Abstract
Coxsackie B viruses (CVBs) and echoviruses (EVs) form the Human Enterovirus-B (HEV-B) species within the family Picornaviridae. HEV-B infections are widespread and generally cause mild disease; however, severe infections occur and HEV-B are associated with various chronic diseases such as cardiomyopathy and type 1 diabetes. Dendritic cells (DCs) are the professional antigen-presenting cells of our immune system and initiate and control immune responses to invading pathogens, yet also maintain tolerance to self-antigens. We previously reported that EVs, but not CVBs, can productively infect in vitro generated monocyte-derived DCs. The interactions between HEV-B and human myeloid DCs (mDCs) freshly isolated from blood, however, remain unknown. Here, we studied the susceptibility and responses of BDCA1+ mDC to HEV-B species and found that these mDC are susceptible to EV, but not CVB infection. Productive EV7 infection resulted in massive, rapid cell death without DC activation. Contrary, EV1 infection, which resulted in lower virus input at the same MOI, resulted in DC activation as observed by production of type I interferon-stimulated genes (ISGs), upregulation of co-stimulatory and co-inhibitory molecules (CD80, CD86, PDL1) and production of IL-6 and TNF-α, with a relative moderate decrease in cell viability. EV1-induced ISG expression depended on virus replication. CVB infection did not affect DC viability and resulted in poor induction of ISGs and CD80 induction in part of the donors. These data show for the first time the interaction between HEV-B species and BDCA1+ mDCs isolated freshly from blood. Our data indicate that different HEV-B species can influence DC homeostasis in various ways, possibly contributing to HEV-B associated pathology.
Highlights
Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system that are key players in initiating and modulating innate and adaptive immune responses as well as in maintaining tolerance
The reason for this may be that the virus entry receptor for EV9 Hill is not present on BDCA1+ myeloid DCs (mDCs) isolated freshly from blood from some donors, but is present on monocyte-derived DCs (moDCs); since the receptor used by EV9 Hill is still matter of debate (16, 18) we were unable to determine receptor expression levels of the EV9 Hill entry receptor
Absence of replication of CVBs can be explained by lack of the CAR receptor on BDCA1+ mDCs, whereas CAR is readily detected on HEK cells and BGM cells (Fig. 1B and data not shown)
Summary
Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system that are key players in initiating and modulating innate and adaptive immune responses as well as in maintaining tolerance. DCs express a variety of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and RIGI-like receptors (RLRs), which they use to recognize pathogens, pathogen-associated molecules, or pathogen induced-damage [1,2]. TLR3 and the RLRs RIG-I (retinoic acid inducible gene I) and Mda (melanoma differentiation- associated gene 5) are PRRs involved in sensing double-stranded (ds) viral RNA. Triggering of PRRs results in phenotypic maturation of the DC and production of pro-inflammatory cytokines, enabling the DC to initiate antiviral responses [3]. DCs (cross)present viral peptides to CD4+ T cells and CD8+ T cells to eliminate virus infected cells [4,5]. Viruses have co-evolved with their hosts and evade antiviral immune responses via several ways
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