Zhu and Lobato et al. uncovered the pathology of hereditary neuropathy caused by sorbitol dehydrogenase deficiency and provided a potential treatment strategy by using an aldose reductase inhibitor, AT-007 (govorestat). The cover image depicts the Drosophila flight muscle neuromuscular junctions immunolabeled with a synaptic active zone marker (Bruchpilot) and a neuronal membrane marker (horseradish peroxidase). Image credit: Tijana Canic, Yi Zhu, and Amanda Lobato.
Given the COVID-19 pandemic, there is interest in understanding ligand-receptor features and targeted antibody-binding attributes against emerging SARS-CoV-2 variants. Here we developed a large-scale structure-based pipeline for analysis of protein-protein interactions regulating SARS-CoV-2 immune evasion. First, we generated computed structural models of the Spike protein of three SARS-CoV-2 variants (B.1.1.529, BA.2.12.1, and BA.5) bound either to a native receptor (ACE2) or to a large panel of targeted ligands (n=282), which included neutralizing or therapeutic monoclonal antibodies. Moreover, by using the Barnes Classification, we noted an overall loss of interfacial interactions (with gain-of-new-interactions in certain cases) at the receptor-binding domain (RBD) mediated by substituted residues for neutralizing complexes in Classes 1 and 2, whereas less destabilization was observed for Classes 3 and 4. Finally, an experimental validation of predicted weakened therapeutic antibody binding was performed on a cell-based assay. Compared to the original Omicron variant (B.1.1.529), derivative variants featured progressive destabilization of antibody-RBD interfaces mediated by a larger set of substituted residues, thereby providing a molecular basis for immune evasion. This approach and findings provide a framework for rapidly and efficiently generating structural models for SARS-CoV-2 variants bound to ligands of mechanistic and therapeutic value.
Joseph H. Lubin, Christopher Markosian, D. Balamurugan, Minh T. Ma, Chih-Hsiung Chen, Dongfang Liu, Renata Pasqualini, Wadih Arap, Stephen K. Burley, Sagar D. Khare
BACKGROUND. A randomized clinical trial from 1984-1992 indicated that vitamin A supplementation had a beneficial effect on the progression of retinitis pigmentosa (RP), while vitamin E had an adverse effect. METHODS. Sequencing of banked DNA samples from that trial provided the opportunity to determine if certain genotypes responded preferentially to vitamin supplementation. RESULTS. The genetic solution rate was 587/765 (77%) of sequenced samples. Combining genetic solutions with electroretinogram outcomes showed that there were systematic differences in severity and progression seen among different genetic subtypes of RP, extending findings made for USH2A, RHO, RPGR, PRPF31, and EYS. Baseline electroretinogram 30Hz flicker implicit time was an independent strong predictor of progression rate. Using additional data and baseline implicit time as a predictor, the deleterious effect of vitamin E was still present. Surprisingly, the effect of vitamin A progression in the cohort as a whole was not detectable, with or without data from subsequent trials. Subgroup analyses are also discussed. CONCLUSION. Overall, genetic subtype and implicit time have significant predictive power for a patient’s rate of progression, which is useful prognostically. While vitamin E supplementation should still be avoided, these data do not support a generalized neuroprotective effect of vitamin A for all types of RP. TRAIL REGISTRATION. ClinicalTrials.gov NCT00000114, NCT00000116, NCT00346333 FUNDING. the Foundation Fighting Blindness and the National Eye Institute: RO1 EY012910 (EAP), R01 EY031036 (JC), R01EY026904 (KMB/EAP), and P30EY014104.
Jason Comander, Carol Weigel DiFranco, Kit Green Sanderson, Emily M. Place, Matthew Maher, Erin Zampaglione, Yan Zhao, Rachel M. Huckfeldt, Kinga M. Bujakowska, Eric A. Pierce
Ulcerative colitis (UC), Crohn’s disease (CD), and celiac disease are prevalent intestinal inflammatory disorders with non-satisfactory therapeutic interventions. Analyzing patient data-driven cohorts can highlight disease pathways and new targets for interventions. Long non-coding RNAs (lncRNAs) are attractive candidates as they are readily targetable by RNA therapeutics, show relative cell-specific expression, and play key cellular functions. Uniformly analyzing gut mucosal transcriptomics from 696 subjects, we highlight lncRNA expression along the gastrointestinal (GI) tract, demonstrating that in control samples, lncRNAs have a more location-specific expression in comparison to protein-coding genes. We defined dysregulation of lncRNAs in treatment-naïve UC, CD, and celiac diseases using independent test and validation cohorts. Using the PROTECT inception UC cohort, we define and prioritize lncRNA linked with UC severity and prospective outcomes, and highlight lncRNAs linked with gut microbes previously implicated in mucosal homeostasis. HNF1A-AS1 lncRNA was reduced in all 3 conditions and was further reduced in more severe UC form. Similarly, the reduction of HNF1A-AS1 ortholog in mice gut epithelial showed higher sensitivity to dextran sodium sulfate-induced colitis which was coupled with alteration in the gut microbial community. These analyses highlight prioritized dysregulated lncRNAs that can guide future preclinical studies for testing them as novel potential targets.
Tzipi Braun, Katya E. Sosnovski, Amnon Amir, Marina BenShoshan, Kelli L. VanDussen, Rebekah Karns, Nina Levhar, Haya Abbas-Egbariya, Rotem Hadar, Gilat Efroni, David Castel, Camila Avivi, Michael J. Rosen, Anne M. Grifiths, Thomas D. Walters, David R. Mack, Brendan M. Boyle, Syed Asad Ali, Sean R. Moore, Melanie Schirmer, Ramnik J. Xavier, Subra Kugathasan, Anil G. Jegga, Batya Weiss, Chen Mayer, Iris Barshack, Shomron Ben-Horin, Igor Ulitsky, Anthony Beucher, Jorge Ferrer, Jeffrey S. Hyams, Lee A. Denson, Yael Haberman
Intratumoral heterogeneity is a defining hallmark of glioblastoma, driving drug resistant and ultimately recurrence. Many somatic drivers of microenvironmental change have been shown to affect this heterogeneity and ultimately treatment response. However, little is known about how germline mutations effect the tumoral microenvironment. Here, we find that the single-nucleotide polymorphism (SNP) rs755622 in promoter of the cytokine macrophage migration inhibitory factor (MIF), is associated with increased leukocyte infiltration in glioblastoma. Furthermore, we identified an association between rs755622 and lactotransferrin expression, which could also be used as a biomarker for immune-infiltrated tumors. These findings demonstrate that a germline SNP in the promoter region of MIF may impact the immune microenvironment and further reveals a link between lactotransferrin and immune activation.
Tyler J. Alban, Matthew M. Grabowski, Balint Otvos, Defne Bayik, Wesley Wang, Ajay H. Zalavadia, Vladimir Makarav, Katie M. Troike, Mary McGraw, Anja Rabljenovic, Adam Lauko, Chase K.A. Neumann, Gustavo Roversi, Kristin A. Waite, Gino Cioffi, Nirav Patil, Thuy T. Tran, Kathleen McCortney, Alicia Steffens, C. Marcela Diaz-Montero, J. Mark Brown, Kathleen M. Egan, Craig Horbinski, Jill S. Barnholtz-Sloan, Prajwal Rajappa, Michael A. Vogelbaum, Richard Bucala, Timothy A. Chan, Manmeet S. Ahluwalia, Justin D. Lathia
SARS-CoV-2 mRNA vaccination generates protective B cell responses targeting the SARS-CoV-2 spike glycoprotein. Whereas anti-spike memory B cell responses are long-lasting, the anti-spike humoral antibody response progressively wanes, making booster vaccinations necessary for maintaining protective immunity. Here we investigated qualitatively the plasmablast responses by measuring from single cells within hours of sampling the affinity of their secreted antibody for the SARS-CoV-2 spike receptor binding domain in cohorts of BNT162b2-vaccinated naive and COVID-19-recovered individuals. Using a unique droplet microfluidic and imaging approach, we analyzed >4,000 single IgG-secreting cells revealing high inter-individual variability in affinity for RBD with variations over 4 logs. High-affinity plasmablasts were induced by BNT162b2 vaccination against Hu-1 and Omicron RBD but disappeared quickly thereafter, whereas low-affinity plasmablasts represented >65% of the plasmablast response at all timepoints. Our droplet-based method thus proves efficient at fast and qualitative immune monitoring and should be helpful for optimization of vaccination protocols.
Matteo Broketa, Aurélien Sokal, Michael Mor, Pablo Canales-Herrerias, Angga Perima, Annalisa Meola, Ignacio Fernández, Bruno Iannascoli, Guilhem Chenon, Alexis Vandenberghe, Laetitia Languille, Marc Michel, Bertrand Godeau, Sebastien Gallien, Giovanna Melica, Marija Backovic, Felix A. Rey, Jean Baudry, Natalia T. Freund, Matthieu Mahevas, Pierre Bruhns
JCI This Month is a digest of the research, reviews, and other features published each month.