The rockefeller university

In psoriatic lesions, interleukin (IL)-17C protein expression has been reported as high as 125 times that of IL-17A; as such, it is crucial to understand the role that IL-17C plays in psoriasis, inflammation, and treatment response. Overexpression or injection of IL-17C in mice results in increased epidermal thickening and inflammation, whereas psoriatic mice with IL-17C knockout have decreased disease severity compared with control littermates. In psoriasis, IL-17C likely acts as a critical inflammatory amplifier via a feed-forward mechanism, wherein IL-17-producing CD4+ helper T (TH17) cells and IL-17-producing CD8+ cytotoxic T (TC17) cells stimulate IL-17C expression in keratinocytes. Then, keratinocyte-derived IL-17C induces IL-17A expression in TH17 and TC17 cells. Additionally, keratinocyte-derived IL-17C propagates its own signaling in an autocrine manner. Furthermore, studies suggest that IL-17C acts as an early mediator of psoriasis. No approved therapies directly target IL-17C. Brodalumab is an IL-17 receptor (IL-17R) A antagonist that inhibits IL-17A, F, C, and E signaling and has a unique mechanism of action among biologic therapies for psoriasis. By way of IL-17RA blockade, brodalumab is the only approved therapy for psoriasis that inhibits IL-17C signaling. This unique mechanism of action is hypothesized to correlate with efficacy in patients with prior failures to anti-IL-17A therapies and relatively higher rates of early skin clearance compared with those of other biologic therapies. Clinical studies are needed to confirm these correlations. In summary, IL-17C is an inflammatory amplifier and early psoriatic mediator, and inhibition of IL-17C may be beneficial in psoriasis management.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by antinuclear antibodies (ANAs). Epstein-Barr virus (EBV) infection has been epidemiologically associated with SLE, yet its role in pathogenesis remains incompletely defined. Here, we developed an EBV-specific single-cell RNA-sequencing platform and used it to demonstrate that EBV infection reprograms autoreactive antinuclear antigen B cells to drive autoimmunity in SLE. We demonstrated that, in SLE, EBV+ B cells are predominantly CD27+CD21low memory B cells that are present at increased frequencies and express ZEB2, TBX21 (T-bet), and antigen-presenting cell transcriptional pathways. Integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA polymerase II occupancy data revealed EBV nuclear antigen 2 (EBNA2) binding at the transcriptional start sites and regulatory regions of CD27, ZEB2, and TBX21, as well as the antigen-presenting cell genes demonstrated to be up-regulated in SLE EBV+ B cells. We expressed recombinant antibodies from SLE EBV+ B cells and demonstrated that they bind prototypical SLE nuclear autoantigens, whereas those from healthy individuals do not. We further found that SLE EBV+ B cells can serve as antigen-presenting cells to drive activation of T peripheral helper cells with concomitant activation of related EBV- antinuclear double-negative 2 B cells and plasmablasts. Our results provide a mechanistic basis for EBV being a driver of SLE through infecting and reprogramming nuclear antigen-reactive B cells to become activated antigen-presenting cells with the potential to promote systemic disease-driving autoimmune responses.

The clinical outcome of SARS-CoV-2 infection spans from asymptomatic viral elimination to lethal COVID-19 pneumonia, which is due to type I interferon (IFN) deficiency in at least 15-20% of cases. We report two unrelated male patients with critical COVID-19 who are heterozygous for rare deleterious variants in RB1CC1, encoding the autophagy-related FIP200 protein. Airway epithelial cells genetically deprived of FIP200 or cell lines expressing the RB1CC1/FIP200 patient variants exhibit elevated SARS-CoV-2 replication and impaired autophagic flux. The antiviral function of FIP200 is independent of canonical autophagy and type I IFN, but involves the selective autophagy receptor NDP52. We identify a non-canonical function of FIP200 in a novel lysosomal degradation pathway, in which SARS-CoV-2 virions are targeted to single-membrane compartments for degradation of viral RNA in LC3B-positive acidified vesicles. This pathway is impaired in FIP200-deficient cells and in cells expressing FIP200 patient haplotypes. Collectively, we describe a cell-autonomous anti-SARS-CoV-2 restriction pathway, dependent on FIP200 and NDP52, and independent of canonical autophagy and type I IFN, which can underlie critical COVID-19 pneumonia.

BackgroundRed mullet (Mullus barbatus) is a key species in Mediterranean fisheries, yet its stock structure and population dynamics remain poorly understood due to a lack of comprehensive genomic resources. This study provides the first high-quality reference genome for M. barbatus and a comprehensive set of SNP markers to investigate its population structure and adaptive potential across the Mediterranean.ResultsUsing the newly generated chromosome-level reference genome, we re-analyzed a Mediterranean-wide reduced-representation genomic dataset. Our analysis reveals a panmictic population structure with strong genetic connectivity across the species' range, likely driven by extensive larval dispersal and multigenerational gene flow. Despite minimal genome-wide differentiation, outlier analysis identified candidate loci under directional selection, linked to key biological processes such as ontogeny and environmental adaptation.ConclusionsThis study presents the first genomic resource for M. barbatus, providing valuable insights into its genetic structure and adaptive mechanisms. While the identification of loci under selection offers promising leads, these findings are preliminary due to the limited genomic coverage of the dataset. Nonetheless, they pave the way for future genomic studies to explore how M. barbatus adapts to environmental and anthropogenic pressures. These results hold significant implications for the sustainable management of Mediterranean fisheries, especially in the context of climate change and conservation.

Juvenile hormones (JH) regulate insect development, reproduction, and behavior. The JH analog Methoprene, widely used in pest control, disrupts these processes by inhibiting maturation rather than causing mortality. Beyond its physiological effects, Methoprene influences insect behavior, including mate choice, social organization, and foraging, by altering neuronal sensitivity and gene expression via the Methoprene-tolerant receptor. These behavioral disruptions may negatively impact insect populations, including pollinators like honeybees. While laboratory studies highlight Methoprene's behavioral consequences, field research is needed to assess its ecological effects. Understanding these broader impacts is crucial for evaluating the risks associated with JH-based pest control strategies.

CD40 agonism enhances antitumor immunity but is limited by systemic toxicity and poor efficacy. Here, we present a phase 1 study (NCT04059588) of intratumoral (i.t.) 2141-V11, an Fc-engineered anti-CD40 agonistic antibody with enhanced binding to the inhibitory receptor Fc gamma RIIB. Among 12 metastatic cancer patients, 2141-V11 was well tolerated without dose-limiting toxicities. Six patients experienced tumor reduction, including two complete responses in melanoma and breast cancer. 2141-V11 induced regression in injected and non-injected lesions, correlating with systemic CD8+T cell activation and mature tertiary lymphoid structures (TLSs) in complete responders. In CD40/Fc gamma Rs humanized mice bearing orthotopic tumors, i.t. 2141-V11 promoted de novo TLS formation, facilitating i.t. CD8+ T cell effector responses independent of lymph node priming. The resulting local immune responses by 2141-V11 mediated abscopal antitumor effects and sustained immune memory. These findings demonstrate that i.t. 2141-V11 is safe and promotes immune-privileged tumor microenvironments that promote systemic and durable antitumor immunity.

Communication is crucial to social life, and in ants, it is mediated primarily through olfaction. Ants have more odorant receptor (OR) genes than any other group of insects, generated through tandem duplications that produce large genomic arrays of related genes. The mechanism by which olfactory sensory neurons (OSNs) produce a single functional OR from these arrays remains unclear. In ant OSNs, only mRNA from one OR in an array is exported into the cytoplasm, while upstream genes are silent and transcripts from downstream genes remain nuclear. Here, we show that readthrough transcription in the downstream direction generates non-translated transcripts. We also find that OR promoters are bidirectional, producing anti-sense long non-coding RNAs. We suspect that neither readthrough nor antisense transcription produces functional RNA but that bidirectional transcription alone is critical to suppressing the expression of all other OR genes in a tandem array. Finally, we present evidence that this regulatory architecture is conserved across ants and bees, suggesting that this mechanism for functionally monogenic OR expression is widespread in insects with expanded OR repertoires.

The cellular basis of COVID-19 severity in patients with deficiencies in type I IFN immunity remains unclear. In this study, we differentiated cardiomyocytes and macrophages from IFNAR1 competent (IFNAR1comp) and deficient (IFNAR1def) induced pluripotent stem cells (iPSCs), and analyzed virus replication and cytokine production after exposure to SARS-CoV-2. Cardiomyocytes expressed the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) and showed abundant SARS-CoV-2 replication, which was higher in IFNAR1def than IFNAR1comp cells. Treatment with exogenous IFN alpha mitigated infection in IFNAR1comp, but not in IFNAR1def cardiomyocytes. In contrast, macrophages did not express ACE2 and did not support SARS-CoV-2 replication, but produced pro-inflammatory cytokines upon virus exposure, which was impaired in IFNAR1def macrophages. In conclusion, type I IFNs decrease SARS-CoV-2 replication in human iPSC-derived cardiomyocytes, while they increase cytokine responses of macrophages.