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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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Increased TLR2 expression in pDCs of patients with severe disease.Analysis of TLR2 expression by flow cytometry of PB mDCs (A) and pDCs (B) in DF patients (n = 19) and DHF patients (n = 11) at different times after the onset of symptoms (days 3, 5 and 15). Data are presented as the median and 25–75 interquartile ranges. Statistical analysis was performed by the Mann Withney test.*p<0.05, ** p<0.01 and ***p<0.001.
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pntd-0002060-g004: Increased TLR2 expression in pDCs of patients with severe disease.Analysis of TLR2 expression by flow cytometry of PB mDCs (A) and pDCs (B) in DF patients (n = 19) and DHF patients (n = 11) at different times after the onset of symptoms (days 3, 5 and 15). Data are presented as the median and 25–75 interquartile ranges. Statistical analysis was performed by the Mann Withney test.*p<0.05, ** p<0.01 and ***p<0.001.

Mentions: The development of DHF is associated with an increased level of circulating pro-inflammatory cytokines and chemokines [28]–[30], and several in vitro studies indicate that TLRs may contribute to this phenomenon [5], [31]. Therefore, we compared the expression profiles of TLR2 and TLR4 in mDCs, pDCs and monocytes of patients with DF and DHF on different days of disease to those of HCs. Similar TLR2 and TLR4 expression levels were detected in monocytes of DF, DHF patients and HCs (data not shown). In contrast, there was a modulation in TLR2 expression in DCs of DF and DHF patients. On day 3 of illness, DF patients presented significantly lower TLR2 expression in mDCs, compared to HCs and DHF patients (p<0.05; Fig. 4A). On days 5 and 15, the level of TLR2 expression was similar in patients with DF and DHF. In pDCs of DHF patients, a significant increase in TLR2 expression was seen on day 3 of illness, compared to HCs (p<0.05; Fig. 4B). This increase reached a maximum on day 5 of acute infection (p<0.001). No differences were found in TLR4 expression levels in mDCs (data not shown).


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)

Increased TLR2 expression in pDCs of patients with severe disease.Analysis of TLR2 expression by flow cytometry of PB mDCs (A) and pDCs (B) in DF patients (n = 19) and DHF patients (n = 11) at different times after the onset of symptoms (days 3, 5 and 15). Data are presented as the median and 25–75 interquartile ranges. Statistical analysis 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-g004: Increased TLR2 expression in pDCs of patients with severe disease.Analysis of TLR2 expression by flow cytometry of PB mDCs (A) and pDCs (B) in DF patients (n = 19) and DHF patients (n = 11) at different times after the onset of symptoms (days 3, 5 and 15). Data are presented as the median and 25–75 interquartile ranges. Statistical analysis was performed by the Mann Withney test.*p<0.05, ** p<0.01 and ***p<0.001.
Mentions: The development of DHF is associated with an increased level of circulating pro-inflammatory cytokines and chemokines [28]–[30], and several in vitro studies indicate that TLRs may contribute to this phenomenon [5], [31]. Therefore, we compared the expression profiles of TLR2 and TLR4 in mDCs, pDCs and monocytes of patients with DF and DHF on different days of disease to those of HCs. Similar TLR2 and TLR4 expression levels were detected in monocytes of DF, DHF patients and HCs (data not shown). In contrast, there was a modulation in TLR2 expression in DCs of DF and DHF patients. On day 3 of illness, DF patients presented significantly lower TLR2 expression in mDCs, compared to HCs and DHF patients (p<0.05; Fig. 4A). On days 5 and 15, the level of TLR2 expression was similar in patients with DF and DHF. In pDCs of DHF patients, a significant increase in TLR2 expression was seen on day 3 of illness, compared to HCs (p<0.05; Fig. 4B). This increase reached a maximum on day 5 of acute infection (p<0.001). No differences were found in TLR4 expression levels in mDCs (data not shown).

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