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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 varies among macrophages, monocyte, and dendritic cell (DC) subsets in the presence or absence of enhancing antibodies. DC-SIGN expression correlates with high infection in the absence of enhancing antibodies (i.e., 1° infection conditions), whereas FcγR expression modulates antibody-enhanced infection during ADE. Macrophages (MΦ) and monocytes express low levels of DC-SIGN, and show little DENV infection in the absence of enhancing antibody, but are highly infected in the presence of enhancing antibody. Under inflammatory conditions, monocytes differentiate to immature monocyte-derived DCs (moDCs) and, further, to mature moDCs after stimulation via PAMPs or inflammatory cytokines. While immature moDCs express high levels of DC-SIGN and can be infected with DENV in the absence of antibodies, mature moDCs express lower levels of DC-SIGN and show moderate permissiveness under these conditions. Accordingly, mature moDCs show a capacity for enhanced infection in the presence of subneutralizing anti-DENV antibodies. Classical DCs (cDCs) that are freshly isolated from human blood do not express DC-SIGN, but express high levels of DC-SIGN after stimulation with GM-CSF and IL-4 in vitro (*), which renders them highly susceptible to DENV infection without antibody, similar to immature moDCs. Plasmacytoid DCs (pDCs) do not express DC-SIGN or support DENV replication in the absence of antibody. cDCs and pDCs express FcγRs, but DENV infection of cDCs and pDCs during ADE has not been determined (n.d.).
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Figure 1: DENV infection varies among macrophages, monocyte, and dendritic cell (DC) subsets in the presence or absence of enhancing antibodies. DC-SIGN expression correlates with high infection in the absence of enhancing antibodies (i.e., 1° infection conditions), whereas FcγR expression modulates antibody-enhanced infection during ADE. Macrophages (MΦ) and monocytes express low levels of DC-SIGN, and show little DENV infection in the absence of enhancing antibody, but are highly infected in the presence of enhancing antibody. Under inflammatory conditions, monocytes differentiate to immature monocyte-derived DCs (moDCs) and, further, to mature moDCs after stimulation via PAMPs or inflammatory cytokines. While immature moDCs express high levels of DC-SIGN and can be infected with DENV in the absence of antibodies, mature moDCs express lower levels of DC-SIGN and show moderate permissiveness under these conditions. Accordingly, mature moDCs show a capacity for enhanced infection in the presence of subneutralizing anti-DENV antibodies. Classical DCs (cDCs) that are freshly isolated from human blood do not express DC-SIGN, but express high levels of DC-SIGN after stimulation with GM-CSF and IL-4 in vitro (*), which renders them highly susceptible to DENV infection without antibody, similar to immature moDCs. Plasmacytoid DCs (pDCs) do not express DC-SIGN or support DENV replication in the absence of antibody. cDCs and pDCs express FcγRs, but DENV infection of cDCs and pDCs during ADE has not been determined (n.d.).

Mentions: Surface expression of viral attachment factors determines the susceptibility to DENV infection. DC-SIGN (dendritic-cell-specific ICAM3-grabbing non-integrin, CD209) is a C-type lectin expressed on the surface of DCs and MΦs that recognizes mannose-type sugars on the surface of bacterial, fungal, and viral pathogens. Signals via DC-SIGN induce the phagocytosis of pathogens and contribute to host defense (54). However, DC-SIGN also interacts with carbohydrates on DENV glycoproteins and mediates the attachment of DENV to moDCs (55–57). Human immature moDCs express high levels of DC-SIGN and are highly susceptible to DENV infection (50, 58, 59). Of note, DC-SIGN mediates virus attachment to the cell surface, but not endocytosis into moDCs (60). Activation of immature moDCs via inflammatory cytokines results in downregulation of DC-SIGN, explaining in part why mature moDCs are less susceptible to DENV infection (51, 58). Further, human cDCs freshly isolated from blood do not express DC-SIGN and, accordingly, become highly susceptible to DENV infection only after culture with GM-CSF and IL-4 that induces DC-SIGN expression (61). Similarly, treatment of monocytes with IL-4 or IL-13 increased DC-SIGN expression and DENV infection (62), but it remains unclear whether these monocytes had differentiated to moDCs or MΦs. Consistent with these findings, higher levels of DC-SIGN expression on cDCs of different blood donors correlated with higher DENV infection (61). Furthermore, a polymorphic variant of the DC-SIGN promoter with a decreased transcriptional activity correlated with protection against DF in humans (63). In summary, changes in DC-SIGN expression on different myeloid cell subsets through differentiation correlate with DENV infection (Figure 1).


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 varies among macrophages, monocyte, and dendritic cell (DC) subsets in the presence or absence of enhancing antibodies. DC-SIGN expression correlates with high infection in the absence of enhancing antibodies (i.e., 1° infection conditions), whereas FcγR expression modulates antibody-enhanced infection during ADE. Macrophages (MΦ) and monocytes express low levels of DC-SIGN, and show little DENV infection in the absence of enhancing antibody, but are highly infected in the presence of enhancing antibody. Under inflammatory conditions, monocytes differentiate to immature monocyte-derived DCs (moDCs) and, further, to mature moDCs after stimulation via PAMPs or inflammatory cytokines. While immature moDCs express high levels of DC-SIGN and can be infected with DENV in the absence of antibodies, mature moDCs express lower levels of DC-SIGN and show moderate permissiveness under these conditions. Accordingly, mature moDCs show a capacity for enhanced infection in the presence of subneutralizing anti-DENV antibodies. Classical DCs (cDCs) that are freshly isolated from human blood do not express DC-SIGN, but express high levels of DC-SIGN after stimulation with GM-CSF and IL-4 in vitro (*), which renders them highly susceptible to DENV infection without antibody, similar to immature moDCs. Plasmacytoid DCs (pDCs) do not express DC-SIGN or support DENV replication in the absence of antibody. cDCs and pDCs express FcγRs, but DENV infection of cDCs and pDCs during ADE has not been determined (n.d.).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: DENV infection varies among macrophages, monocyte, and dendritic cell (DC) subsets in the presence or absence of enhancing antibodies. DC-SIGN expression correlates with high infection in the absence of enhancing antibodies (i.e., 1° infection conditions), whereas FcγR expression modulates antibody-enhanced infection during ADE. Macrophages (MΦ) and monocytes express low levels of DC-SIGN, and show little DENV infection in the absence of enhancing antibody, but are highly infected in the presence of enhancing antibody. Under inflammatory conditions, monocytes differentiate to immature monocyte-derived DCs (moDCs) and, further, to mature moDCs after stimulation via PAMPs or inflammatory cytokines. While immature moDCs express high levels of DC-SIGN and can be infected with DENV in the absence of antibodies, mature moDCs express lower levels of DC-SIGN and show moderate permissiveness under these conditions. Accordingly, mature moDCs show a capacity for enhanced infection in the presence of subneutralizing anti-DENV antibodies. Classical DCs (cDCs) that are freshly isolated from human blood do not express DC-SIGN, but express high levels of DC-SIGN after stimulation with GM-CSF and IL-4 in vitro (*), which renders them highly susceptible to DENV infection without antibody, similar to immature moDCs. Plasmacytoid DCs (pDCs) do not express DC-SIGN or support DENV replication in the absence of antibody. cDCs and pDCs express FcγRs, but DENV infection of cDCs and pDCs during ADE has not been determined (n.d.).
Mentions: Surface expression of viral attachment factors determines the susceptibility to DENV infection. DC-SIGN (dendritic-cell-specific ICAM3-grabbing non-integrin, CD209) is a C-type lectin expressed on the surface of DCs and MΦs that recognizes mannose-type sugars on the surface of bacterial, fungal, and viral pathogens. Signals via DC-SIGN induce the phagocytosis of pathogens and contribute to host defense (54). However, DC-SIGN also interacts with carbohydrates on DENV glycoproteins and mediates the attachment of DENV to moDCs (55–57). Human immature moDCs express high levels of DC-SIGN and are highly susceptible to DENV infection (50, 58, 59). Of note, DC-SIGN mediates virus attachment to the cell surface, but not endocytosis into moDCs (60). Activation of immature moDCs via inflammatory cytokines results in downregulation of DC-SIGN, explaining in part why mature moDCs are less susceptible to DENV infection (51, 58). Further, human cDCs freshly isolated from blood do not express DC-SIGN and, accordingly, become highly susceptible to DENV infection only after culture with GM-CSF and IL-4 that induces DC-SIGN expression (61). Similarly, treatment of monocytes with IL-4 or IL-13 increased DC-SIGN expression and DENV infection (62), but it remains unclear whether these monocytes had differentiated to moDCs or MΦs. Consistent with these findings, higher levels of DC-SIGN expression on cDCs of different blood donors correlated with higher DENV infection (61). Furthermore, a polymorphic variant of the DC-SIGN promoter with a decreased transcriptional activity correlated with protection against DF in humans (63). In summary, changes in DC-SIGN expression on different myeloid cell subsets through differentiation correlate with DENV infection (Figure 1).

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