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Differential expression of Toll-like receptors in dendritic cells of patients with dengue during early and late acute phases of the disease.

Torres S, Hernández JC, Giraldo D, Arboleda M, Rojas M, Smit JM, Urcuqui-Inchima S - PLoS Negl Trop Dis (2013)

Bottom Line: In addition, we found a lower expression of TLR2 in patients with DF compared to DHF.This suggests that the virus can affect the interferon response through this signaling pathway.Changes in TLRs expression could play a central role in DC activation, thereby influencing the innate immune response.

View Article: PubMed Central - PubMed

Affiliation: Grupo Inmunovirología, Sede de Investigación Universitaria, Universidad de Antioquia, Medellín, Colombia.

ABSTRACT

Background: Dengue hemorrhagic fever (DHF) is observed in individuals that have pre-existing heterotypic dengue antibodies and is associated with increased viral load and high levels of pro-inflammatory cytokines early in infection. Interestingly, a recent study showed that dengue virus infection in the presence of antibodies resulted in poor stimulation of Toll-like receptors (TLRs), thereby facilitating virus particle production, and also suggesting that TLRs may contribute to disease pathogenesis.

Methodology/principal findings: We evaluated the expression levels of TLR2, 3, 4 and 9 and the co-stimulatory molecules CD80 and CD86 by flow cytometry. This was evaluated in monocytes, in myeloid and plasmacytoid dendritic cells (mDCs and pDCs) from 30 dengue patients with different clinical outcomes and in 20 healthy controls. Increased expression of TLR3 and TLR9 in DCs of patients with dengue fever (DF) early in infection was detected. In DCs from patients with severe manifestations, poor stimulation of TLR3 and TLR9 was observed. In addition, we found a lower expression of TLR2 in patients with DF compared to DHF. Expression levels of TLR4 were not affected. Furthermore, the expression of CD80 and CD86 was altered in mDCs and CD86 in pDCs of severe dengue cases. We show that interferon alpha production decreased in the presence of dengue virus after stimulation of PBMCs with the TLR9 agonist (CpG A). This suggests that the virus can affect the interferon response through this signaling pathway.

Conclusions/significance: These results show that during dengue disease progression, the expression profile of TLRs changes depending on the severity of the disease. Changes in TLRs expression could play a central role in DC activation, thereby influencing the innate immune response.

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Related in: MedlinePlus

Expression of the co-stimulatory molecules CD80 and CD86 is affected in mDCs of DHF patients.Expression of CD80 (A) and CD86 (B) was evaluated by flow cytometry based on the FMI analysis in mDCs and pDCs (C) of DF and DHF patients on day 3 of illness and compared to that of healthy controls (HC). Data are presented as the median and the statistical analysis of the expression of CD80 and CD86 was performed by the Mann Withney test.*p<0.05, ** p<0.01 and ***p<0.001.
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pntd-0002060-g006: Expression of the co-stimulatory molecules CD80 and CD86 is affected in mDCs of DHF patients.Expression of CD80 (A) and CD86 (B) was evaluated by flow cytometry based on the FMI analysis in mDCs and pDCs (C) of DF and DHF patients on day 3 of illness and compared to that of healthy controls (HC). Data are presented as the median and the statistical analysis of the expression of CD80 and CD86 was performed by the Mann Withney test.*p<0.05, ** p<0.01 and ***p<0.001.

Mentions: Infection of mDCs with DENV has been reported to induce DC maturation and activation, albeit to lower levels than observed in uninfected DCs [34], [35]. Since the effect of DENV on DC maturation is unclear in vivo, we assessed here the maturation state of the mDCs and pDCs by examining the expression profile of the co-stimulatory molecules CD80/CD86 in DF and DHF patients. Because the co-stimulatory molecule CD80 appears to be expressed in resting unstimulated mDCs [36], we quantified the expression level of CD80 in mDCs of patients with DF and DHF and compared it with the expression in mDCs of HCs. Analysis of the MFI showed that the mDCs of DHF patients express significantly lower levels of CD80 (p<0.05) and CD86 (p<0.001), when compared to HCs (Fig. 6A and 6B). Likewise, in pDCs, a significant decrease in the expression level of CD86 was seen in patients with DF and DHF (p<0.05 and p<0.01, respectively), compared to HCs. No differences were found in the expression of CD80 in pDCs (data not shown). Taken together, we observed low expression of TLR3, TLR9, CD80/CD86 in DCs of DHF patients.


Differential expression of Toll-like receptors in dendritic cells of patients with dengue during early and late acute phases of the disease.

Torres S, Hernández JC, Giraldo D, Arboleda M, Rojas M, Smit JM, Urcuqui-Inchima S - PLoS Negl Trop Dis (2013)

Expression of the co-stimulatory molecules CD80 and CD86 is affected in mDCs of DHF patients.Expression of CD80 (A) and CD86 (B) was evaluated by flow cytometry based on the FMI analysis in mDCs and pDCs (C) of DF and DHF patients on day 3 of illness and compared to that of healthy controls (HC). Data are presented as the median and the statistical analysis of the expression of CD80 and CD86 was performed by the Mann Withney test.*p<0.05, ** p<0.01 and ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585035&req=5

pntd-0002060-g006: Expression of the co-stimulatory molecules CD80 and CD86 is affected in mDCs of DHF patients.Expression of CD80 (A) and CD86 (B) was evaluated by flow cytometry based on the FMI analysis in mDCs and pDCs (C) of DF and DHF patients on day 3 of illness and compared to that of healthy controls (HC). Data are presented as the median and the statistical analysis of the expression of CD80 and CD86 was performed by the Mann Withney test.*p<0.05, ** p<0.01 and ***p<0.001.
Mentions: Infection of mDCs with DENV has been reported to induce DC maturation and activation, albeit to lower levels than observed in uninfected DCs [34], [35]. Since the effect of DENV on DC maturation is unclear in vivo, we assessed here the maturation state of the mDCs and pDCs by examining the expression profile of the co-stimulatory molecules CD80/CD86 in DF and DHF patients. Because the co-stimulatory molecule CD80 appears to be expressed in resting unstimulated mDCs [36], we quantified the expression level of CD80 in mDCs of patients with DF and DHF and compared it with the expression in mDCs of HCs. Analysis of the MFI showed that the mDCs of DHF patients express significantly lower levels of CD80 (p<0.05) and CD86 (p<0.001), when compared to HCs (Fig. 6A and 6B). Likewise, in pDCs, a significant decrease in the expression level of CD86 was seen in patients with DF and DHF (p<0.05 and p<0.01, respectively), compared to HCs. No differences were found in the expression of CD80 in pDCs (data not shown). Taken together, we observed low expression of TLR3, TLR9, CD80/CD86 in DCs of DHF patients.

Bottom Line: In addition, we found a lower expression of TLR2 in patients with DF compared to DHF.This suggests that the virus can affect the interferon response through this signaling pathway.Changes in TLRs expression could play a central role in DC activation, thereby influencing the innate immune response.

View Article: PubMed Central - PubMed

Affiliation: Grupo Inmunovirología, Sede de Investigación Universitaria, Universidad de Antioquia, Medellín, Colombia.

ABSTRACT

Background: Dengue hemorrhagic fever (DHF) is observed in individuals that have pre-existing heterotypic dengue antibodies and is associated with increased viral load and high levels of pro-inflammatory cytokines early in infection. Interestingly, a recent study showed that dengue virus infection in the presence of antibodies resulted in poor stimulation of Toll-like receptors (TLRs), thereby facilitating virus particle production, and also suggesting that TLRs may contribute to disease pathogenesis.

Methodology/principal findings: We evaluated the expression levels of TLR2, 3, 4 and 9 and the co-stimulatory molecules CD80 and CD86 by flow cytometry. This was evaluated in monocytes, in myeloid and plasmacytoid dendritic cells (mDCs and pDCs) from 30 dengue patients with different clinical outcomes and in 20 healthy controls. Increased expression of TLR3 and TLR9 in DCs of patients with dengue fever (DF) early in infection was detected. In DCs from patients with severe manifestations, poor stimulation of TLR3 and TLR9 was observed. In addition, we found a lower expression of TLR2 in patients with DF compared to DHF. Expression levels of TLR4 were not affected. Furthermore, the expression of CD80 and CD86 was altered in mDCs and CD86 in pDCs of severe dengue cases. We show that interferon alpha production decreased in the presence of dengue virus after stimulation of PBMCs with the TLR9 agonist (CpG A). This suggests that the virus can affect the interferon response through this signaling pathway.

Conclusions/significance: These results show that during dengue disease progression, the expression profile of TLRs changes depending on the severity of the disease. Changes in TLRs expression could play a central role in DC activation, thereby influencing the innate immune response.

Show MeSH
Related in: MedlinePlus