Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

Measles virus （MV） is highly contagious pathogen, which causes a profound immunosuppression, resulting in high infant mortality. This virus infects dendritic cells （DCs） following the binding of MV hemagglutinin （MV-H） to CD150 receptor and alters DC functions by a mechanism that is not completely understood. We have analyzed the effect of MV-H interaction with CD150-expressing DCs on the DC signaling pathways and consequent phenotypic and functional changes in the absence of infectious context. We demonstrated that contact between CD150 on human DCs and MV-H expressed on membrane of transfected CHO cells was sufficient to modulate the activity of two major regulatory pathways of DC differentiation and function： to stimulate Akt and inhibit p38 MAPK phosphorylation, without concomitant ERK1/2 activation. Furthermore, interaction with MV-H decreased the expression level of DC activation markers CD80, CD83, CD86, and HLA-DR and strongly downregulated IL-12 production but did not modulate IL-IO secretion. Moreover, contact with MV-H suppressed DC-mediated T-cell alloproliferation, demonstrating profound alteration of DC maturation and functions. Finally, engagement of CD150 by MV-H in mice transgenic for human CD150 decreased inflammatory responses, showing the immunosuppressive effect of CD150-MV-H interaction in vivo. Altogether, these results uncover novel mechanism of MV-induced immunosuppression, implicating modulation of cell signaling pathways following MV-H interaction with CD150-expressing DCs and reveal anti-inflammatory effects of CD150 stimulation.

Human Endogenous Retrovirus Type W Envelope from Multiple Sclerosis Demyelinating Lesions Shows Unique Solubility and Antigenic Characteristics

In multiple sclerosis(MS),human endogenous retrovirus W family(HERV-W)envelope protein,pHERV-W ENV,limits remyelination and induces microglia-mediated neurodegeneration.To better understand its role,we examined the soluble pHERV-W antigen from MS brain lesions detected by specific antibodies.Physico-chemical and antigenic characteristics confirmed differences between pHERV-W ENV and syncytin-1.pHERV-W ENV monomers and trimers remained associated with membranes,while hexamers self-assembled from monomers into a soluble macrostructure involving sulfatides in MS brain.Extracellular hexamers are stabilized by internal hydrophobic bonds and external hydrophilic moieties.HERV-W studies in MS also suggest that this diffusible antigen may correspond to a previously described highmolecular-weight neurotoxic factor secreted by MS B-cells and thus represents a major agonist in MS pathogenesis.Adapted methods are now needed to identify encoding HERV provirus(es)in affected cells DNA.The properties and origin of MS brain pHERV-W ENV soluble antigen will allow a better understanding of the role of HERVs in MS pathogenesis.The present results anyhow pave the way to an accurate detection of the different forms of pHERV-W ENV antigen with appropriate conditions that remained unseen until now.

Single-chain variable fragment antibody constructs neutralize measles virus infection in vitro and in vivo

Despite the availability of an effective measles virus(MeV)vaccine and efforts to increase vaccine coverage by the WHO,UNICEF,and their partners,MeV has not been eradicated,and the estimated global measles death rose from 89,780 in 2016 to 207,500 in 2019.1 Because there is an effective measles vaccine,antiviral development for measles has not been prioritized,but recent outbreaks have highlighted the need for drugs to prevent transmission in unvaccinated populations and to protect and treat immunocompromised individuals.We identified several neutralizing mouse monoclonal antibodies(mAbs)that target the MeV fusion(F)protein in its prefusion state2 and inhibit fusion and viral infection.We engineered a single-chain variable fragment(scFv)from the most potent anti-MeV F mAb.The scFv retains the ability to inhibit fusion and prevents infection in vitro,and intranasal administration of the scFv antibody construct prevents infection in vivo.

Correction to: Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

In this article,published online on 15 June 2015,there was an unintended error during the image processing of Figs.2 and 4.In Fig.2c,the time point 12 h was omitted and is included in the corrected Fig.2c.Figure 4a and b contain blots not intended for that experiment,which now have been replaced with the blots generated for that experiment.The conclusions drawn from the presented experiments remain unaltered,and this correction has no bearing on the final outcome of the study.The inconvenience caused by this error is deeply regretted.