Binding of herpes simplex virus (HSV) glycoprotein D (gD) to a cell surface receptor is required to trigger membrane fusion during entry into host cells. Nectin-1 is a cell adhesion molecule and the main HSV receptor in neurons and epithelial cells. We report the structure of gD bound to nectin-1 determined by x-ray crystallography to 4.0 Å resolution. The structure reveals that the nectin-1 binding site on gD differs from the binding site of the HVEM receptor. A surface on the first Ig-domain of nectin-1, which mediates homophilic interactions of Ig-like cell adhesion molecules, buries an area composed by residues from both the gD N- and C-terminal extensions. Phenylalanine 129, at the tip of the loop connecting β-strands F and G of nectin-1, protrudes into a groove on gD, which is otherwise occupied by C-terminal residues in the unliganded gD and by N-terminal residues in the gD/HVEM complex. Notably, mutation of Phe129 to alanine prevents nectin-1 binding to gD and HSV entry. Together these data are consistent with previous studies showing that gD disrupts the normal nectin-1 homophilic interactions. Furthermore, the structure of the complex supports a model in which gD-receptor binding triggers HSV entry through receptor-mediated displacement of the gD C-terminal region.

Regulation of Natural Killer (NK) cell activity is achieved by the integration of both activating and inhibitory signals acquired at the immunological synapse with potential target cells. NK cells express paired receptors from the immunoglobulin family which share common ligands from the nectin family of adhesion molecules. The activating receptor CD226 (DNAM-1) binds to nectin-2 and CD155, which are also recognized by the inhibitory receptor TIGIT. The third receptor in this family is CD96, which is less well characterized and may have different functions in human and mouse models. Human CD96 interacts with CD155 and ligation of this receptor activates NK cells, while in mice the presence of CD96 correlates with decreased NK cell activation. Mouse CD96 also binds nectin-1, but the effect of this interaction has not yet been determined. Here we show that human nectin-1 directly interacts with CD96 in vitro . The binding site for CD96 is located on the nectin-1 V-domain, which comprises a canonical interface that is shared by nectins to promote cell adhesion. The affinity of nectin-1 for CD96 is lower than for other nectins such as nectin-3 and nectin-1 itself. However, the affinity of nectin-1 for CD96 is similar to its affinity for herpes simplex virus glycoprotein D (HSV gD), which binds the nectin-1 V-domain during virus entry. The affinity of human CD96 for nectin-1 is lower than for its known activating ligand CD155. We also found that human erythroleukemia K562 cells, which are commonly used as susceptible targets to assess NK cell cytotoxicity did not express nectin-1 on their surface and were resistant to HSV infection. When expressed in K562 cells, nectin-1-GFP accumulated at cell contacts and allowed HSV entry. Furthermore, overexpression of nectin-1-GFP led to an increased susceptibility of K562 cells to NK-92 cell cytotoxicity.

The motility of many parasites is critical for the infection process of their host, as exemplified by the transmission cycle of the blood fluke Schistosoma mansoni [1]. In their human infectious stage, immature, submillimetre-scale forms of the parasite known as cercariae swim in freshwater and infect human hosts by penetrating through the skin [1,2]. This infection causes Schistosomiasis, a parasitic disease that is comparable to malaria in terms of global socio-economic impact [3,4]. Given that cercariae do not feed and hence have a finite lifetime of around 12 hours [5,6], efficient motility is crucial for the parasite's survival and transmission of the Schistosomiasis disease. However, a first-principles understanding of how cercariae swim is completely lacking. Via a combined experimental, theoretical and robotics based approach -we demonstrate that cercariae efficiently propel themselves against gravity by exploiting a unique elastohydrodynamic coupling. We show that cercariae beat their tail in a periodic fashion while maintaining a fixed flexibility near their posterior and anterior ends. The flexibility in these regions allows an interaction between the fluid drag and bending resistance -an elastohydrodynamic coupling, to naturally break time-reversal symmetry and enable locomotion at small length-scales [7]. We present a theoretical model, a 'T-swimmer', which captures the key swimming phenotype of cercariae. We further validate our results experimentally through a macro-scale robotic realization of the 'T-swimmer', explaining the unique forked-tail geometry of cercariae.Finally, we find that cercariae maintain the flexibility at their posterior and anterior ends at an optimal regime for efficient swimming, as predicted by our theoretical model. We anticipate that our work sets the ground for linking the swimming of S. mansoni cercariae to disease transmission and enables explorations of novel strategies for Schistosomiasis control and prevention.

Herpes simplex virus (HSV) uses the cell adhesion molecule nectin-1 as a receptor to enter neurons and epithelial cells. The viral glycoprotein D (gD) is used as a non-canonical ligand for nectin-1. The gD binding site on nectin-1 overlaps with a functional adhesive site involved in nectin-nectin homophilic trans-interaction. Consequently, when nectin-1 is engaged with a cellular ligand at cell junctions, the gD binding site is occupied. Here we report that HSV gD is able to disrupt intercellular homophilic trans-interaction of nectin-1 and induce a rapid redistribution of nectin-1 from cell junctions. This movement does not require the receptor's interaction with the actin-binding adaptor afadin. Interaction of nectin-1 with afadin is also dispensable for virion surfing along nectin-1-rich filopodia. Cells seeded on gD-coated surfaces also fail to accumulate nectin-1 at cell contact. These data indicate that HSV gD affects nectin-1 locally through direct interaction and more globally through signaling.

We present an automatic annotation pipeline to recover 9D cuboids and 3D shape from pre-trained off-the-shelf 2D detectors and sparse LIDAR data. Our autolabeling method solves this challenging ill-posed inverse problem by relying on learned shape priors and optimization of geometric and physical parameters. To that end, we propose a novel differentiable shape renderer over signed distance fields (SDF), which we leverage in combination with normalized object coordinate spaces (NOCS). Initially trained on synthetic data to predict shape and coordinates, our method uses these predictions for projective and geometrical alignment over real samples. We also propose a curriculum learning strategy, iteratively retraining on samples of increasing difficulty for subsequent self-improving annotation rounds. Our experiments on the KITTI3D dataset show that we can recover a substantial amount of accurate cuboids, and that these autolabels can be used to train 3D vehicle detectors with state-of-the-art results. We will make the code publicly available soon.