Erratum in Cell. 2022 Jun 23;185(13):2390.

Author information: (1)The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. (2)Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3)Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4)Amsterdam University Medical Centers/VUmc, Amsterdam, the Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. (5)Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (6)School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Brazil, Ribeirao Preto, São Paulo, Brazil. (7)Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, MI, USA. (8)service d'anatomopathologie, Hôpital de l'Enfant-Jésus du Centre hospitalier universitaire de Québec, Université Laval, Quebec City, QC, Canada. (9)Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria. (10)National Cancer Institute, Bethesda, MD, USA. (11)Department of Cellular and Molecular Pathology, Leeds Teaching Hospital NHS Trust, St James's University Hospital, Leeds, UK. (12)The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Cancer and Cell Biology Division, the Translational Genomics Research Institute, Phoenix, AZ, USA. (13)The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Department of Biopharmaceutical Convergence, Department of Pharmacy, Sungkyunkwan University, Suwon-si, Gyeong gi-do, South Korea. (14)The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany. (15)University of Leeds, Leeds, UK. (16)Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland. (17)Department of Public Health Sciences, Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, MI, USA. (18)Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea. (19)Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA. (20)Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, OH, USA; Center for Biomedical Informatics and Information Technology & Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. (21)Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA. (22)Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia. (23)Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (24)Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA. (25)Department of Neurosurgery, School of Medicine and O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. (26)Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands. (27)Academic Department of Neurosurgery, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. (28)Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zürich, Switzerland. (29)Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA; Department of Neurology, Columbia University Medical Center, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA. (30)The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Department of Neurosurgery, Amsterdam University Medical Centers/VUmc, Amsterdam, the Netherlands. Electronic address: roel.verhaak@jax.org.

Soon after the emergence and global spread of the SARS-CoV-2 Omicron lineage BA.1, another Omicron lineage, BA.2, began outcompeting BA.1. The results of statistical analysis showed that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralization experiments revealed that immunity induced by COVID vaccines widely administered to human populations is not effective against BA.2, similar to BA.1, and that the antigenicity of BA.2 is notably different from that of BA.1. Cell culture experiments showed that the BA.2 spike confers higher replication efficacy in human nasal epithelial cells and is more efficient in mediating syncytia formation than the BA.1 spike. Furthermore, infection experiments using hamsters indicated that the BA.2 spike-bearing virus is more pathogenic than the BA.1 spike-bearing virus. Altogether, the results of our multiscale investigations suggest that the risk of BA.2 to global health is potentially higher than that of BA.1.

Comment in Nat Rev Mol Cell Biol. 2022 Jul;23(7):447.

Comment in Nat Rev Neurosci. 2022 Aug;23(8):456-457.

Comment in Trends Cancer. 2022 Aug;8(8):626-628. Cell Res. 2022 Sep;32(9):799-800.

Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.

Comment in Cell. 2022 Jun 9;185(12):2013-2015. Nature. 2022 Aug;608(7921):38-39.

Comment in Cell. 2022 Jun 9;185(12):2011-2013.

Comment in Mol Cell. 2022 Jul 7;82(13):2355-2357.

Comment in Signal Transduct Target Ther. 2022 Sep 27;7(1):338.

Comment on Cell. 2022 Jun 9;185(12):2057-2070.e15.

Significant disparities in the clinical usefulness of genomic information across diverse groups are due to underrepresentation in genetic databases and inequitable access to genetic services. Remedying disparities is immediately needed to ensure that genomic medicine is more equitable but will take a long-term commitment and active engagement of diverse communities.

Comment on Cell Rep. 2022 May 17;39(7):110834. Cell. 2022 Jun 9;185(12):2148-2163.e27.

Comment in Nat Rev Microbiol. 2022 Sep;20(9):510. Cell. 2022 Jul 7;185(14):2395-2397. Cell Res. 2022 Dec;32(12):1040-1041.

Comment in Cell. 2022 Jun 23;185(13):2201-2203.

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system (CNS). Bone marrow hematopoietic stem and progenitor cells (HSPCs) rapidly sense immune activation, yet their potential interplay with autoreactive T cells in MS is unknown. Here, we report that bone marrow HSPCs are skewed toward myeloid lineage concomitant with the clonal expansion of T cells in MS patients. Lineage tracing in experimental autoimmune encephalomyelitis, a mouse model of MS, reveals remarkable bone marrow myelopoiesis with an augmented output of neutrophils and Ly6Chigh monocytes that invade the CNS. We found that myelin-reactive T cells preferentially migrate into the bone marrow compartment in a CXCR4-dependent manner. This aberrant bone marrow myelopoiesis involves the CCL5-CCR5 axis and augments CNS inflammation and demyelination. Our study suggests that targeting the bone marrow niche presents an avenue to treat MS and other autoimmune disorders.

Comment in Cell. 2022 Jun 23;185(13):2208-2209.

Comment in Cell. 2022 Jun 23;185(13):2203-2205.

Lysosomes require an acidic lumen between pH 4.5 and 5.0 for effective digestion of macromolecules. This pH optimum is maintained by proton influx produced by the V-ATPase and efflux through an unidentified "H+ leak" pathway. Here we show that TMEM175, a genetic risk factor for Parkinson's disease (PD), mediates the lysosomal H+ leak by acting as a proton-activated, proton-selective channel on the lysosomal membrane (LyPAP). Acidification beyond the normal range potently activated LyPAP to terminate further acidification of lysosomes. An endogenous polyunsaturated fatty acid and synthetic agonists also activated TMEM175 to trigger lysosomal proton release. TMEM175 deficiency caused lysosomal over-acidification, impaired proteolytic activity, and facilitated α-synuclein aggregation in vivo. Mutational and pH normalization analyses indicated that the channel's H+ conductance is essential for normal lysosome function. Thus, modulation of LyPAP by cellular cues may dynamically tune the pH optima of endosomes and lysosomes to regulate lysosomal degradation and PD pathology.

Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) is proving successful to treat several genetic diseases. HSPCs are mobilized, harvested, genetically corrected ex vivo, and infused, after the administration of toxic myeloablative conditioning to deplete the bone marrow (BM) for the modified cells. We show that mobilizers create an opportunity for seamless engraftment of exogenous cells, which effectively outcompete those mobilized, to repopulate the depleted BM. The competitive advantage results from the rescue during ex vivo culture of a detrimental impact of mobilization on HSPCs and can be further enhanced by the transient overexpression of engraftment effectors exploiting optimized mRNA-based delivery. We show the therapeutic efficacy in a mouse model of hyper IgM syndrome and further developed it in human hematochimeric mice, showing its applicability and versatility when coupled with gene transfer and editing strategies. Overall, our findings provide a potentially valuable strategy paving the way to broader and safer use of HSPC-GT.

Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.

The isolation of CCoV-HuPn-2018 from a child respiratory swab indicates that more coronaviruses are spilling over to humans than previously appreciated. We determined the structures of the CCoV-HuPn-2018 spike glycoprotein trimer in two distinct conformational states and showed that its domain 0 recognizes sialosides. We identified that the CCoV-HuPn-2018 spike binds canine, feline, and porcine aminopeptidase N (APN) orthologs, which serve as entry receptors, and determined the structure of the receptor-binding B domain in complex with canine APN. The introduction of an oligosaccharide at position N739 of human APN renders cells susceptible to CCoV-HuPn-2018 spike-mediated entry, suggesting that single-nucleotide polymorphisms might account for viral detection in some individuals. Human polyclonal plasma antibodies elicited by HCoV-229E infection and a porcine coronavirus monoclonal antibody inhibit CCoV-HuPn-2018 spike-mediated entry, underscoring the cross-neutralizing activity among ɑ-coronaviruses. These data pave the way for vaccine and therapeutic development targeting this zoonotic pathogen representing the eighth human-infecting coronavirus.

The type III-E CRISPR-Cas effector Cas7-11, with dual RNase activities for precursor CRISPR RNA (pre-crRNA) processing and crRNA-guided target RNA cleavage, is a new platform for bacterial and mammalian RNA targeting. We report the 2.5-Å resolution cryoelectron microscopy structure of Cas7-11 in complex with a crRNA and its target RNA. Cas7-11 adopts a modular architecture comprising seven domains (Cas7.1-Cas7.4, Cas11, INS, and CTE) and four interdomain linkers. The crRNA 5' tag is recognized and processed by Cas7.1, whereas the crRNA spacer hybridizes with the target RNA. Consistent with our biochemical data, the catalytic residues for programmable cleavage in Cas7.2 and Cas7.3 neighbor the scissile phosphates before the flipped-out fourth and tenth nucleotides in the target RNA, respectively. Using structural insights, we rationally engineered a compact Cas7-11 variant (Cas7-11S) for single-vector AAV packaging for transcript knockdown in human cells, enabling in vivo Cas7-11 applications.

Comment in Nat Rev Mol Cell Biol. 2022 Aug;23(8):520.

Comment in Cell. 2022 Jun 23;185(13):2205-2207.

Comment on Cell. 2022 Jun 23;185(13):2338-2353.e18.

Comment on Cell. 2022 Jun 23;185(13):2370-2386.e18.

Comment on Cell. 2022 Jun 23;185(13):2213-2233.e25.

Many approved drugs, including antivirals, are small-molecule inhibitors of disease-causing proteins. Such inhibitors often elicit resistance during treatment. Chaturvedi et al. propose new, feedback-disruptor (FD) antivirals that efficiently cure infected cells from viruses and minimize the chance of resistance, providing a new paradigm to treat viral infections and possibly other diseases.

Comment on Cell. 2022 Jun 23;185(13):2354-2369.e17.