Tracking Plasmacytoid Dendritic Cell Response to Physical Contact with Infected Cells.

Dendritic cells (DCs) are key regulators of both innate and adaptive immunity via varied functions, including cytokine production and antigen presentation. Plasmacytoid DC (pDC) is a DC subset specialized in the production of type I and III interferons (IFNs). They are thus pivotal players of the host antiviral response during the acute phase of infection by genetically distant viruses. The pDC response is primarily triggered by the endolysosomal sensors Toll-like receptors, which recognize nucleic acids from pathogens. In some pathologic contexts, pDC response can also be triggered by host nucleic acids, hereby contributing to the pathogenesis of autoimmune diseases, such as, e.g., systemic lupus erythematosus. Importantly, recent in vitro studies from our laboratory and others uncovered that pDCs sense viral infections when a physical contact is established with infected cells. This specialized synapse-like feature enables a robust type I and III IFN secretion at the infected site. Therefore, this concentrated and confined response likely limits the correlated deleterious impacts of excessive cytokine production to the host, notably due to tissue damages. Here we provide a pipeline of methods for ex vivo studies of pDC antiviral functions, designed to address how pDC activation is regulated by cell-cell contact with virally infected cells and the current approaches enabling to decipher the underlying molecular events leading to an efficient antiviral response.

Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2.

Type I and III interferons (IFN-I/λ) are important antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells (pDC) are the predominant IFN-I/λ source following their sensing of SARS-CoV-2-infected cells. Mechanistically, this short-range sensing by pDCs requires sustained integrin-mediated cell adhesion with infected cells. In turn, pDCs restrict viral spread by an IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likely via a local response at the contact site with infected cells. By exploring the pDC response in SARS-CoV-2 patients, we further demonstrate that pDC responsiveness inversely correlates with the severity of the disease. The pDC response is particularly impaired in severe COVID-19 patients. Overall, we propose that pDC activation is essential to control SARS-CoV-2-infection. Failure to develop this response could be important to understand severe cases of COVID-19.

Bacteria-Resistant Single Chain Cyclized/Knotted Polymer Coatings.

Further to conventional linear, branched, crosslinked, and dendritic polymers, single chain cyclized/knotted polymers (SCKPs) have emerged as a new class of polymer structure with unique properties. Herein, the development of bacteria-resistant SCKPs is reported and the effect of this structure on the resistance of polymer materials to bacteria is investigated. Four SCKPs were synthesized by reversible addition fragmentation chain transfer (RAFT) homopolymerization of multivinyl monomers (MVMs) and then crosslinked by UV light to form SCKP films. Regardless of MVM type used, the resulting SCKP films showed much higher resistance to bacteria, and up to 75 % less bacterial attachment and biofilm formation, in comparison with the corresponding non-SCKP films. This is due to the altered surface morphology and hydrophobicity of the SCKP films. These results highlight the critical role of the SCKP structure in enhancing the resistance of polymeric materials to bacteria.

Versatile Hyperbranched Poly(ß-hydrazide ester) Macromers as Injectable Antioxidative Hydrogels.

Synthetic reactive oxygen species (ROS)-responsive biomaterials have emerged as a useful platform for regulating critical aspects of ROS-induced pathologies and can improve such hostile microenvironments. Here, we report a series of new hyperbranched poly(ß-hydrazide ester) macromers (HB-PBHEs) with disulfide moieties synthesized via an "A2 + B4" Michael addition approach. The three-dimensional structure of HB-PBHEs with multiacrylate end groups endows the macromers with rapid gelation capabilities to form (1) injectable hydrogels via cross-linking with thiolated hyaluronic acid and (2) robust UV-cross-linked hydrogels. The disulfide-containing macromers and hydrogels exhibit H2O2-responsive degradation compared with the counterparts synthesized by a dihydrazide monomer without disulfide moieties. The cell viability under a high ROS environment can be well-maintained under the protection of the disulfide containing hydrogels.