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Dendritic cells in dengue virus infection: targets of virus replication and mediators of immunity.

Schmid MA, Diamond MS, Harris E - Front Immunol (2014)

Bottom Line: DENV causes the most prevalent arthropod-borne viral disease in humans, yet no vaccine or specific therapeutic is currently licensed.We discuss the dual role of DCs as both targets of DENV replication and mediators of innate and adaptive immunity, and summarize immune evasion strategies whereby DENV impairs the function of infected DCs.We suggest that DCs play a key role in priming DENV-specific neutralizing or potentially harmful memory B- and T-cell responses, and that future DC-directed therapies may help induce protective memory responses and reduce dengue pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California Berkeley , Berkeley, CA , USA.

ABSTRACT
Dendritic cells (DCs) are sentinels of the immune system and detect pathogens at sites of entry, such as the skin. In addition to the ability of DCs to control infections directly via their innate immune functions, DCs help to prime adaptive B- and T-cell responses by processing and presenting antigen in lymphoid tissues. Infected Aedes aegypti or Aedes albopictus mosquitoes transmit the four dengue virus (DENV) serotypes to humans while probing for small blood vessels in the skin. DENV causes the most prevalent arthropod-borne viral disease in humans, yet no vaccine or specific therapeutic is currently licensed. Although primary DENV infection confers life-long protective immunity against re-infection with the same DENV serotype, secondary infection with a different DENV serotype can lead to increased disease severity via cross-reactive T-cells or enhancing antibodies. This review summarizes recent findings in humans and animal models about DENV infection of DCs, monocytes, and macrophages. We discuss the dual role of DCs as both targets of DENV replication and mediators of innate and adaptive immunity, and summarize immune evasion strategies whereby DENV impairs the function of infected DCs. We suggest that DCs play a key role in priming DENV-specific neutralizing or potentially harmful memory B- and T-cell responses, and that future DC-directed therapies may help induce protective memory responses and reduce dengue pathogenesis.

No MeSH data available.


Related in: MedlinePlus

DENV infection impairs DC activation and priming of adaptive T-cell responses. (A) Maturation of human moDCs is inhibited by DENV infection, due to DENV non-structural proteins blocking induction and intracellular signaling of IFN-α/β. However, non-infected bystander DCs respond to PAMPs and/or cytokines associated with DENV infection and upregulate MHC class I and II molecules, co-stimulatory molecules, and the expression of inflammatory cytokines and chemokines. (B) Mature, bystander DCs efficiently prime adaptive T-cell responses, whereas DENV-infected DCs prime naïve T-cells less efficiently. (C) Activated T-cells display CD40L on their surface or secrete CD40L that acts on DENV-infected DCs and can restore DC maturation and function. Purple denotes DENV infection, while orange denotes inflammation/cell activation.
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Figure 2: DENV infection impairs DC activation and priming of adaptive T-cell responses. (A) Maturation of human moDCs is inhibited by DENV infection, due to DENV non-structural proteins blocking induction and intracellular signaling of IFN-α/β. However, non-infected bystander DCs respond to PAMPs and/or cytokines associated with DENV infection and upregulate MHC class I and II molecules, co-stimulatory molecules, and the expression of inflammatory cytokines and chemokines. (B) Mature, bystander DCs efficiently prime adaptive T-cell responses, whereas DENV-infected DCs prime naïve T-cells less efficiently. (C) Activated T-cells display CD40L on their surface or secrete CD40L that acts on DENV-infected DCs and can restore DC maturation and function. Purple denotes DENV infection, while orange denotes inflammation/cell activation.

Mentions: Pathogen recognition leads to DC maturation, which is characterized by increased expression of MHC II and co-stimulatory markers required for efficient priming of T-cell responses (117). After exposure to DENV, non-infected bystander moDCs upregulate MHC I and II molecules, as well as co-stimulatory molecules CD80 (B7-1), CD83, and CD86 (B7-2), although DENV blocks activation and maturation of infected moDCs within the same cultures (59, 116) (Figure 2A). Intracellular staining for DENV proteins revealed a block in activation of DENV-infected moDCs that was not observed in bulk culture (50, 59). Similarly, non-infected bystander monocytes, moDCs and cDCs, expressed higher levels of CD80 and CD86 than DENV-infected cells in the dermis of intradermally infected Ifnar−/− mice (53). In addition, DCs produce cytokines and chemokines to modulate T-cell responses. DENV-exposed moDCs (50, 59, 116) or cDCs (61), produce IL-6, IL-10, TNFα, and IFN-α. Furthermore, DENV-exposed moDCs secrete CXCL9, CXCL10, and CXCL11 (118) that bind the chemokine receptor CXCR3 and could attract effector and memory T-cells. However, it remains unclear whether it is the DENV-infected or non-infected DCs that produce these inflammatory mediators. Together, these data suggest that DENV blocks activation in infected DCs, which may decrease the priming of CD4+ or CD8+ T-cells, whereas non-infected bystander cells still can become activated.


Dendritic cells in dengue virus infection: targets of virus replication and mediators of immunity.

Schmid MA, Diamond MS, Harris E - Front Immunol (2014)

DENV infection impairs DC activation and priming of adaptive T-cell responses. (A) Maturation of human moDCs is inhibited by DENV infection, due to DENV non-structural proteins blocking induction and intracellular signaling of IFN-α/β. However, non-infected bystander DCs respond to PAMPs and/or cytokines associated with DENV infection and upregulate MHC class I and II molecules, co-stimulatory molecules, and the expression of inflammatory cytokines and chemokines. (B) Mature, bystander DCs efficiently prime adaptive T-cell responses, whereas DENV-infected DCs prime naïve T-cells less efficiently. (C) Activated T-cells display CD40L on their surface or secrete CD40L that acts on DENV-infected DCs and can restore DC maturation and function. Purple denotes DENV infection, while orange denotes inflammation/cell activation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4269190&req=5

Figure 2: DENV infection impairs DC activation and priming of adaptive T-cell responses. (A) Maturation of human moDCs is inhibited by DENV infection, due to DENV non-structural proteins blocking induction and intracellular signaling of IFN-α/β. However, non-infected bystander DCs respond to PAMPs and/or cytokines associated with DENV infection and upregulate MHC class I and II molecules, co-stimulatory molecules, and the expression of inflammatory cytokines and chemokines. (B) Mature, bystander DCs efficiently prime adaptive T-cell responses, whereas DENV-infected DCs prime naïve T-cells less efficiently. (C) Activated T-cells display CD40L on their surface or secrete CD40L that acts on DENV-infected DCs and can restore DC maturation and function. Purple denotes DENV infection, while orange denotes inflammation/cell activation.
Mentions: Pathogen recognition leads to DC maturation, which is characterized by increased expression of MHC II and co-stimulatory markers required for efficient priming of T-cell responses (117). After exposure to DENV, non-infected bystander moDCs upregulate MHC I and II molecules, as well as co-stimulatory molecules CD80 (B7-1), CD83, and CD86 (B7-2), although DENV blocks activation and maturation of infected moDCs within the same cultures (59, 116) (Figure 2A). Intracellular staining for DENV proteins revealed a block in activation of DENV-infected moDCs that was not observed in bulk culture (50, 59). Similarly, non-infected bystander monocytes, moDCs and cDCs, expressed higher levels of CD80 and CD86 than DENV-infected cells in the dermis of intradermally infected Ifnar−/− mice (53). In addition, DCs produce cytokines and chemokines to modulate T-cell responses. DENV-exposed moDCs (50, 59, 116) or cDCs (61), produce IL-6, IL-10, TNFα, and IFN-α. Furthermore, DENV-exposed moDCs secrete CXCL9, CXCL10, and CXCL11 (118) that bind the chemokine receptor CXCR3 and could attract effector and memory T-cells. However, it remains unclear whether it is the DENV-infected or non-infected DCs that produce these inflammatory mediators. Together, these data suggest that DENV blocks activation in infected DCs, which may decrease the priming of CD4+ or CD8+ T-cells, whereas non-infected bystander cells still can become activated.

Bottom Line: DENV causes the most prevalent arthropod-borne viral disease in humans, yet no vaccine or specific therapeutic is currently licensed.We discuss the dual role of DCs as both targets of DENV replication and mediators of innate and adaptive immunity, and summarize immune evasion strategies whereby DENV impairs the function of infected DCs.We suggest that DCs play a key role in priming DENV-specific neutralizing or potentially harmful memory B- and T-cell responses, and that future DC-directed therapies may help induce protective memory responses and reduce dengue pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California Berkeley , Berkeley, CA , USA.

ABSTRACT
Dendritic cells (DCs) are sentinels of the immune system and detect pathogens at sites of entry, such as the skin. In addition to the ability of DCs to control infections directly via their innate immune functions, DCs help to prime adaptive B- and T-cell responses by processing and presenting antigen in lymphoid tissues. Infected Aedes aegypti or Aedes albopictus mosquitoes transmit the four dengue virus (DENV) serotypes to humans while probing for small blood vessels in the skin. DENV causes the most prevalent arthropod-borne viral disease in humans, yet no vaccine or specific therapeutic is currently licensed. Although primary DENV infection confers life-long protective immunity against re-infection with the same DENV serotype, secondary infection with a different DENV serotype can lead to increased disease severity via cross-reactive T-cells or enhancing antibodies. This review summarizes recent findings in humans and animal models about DENV infection of DCs, monocytes, and macrophages. We discuss the dual role of DCs as both targets of DENV replication and mediators of innate and adaptive immunity, and summarize immune evasion strategies whereby DENV impairs the function of infected DCs. We suggest that DCs play a key role in priming DENV-specific neutralizing or potentially harmful memory B- and T-cell responses, and that future DC-directed therapies may help induce protective memory responses and reduce dengue pathogenesis.

No MeSH data available.


Related in: MedlinePlus