Pivotal Advance: The promotion of soluble DC-SIGN release by inflammatory signals and its enhancement of cytomegalovirus-mediatedcis-infection of myeloid dendritic cells

Abstract

DC-SIGN is a member of the C-type lectin family. Mainly expressed by myeloid DCs, it is involved in the capture and internalization of pathogens, including human CMV. Several transcripts have been identified, some of which code for putative soluble proteins. However, little is known about the regulation and the functional properties of such putative sDC-SIGN variants. To better understand how sDC-SIGN could be involved in CMV infection, we set out to characterize biochemical and functional properties of rDC-SIGN as well as naturally occurring sDC-SIGN. We first developed a specific, quantitative ELISA and then used it to detect the presence sDC-SIGN in in vitro-generated DC culture supernatants as cell-free secreted tetramers. Next, in correlation with their inflammatory status, we demonstrated the presence of sDC-SIGN in several human body fluids, including serum, joint fluids, and BALs. CMV infection of human tissues was also shown to promote sDC-SIGN release. Based on the analysis of the cytokine/chemokine content of sDC-SIGN culture supernatants, we identified IFN-γ and CXCL8/IL-8 as inducers of sDC-SIGN production by MoDC. Finally, we demonstrated that sDC-SIGN was able to interact with CMV gB under native conditions, leading to a significant increase in MoDC CMV infection. Overall, our results confirm that sDC-SIGN, like its well-known, counterpart mDC-SIGN, may play a pivotal role in CMV-mediated pathogenesis.

Bifunctional CD4–DC-SIGN Fusion Proteins Demonstrate Enhanced Avidity to gp120 and Inhibit HIV-1 Infection and Dissemination

“…Whether they can be used prophylactically or therapeutically requires further evaluation. Given that the soluble forms of CD4 and DC-SIGN occur normally in vivo and that the Gly4Ser repeat linker is poorly immunogenic (43,44), further improvement of CLDs may render them potentially useful as prophylactic or therapeutic agents.…”

Exosomes in Viral Disease

“…DC-SIGN is a C-type lectin family member that is necessary for virus uptake [132]. It was shown that this release mediated infection of myeloid DCs by CMV and increased overall CMV infectivity [131]. HHV-6, another betaherpesvirus, has already been discussed in terms of the viral association with the endosomal pathway and MVBs.…”

The Role of HTLV-1 in Alteration of Immune Regulation Through Regulatory T Cell Dysfunction and Exosomal Manipulation

“…Severe fever with thrombocytopenia syndrome virus was found to package virions within CD63 + extracellular vesicles (exosomes), which allowed for efficient receptor-independent uptake by neighboring cells [141]. Of note, pheleboviruses also have DC-SIGN as a receptor [142] , which has been shown to be packaged into exosomes for uptake in uninfected cells by CMV [131]. Further investigation should be undertaken to observe if a similar mechanism for viral spread is employed by phleboviruses and bunyaviruses in general.…”

“…DC-SIGN is a C-type lectin family member that is necessary for virus uptake [132]. It was shown that this release mediated infection of myeloid DCs by CMV and increased overall CMV infectivity [131].…”

“…The authors proposed that this was a potential contributor to allograft rejection in transplant recipients. In addition to promoting an activated immune response, CMV infection can also increase the release of DC-SIGN on exosomes in complex with the viral glycoprotein gB [131]. DC-SIGN is a C-type lectin family member that is necessary for virus uptake [132].…”