to
enter and produce virus particles. In addition, this conclusion was
consistently observed in four different serotypes of DV infection (Fig. 4
). In our hands, both purified human T and B lymphocytes were poorly
infected by DV (unpublished observations). According to Rosen et al.
(48), 7 of 16 mesenteric lymph node specimens and 13 of 18
spleen specimens from children dying of DHF contain DV RNA. It is
highly possible that DC may be one of the primary targets of DV in
these infected tissues. In support of this idea as well as our
observations, while this paper was under review Wu et al.
(49) provided convincing evidence that DV could infect DC
both in vitro and in vivo.
By using different approaches, many known or sequence-unidentified molecules were reported to be potential DV receptors (50, 51, 52). Among previous reports, Chen et al. (53), using Vero cells as target cells, presented convincing evidence showing that the highly sulfated glycosaminoglycan (GAG) is the putative cellular receptor for DV. Interestingly, we found that among the GAGs examined, heparin, heparan sulfate, and dermatan sulfate, but not chondroitin sulfate A, could inhibit DV-DC binding (unpublished observations). Examination of the molecular mass (kilodaltons) and the number of sulfate groups per disaccharide unit (SO3-/COO- ratio) of these compounds shows the order of molecular mass as chondroitin sulfate A (30 kDa)>dermatan sulfate (28 kDa)>heparan sulfate (18 kDa)>heparin (13.6 kDa), and the order of SO3-/COO- ratio as heparin (2.14)>dermatan sulfate (1.22)>chondroitin sulfate A (1)>heparan sulfate (0.93) (54). Thus, although the sulfation of GAGs is important for virus-DC binding in several examples (53, 54, 55, 56, 57), our preliminary observations suggest that, in contrast to Vero cells, the binding of DV to DC may have no strong correlation with the levels of sulfation of GAGs.
DC undergo the maturation process and migrate from peripheral tissues
to lymph nodes after being directly infected or phagocytosing apoptotic
infected cells (58, 59). The DC maturation process can be
regulated by a variety of stimuli such as cytokines, viral products,
and CD40 ligand. In the context of infection, micro-organisms use the
mechanism of modulating the DC maturation process to influence the
immune response. For example, the infection of DC by vaccinia virus
inhibits DC maturation and therefore down-regulates its stimulatory
capacity to T lymphocytes (42). A similar mechanism was
demonstrated in herpes simplex virus infection (60). The
infection of erythrocytes by Plasmodium falciparum induces
the expression of PfEMP-1 Ag, which, after binding to DC, inhibits
maturation of immature DC (61). The infection of DC by
Trypanosoma cruzi also results in inhibition of the
maturation process (62); through the suppression of DC
maturation, it may help virus to evade the immune regulation and to
minimize the immune response. Although some micro-organism infections
may impair the maturation process of DC, other pathogens could drive DC
maturation after infection. As reported by Schnorr et al.
(63), measles virus infection of DC induces DC maturation
that, in turn, causes immunosuppression through as yet unidentified
mechanisms. The induction of DC maturation may also result in
protection against a viral cytopathic effect and help stabilize the
production of viral progeny (26). Similar effects were
indeed observed in the example of DV infection of human DC shown in
this report (Fig. 7).
In reaction to the entrance of virus, DC may release various cytokines
to initiate an immune response and probably leading to the pathological
changes seen in virus infection (59). The production of
cytokines from DV-infected DC seem to be differentially regulated; only
TNF- and IFN-, not IL-6 and IL-12, were significantly induced
(Fig. 6A). The induction of TNF- in DV-infected DC was
correlated very well with clinical observations examining TNF-
levels in plasma samples from DV-infected patients (11, 64). Importantly, the increase in TNF- was more often
detected in DHF patients’ plasma than in that from DF patients or
non-Dengue febrile illness patients (11). Because the
secretion of cytokines may be regulated in different kinetics, we do
not exclude the possibility that both IL-6 and IL-12 may be maximally
induced at later time points after infection. Regarding the cytokines
secreted from DV-infected DC, the type 1 IFN has been shown to mediate
the antiviral response (65, 66, 67). In the example of dsRNA
infection of DC, the anti-apoptotic mechanism of IFN- is
associated with the induction of MxA protein that exerts
anti-cytopathic effects (26, 68). Similarly, TNF-
can protect DC from cell death through up-regulating anti-apoptotic
factors such as Bcl-xl (69, 70). Thus, aside from cell
maturation, the virus-induced production of TNF- and IFN- may
also contribute to the lesser cell death in DV-infected DC in the late
phase of virus infection (Fig. 7).
Whether DV infection results in DC apoptosis is still an open question. In our system because DC were infected with DV in the absence of feeding cytokines, it has been very difficult to differentiate DV-induced apoptosis from cytokine withdrawal-induced apoptosis. Our preliminary results also suggest that DV infection could not induce the expression of Fas/Fas ligand on DC (our unpublished observations). The addition of both IL-4 and GM-CSF growth factors to the culture could rescue DV-infected DC from undergoing apoptosis (our unpublished observations). Apparently, more sophisticated experiments are required to resolve this issue.
In conclusion, in this study we provide evidence that human DC support the active replication of DV. After infection by DV, DC secrete cytokines that probably lead to cell maturation. Through the infection and activation of DC, it may induce the activation of T lymphocytes and initiate an adaptive immune response. Although DV infection might accelerate the apoptotic process in cytokine-withdrawn DC, both cell maturation and cytokine production could delay or block the ongoing process of apoptosis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jenn-Haung Lai, Rheumatology/Immunology & Allergy, Tri-Service General Hospital, No. 325, Sec. 2, Cheng-Kung Road, Naihu 114, Taipei, Taiwan, Republic of China.
3 Abbreviations used in this paper: DV, Dengue virus(es); DC, dendritic cells; PI, propidium iodide; NS1, nonstructural protein 1; DHF, Dengue hemorrhagic fever; DSS, Dengue shock syndrome; BHK, baby hamster kidney; MOI, multiplicity of infection; GAG, glycosaminoglycan.
Received for publication May 30, 2000. Accepted for publication November 14, 2000.
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H. Zhou and S. Perlman Preferential Infection of Mature Dendritic Cells by Mouse Hepatitis Virus Strain JHM J. Virol., March 1, 2006; 80(5): 2506 - 2514. [Abstract] [Full Text] [PDF]
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B. Shrestha, M. A. Samuel, and M. S. Diamond CD8+ T Cells Require Perforin To Clear West Nile Virus from Infected Neurons J. Virol., January 1, 2006; 80(1): 119 - 129. [Abstract] [Full Text] [PDF]
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C. F. Narvaez, J. Angel, and M. A. Franco Interaction of Rotavirus with Human Myeloid Dendritic Cells J. Virol., December 1, 2005; 79(23): 14526 - 14535. [Abstract] [Full Text] [PDF]
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S. Shresta, K. L. Sharar, D. M. Prigozhin, H. M. Snider, P. R. Beatty, and E. Harris Critical Roles for Both STAT1-Dependent and STAT1-Independent Pathways in the Control of Primary Dengue Virus Infection in Mice J. Immunol., September 15, 2005; 175(6): 3946 - 3954. [Abstract] [Full Text] [PDF]
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C. L. Medin, K. A. Fitzgerald, and A. L. Rothman Dengue Virus Nonstructural Protein NS5 Induces Interleukin-8 Transcription and Secretion J. Virol., September 1, 2005; 79(17): 11053 - 11061. [Abstract] [Full Text] [PDF]
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 C. R. Lambeth, L. J. White, R. E. Johnston, and A. M. de Silva Flow Cytometry-Based Assay for Titrating Dengue Virus J. Clin. Microbiol., July 1, 2005; 43(7): 3267 - 3272. [Abstract] [Full Text] [PDF]
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 P.-Y. Lozach, L. Burleigh, I. Staropoli, E. Navarro-Sanchez, J. Harriague, J.-L. Virelizier, F. A. Rey, P. Despres, F. Arenzana-Seisdedos, and A. Amara Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN)-mediated Enhancement of Dengue Virus Infection Is Independent of DC-SIGN Internalization Signals J. Biol. Chem., June 24, 2005; 280(25): 23698 - 23708. [Abstract] [Full Text] [PDF]
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W.-H. Kwan, A.-M. Helt, C. Maranon, J.-B. Barbaroux, A. Hosmalin, E. Harris, W. H. Fridman, and C. G. F. Mueller Dendritic Cell Precursors Are Permissive to Dengue Virus and Human Immunodeficiency Virus Infection J. Virol., June 15, 2005; 79(12): 7291 - 7299. [Abstract] [Full Text] [PDF]
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E. Mehlhop, K. Whitby, T. Oliphant, A. Marri, M. Engle, and M. S. Diamond Complement Activation Is Required for Induction of a Protective Antibody Response against West Nile Virus Infection J. Virol., June 15, 2005; 79(12): 7466 - 7477. [Abstract] [Full Text] [PDF]
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L.-J. Ho, L.-F. Hung, C.-Y. Weng, W.-L. Wu, P. Chou, Y.-L. Lin, D.-M. Chang, T.-Y. Tai, and J.-H. Lai Dengue Virus Type 2 Antagonizes IFN-{alpha} but Not IFN-{gamma} Antiviral Effect via Down-Regulating Tyk2-STAT Signaling in the Human Dendritic Cell J. Immunol., June 15, 2005; 174(12): 8163 - 8172. [Abstract] [Full Text] [PDF]
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C. M. P. Ribeiro, A. M. Paradiso, U. Schwab, J. Perez-Vilar, L. Jones, W. O'Neal, and R. C. Boucher Chronic Airway Infection/Inflammation Induces a Ca2+i-dependent Hyperinflammatory Response in Human Cystic Fibrosis Airway Epithelia J. Biol. Chem., May 6, 2005; 280(18): 17798 - 17806. [Abstract] [Full Text] [PDF]
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D. R. Palmer, P. Sun, C. Celluzzi, J. Bisbing, S. Pang, W. Sun, M. A. Marovich, and T. Burgess Differential Effects of Dengue Virus on Infected and Bystander Dendritic Cells J. Virol., February 15, 2005; 79(4): 2432 - 2439. [Abstract] [Full Text] [PDF]
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S. BRANDLER, N. BROWN, T. H. ERMAK, F. MITCHELL, M. PARSONS, Z. ZHANG, J. LANG, T. P. MONATH, and F. GUIRAKHOO REPLICATION OF CHIMERIC YELLOW FEVER VIRUS-DENGUE SEROTYPE 1-4 VIRUS VACCINE STRAINS IN DENDRITIC AND HEPATIC CELLS Am J Trop Med Hyg, January 1, 2005; 72(1): 74 - 81. [Abstract] [Full Text] [PDF]
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C.-F. Lin, S.-C. Chiu, Y.-L. Hsiao, S.-W. Wan, H.-Y. Lei, A.-L. Shiau, H.-S. Liu, T.-M. Yeh, S.-H. Chen, C.-C. Liu, et al. Expression of Cytokine, Chemokine, and Adhesion Molecules during Endothelial Cell Activation Induced by Antibodies against Dengue Virus Nonstructural Protein 1 J. Immunol., January 1, 2005; 174(1): 395 - 403. [Abstract] [Full Text] [PDF]
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 G N Malavige, S Fernando, D J Fernando, and S L Seneviratne Dengue viral infections Postgrad. Med. J., October 1, 2004; 80(948): 588 - 601. [Abstract] [Full Text] [PDF]
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L. Fantuzzi, C. Purificato, K. Donato, F. Belardelli, and S. Gessani Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis J. Virol., September 15, 2004; 78(18): 9763 - 9772. [Abstract] [Full Text] [PDF]
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H. Niiya, T. Azuma, L. Jin, N. Uchida, A. Inoue, H. Hasegawa, S. Fujita, M. Tohyama, K. Hashimoto, and M. Yasukawa Transcriptional downregulation of DC-SIGN in human herpesvirus 6-infected dendritic cells J. Gen. Virol., September 1, 2004; 85(9): 2639 - 2642. [Abstract] [Full Text] [PDF]
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R.-J. Lin, C.-L. Liao, E. Lin, and Y.-L. Lin Blocking of the Alpha Interferon-Induced Jak-Stat Signaling Pathway by Japanese Encephalitis Virus Infection J. Virol., September 1, 2004; 78(17): 9285 - 9294. [Abstract] [Full Text] [PDF]
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C. P. Carrasco, R. C. Rigden, I. E. Vincent, C. Balmelli, M. Ceppi, O. Bauhofer, V. Tache, B. Hjertner, F. McNeilly, H. G. van Gennip, et al. Interaction of classical swine fever virus with dendritic cells J. Gen. Virol., June 1, 2004; 85(6): 1633 - 1641. [Abstract] [Full Text] [PDF]
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 A. Granelli-Piperno, A. Golebiowska, C. Trumpfheller, F. P. Siegal, and R. M. Steinman HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation PNAS, May 18, 2004; 101(20): 7669 - 7674. [Abstract] [Full Text] [PDF]
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S. Shresta, J. L. Kyle, H. M. Snider, M. Basavapatna, P. R. Beatty, and E. Harris Interferon-Dependent Immunity Is Essential for Resistance to Primary Dengue Virus Infection in Mice, Whereas T- and B-Cell-Dependent Immunity Are Less Critical J. Virol., March 15, 2004; 78(6): 2701 - 2710. [Abstract] [Full Text] [PDF]
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J.-J. Hung, M.-T. Hsieh, M.-J. Young, C.-L. Kao, C.-C. King, and W. Chang An External Loop Region of Domain III of Dengue Virus Type 2 Envelope Protein Is Involved in Serotype-Specific Binding to Mosquito but Not Mammalian Cells J. Virol., January 1, 2004; 78(1): 378 - 388. [Abstract] [Full Text] [PDF]
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I. E. Vincent, C. P. Carrasco, B. Herrmann, B. M. Meehan, G. M. Allan, A. Summerfield, and K. C. McCullough Dendritic Cells Harbor Infectious Porcine Circovirus Type 2 in the Absence of Apparent Cell Modulation or Replication of the Virus J. Virol., December 15, 2003; 77(24): 13288 - 13300. [Abstract] [Full Text] [PDF]
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 T. W. Geisbert, L. E. Hensley, T. Larsen, H. A. Young, D. S. Reed, J. B. Geisbert, D. P. Scott, E. Kagan, P. B. Jahrling, and K. J. Davis Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques: Evidence that Dendritic Cells Are Early and Sustained Targets of Infection Am. J. Pathol., December 1, 2003; 163(6): 2347 - 2370. [Abstract] [Full Text]
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S. Pichyangkul, T. P. Endy, S. Kalayanarooj, A. Nisalak, K. Yongvanitchit, S. Green, A. L. Rothman, F. A. Ennis, and D. H. Libraty A Blunted Blood Plasmacytoid Dendritic Cell Response to an Acute Systemic Viral Infection Is Associated with Increased Disease Severity J. Immunol., November 15, 2003; 171(10): 5571 - 5578. [Abstract] [Full Text] [PDF]
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 B. Tassaneetrithep, T. H. Burgess, A. Granelli-Piperno, C. Trumpfheller, J. Finke, W. Sun, M. A. Eller, K. Pattanapanyasat, S. Sarasombath, D. L. Birx, et al. DC-SIGN (CD209) Mediates Dengue Virus Infection of Human Dendritic Cells J. Exp. Med., April 7, 2003; 197(7): 823 - 829. [Abstract] [Full Text] [PDF]
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R. Cologna and R. Rico-Hesse American Genotype Structures Decrease Dengue Virus Output from Human Monocytes and Dendritic Cells J. Virol., April 1, 2003; 77(7): 3929 - 3938. [Abstract] [Full Text] [PDF]
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S. Mahanty, K. Hutchinson, S. Agarwal, M. Mcrae, P. E. Rollin, and B. Pulendran Cutting Edge: Impairment of Dendritic Cells and Adaptive Immunity by Ebola and Lassa Viruses J. Immunol., March 15, 2003; 170(6): 2797 - 2801. [Abstract] [Full Text] [PDF]
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Y.-W. Lin, K.-J. Wang, H.-Y. Lei, Y.-S. Lin, T.-M. Yeh, H.-S. Liu, C.-C. Liu, and S.-H. Chen Virus Replication and Cytokine Production in Dengue Virus-Infected Human B Lymphocytes J. Virol., October 25, 2002; 76(23): 12242 - 12249. [Abstract] [Full Text] [PDF]
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M. J. Raftery, A. A. Kraus, R. Ulrich, D. H. Kruger, and G. Schonrich Hantavirus Infection of Dendritic Cells J. Virol., October 2, 2002; 76(21): 10724 - 10733. [Abstract] [Full Text] [PDF]
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M. Kakimoto, A. Hasegawa, S. Fujita, and M. Yasukawa Phenotypic and Functional Alterations of Dendritic Cells Induced by Human Herpesvirus 6 Infection J. Virol., September 11, 2002; 76(20): 10338 - 10345. [Abstract] [Full Text] [PDF]
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 L. Li, D. Liu, L. Hutt-Fletcher, A. Morgan, M. G. Masucci, and V. Levitsky Epstein-Barr virus inhibits the development of dendritic cells by promoting apoptosis of their monocyte precursors in the presence of granulocyte macrophage-colony-stimulating factor and interleukin-4 Blood, May 15, 2002; 99(10): 3725 - 3734. [Abstract] [Full Text] [PDF]
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M. M. B. Moreno-Altamirano, F. J. Sanchez-Garcia, and M. L. Munoz Non Fc receptor-mediated infection of human macrophages by dengue virus serotype 2 J. Gen. Virol., May 1, 2002; 83(5): 1123 - 1130. [Abstract] [Full Text] [PDF]
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I. Anraku, T. J. Harvey, R. Linedale, J. Gardner, D. Harrich, A. Suhrbier, and A. A. Khromykh Kunjin Virus Replicon Vaccine Vectors Induce Protective CD8+ T-Cell Immunity J. Virol., March 19, 2002; 76(8): 3791 - 3799. [Abstract] [Full Text] [PDF]
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 M. F. Lipscomb and B. J. Masten Dendritic Cells: Immune Regulators in Health and Disease Physiol Rev, January 1, 2002; 82(1): 97 - 130. [Abstract] [Full Text] [PDF]
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