The rockefeller university

The life-threatening coronavirus disease 2019 (COVID-19) affects about 1 in 1,000 healthy people under 50 without underlying conditions. Among patients with critical COVID-19 pneumonia, rare germline variants at genes controlling type I IFN immunity have been reported in up to 5% of patients. Causal etiologies in 80-85% of cases are still unknown. We analyzed two families with hypoxemic COVID-19 pneumonia for known single-gene inborn errors of immunity. In Family 1, two siblings with critical COVID-19 were homozygous for a DOCK2 variant, c.3624+5G>A. DOCK2 deficiency is a known T-cell disorder underlying severe viral diseases. The variant resulted in skipping exon 35, which was predicted to produce a frameshift truncated protein (p.L1157Ifs*12). The proband showed markedly decreased blood CD4 T-helper cell counts, impaired T lymphocyte transformation test, and increased serum IgG, IgA, and IgE levels, as documented in other DOCK2-deficient patients. In Family 2, the proband had lethal COVID-19 and HPV-2-associated multiple recalcitrant warts. She was heterozygous for a deletion in GATA2:c.1075_1102del28, p.W360Sfs*18. GATA2 haploinsufficiency is a known cause of severe viral diseases due to a lack of plasmacytoid dendritic cell (pDC) development. The proband had monocytopenia and a lack of circulating pDCs, as reported in other patients with GATA2 haploinsufficiency. Overall, both DOCK2 deficiency and GATA2 haploinsufficiency are associated with critical and often fatal COVID-19 pneumonia.

T cell exhaustion is a major barrier to effective cancer immunotherapy. Although immune checkpoint blockade can reinvigorate exhausted T cells, not all patients achieve long-term responses, partly due to the refractory nature of terminally exhausted T cells. Beyond persistent antigen stimulation, the environmental drivers of exhaustion remain to be thoroughly characterized. Here we identify CD47 upregulation in tumor-infiltrating exhausted CD8+ T cells in both human and murine tumors. We reveal a novel role for the extracellular matrix protein thrombospondin-1 (TSP-1) in engaging CD47 on T cells to promote exhaustion. This interaction activates calcineurin-NFAT signaling, inducing upregulation of TOX and expression of inhibitory receptors, and impairing effector function during tumor progression. Importantly, disrupting the TSP-1-CD47 axis prevents T cell exhaustion and enhances tumor control. Our findings identify a novel pathway promoting T cell dysfunction and suggest that targeting the TSP-1-CD47 axis is a promising strategy to enhance T cell immunity and immunotherapy efficacy.

Fulminant viral hepatitis (FVH) is a devastating condition caused by hepatotropic viruses such as hepatitis A virus (HAV), hepatitis B virus (HBV), and HSV-1/2. We studied 149 FVH patients (73 males and 76 females, aged 1-76) for blood autoantibodies (auto-Abs) neutralizing type I interferons (IFNs; IFN-alpha 2, -beta, -omega). Six of 16 (37.5%) HSV-triggered FVH patients carried such auto-Abs on admission, including three with a previously known autoimmune disease. These patients contrasted with 133 HAV- (n = 46) or HBV-triggered (n = 87) patients, none of whom had such detectable auto-Abs. Odds ratios for HSV-triggered FVH in individuals with auto-Abs ranged from 35.3 (95% CI: 13.0-96.2; P < 10-7) for those neutralizing only 100 pg/ml IFN-alpha/omega to 1,895 (CI: 448.5-8,002; P < 10-12) for those neutralizing both IFN-alpha and IFN-omega at 10 ng/ml. Over one third of HSV-triggered FVH cases in this international cohort were due to preexisting auto-Abs. This finding highlights auto-Abs against type I IFNs as a major determinant of HSV-FVH and paves the way for targeted preventive or therapeutic interventions.

Optogenetics has transformed basic research on neural circuitry, led to diverse experimental insights into human brain function and dysfunction, and opened pathways for clinical translation based on new understanding of how specific cell types contribute to cognition and behavior. Many of these translational pathways do not rely on the direct application of optogenetics in humans, but rather develop and advance other treatment modalities by leveraging causal knowledge derived from optogenetic circuit neuroscience. However, a recent proof-of-principle study-showing that optogenetics applied directly to the human central nervous system can treat blindness-underscores not only the curative potential but also the need for careful ethical consideration in the extension of direct optogenetic intervention to other disorders. Here, we review relevant considerations-including the selection of clinical indications, identification of molecular and optical strategies for specificity, and navigation of safety and regulatory issues-that together inform the development of optogenetic translation targeting cells and circuits that have been causally implicated through optogenetic discoveries.

Ants primarily communicate via pheromones, and other modes of communication have remained understudied. A new paper shows that fire ant workers employ substrate-borne vibrations to induce the killing and cannibalism of young queens when the colony is starved, showing that ant communication can be multifaceted.

Somatic CAG instability in the mutant Huntingtin (HTT) gene is increasingly recognized as a key hallmark of Huntington's disease (HD). Using our novel human CAGinSTEM platform, we manipulated cis genetic elements influencing instability in human HD neurons, monitoring repeat length. Quality-controlled CRISPR-engineered stem cells with increasing CAG lengths and clinical haplotypes were analyzed using third-generation sequencing. Our findings link interruptions in the CAG repeat, especially the loss or duplication of the penultimate CAA of canonical alleles, to significant instability modulation. Notably, four internal CAA interruptions completely abolish CAG instability, reversing HD phenotypes such as altered striatal fate acquisition and nuclear disorganization. This platform highlights the role of cis modifiers, emphasizing the direct influence of HTT DNA repeat composition on CAG instability and providing a robust framework for modeling HTT repeat instability in vitro.

The T-cell receptor (TCR) initiates T-lymphocyte activation, but the mechanism of TCR activation remains uncertain. Here, we present cryogenic electron microscopy structures for the unliganded and human leukocyte antigen (HLA)-bound human TCR-CD3 complex in nanodiscs that provide a native-like lipid environment. Distinct from the open and extended conformation seen in detergent, the unliganded TCR-CD3 in nanodiscs adopts two related closed and compacted conformations that represent its physiologic resting state in vivo. By contrast, the HLA-bound complex adopts the open and extended conformation, and conformation-locking disulfide mutants show that ectodomain opening is necessary for maximal ligand-dependent T-cell activation. These structures also reveal conformation-dependent protein-lipid and glycan-glycan interactions within the TCR. Together, these results establish allosteric conformational change during TCR activation, reveal avenues for immunotherapeutic engineering, and highlight the importance of native-like lipid environments for membrane protein structure determination.

Interferon-gamma (IFN1) is critical for immunity against intra-macrophagic pathogens, signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway to induce a tyrosinephosphorylation cascade that ensures a potent immune response. Excessive JAK-STAT signaling can drive hyperinflammation and autoimmunity; thus, signaling is tightly and selectively regulated by the IFN1-induci-ble protein, suppressor of cytokine signaling 1 (SOCS1). SOCS1 inhibits signaling by directly blocking JAK kinase activity. Here, we identified a SOCS1-interacting partner, ankyrin repeat and pleckstrin homology domain 2 (ARAP2), that fine-tunes SOCS1 function. We report that tyrosine 415 in ARAP2 binds the SOCS1-Src homology 2 (SH2) domain and limits the ability of SOCS1 to inhibit IFN1 signaling. Our findings show that ARAP2 promotes the IFN1 response through a phosphorylation-dependent interaction with the negative regulator SOCS1, and this exacerbates inflammation in a mouse model of influenza virus infection.

The COVID-19 pandemic has increased public reliance on natural treatments, particularly in regions with strong cultural ties to herbal medicine or limited access to conventional healthcare. Globally, surveys have reported heightened use of plant-based remedies and dietary supplements, perceived as safe and effective. In Israel, this trend was evident within an integrative healthcare system that combines conventional and complementary medicine. The public demonstrated significant interest in herbal remedies and supplements to boost immunity and manage pandemic-induced stress. Natural compounds with anti-inflammatory and antiviral properties offer potential pharmacological benefits, warranting clinical investigation. However, restrictive trial criteria hinder broader applicability of findings. To address this gap, we evaluated the effects of bioactive dietary supplements on COVID-19 severity and duration through an online survey. Among respondents, Boswellia emerged as the most popular supplement. Disease duration in Boswellia users was significantly reduced (11.8 +/- 7.1 days) compared to untreated cases or those taking other supplements (18.0 +/- 9.7 days). Known as frankincense, Boswellia's gum resin has traditionally been used for its anti-inflammatory properties. Its bioactive compounds, boswellic acids and incensole acetate, inhibit cytokines like TNF alpha, IL-1 beta, and IL-6, implicated in COVID-19-related cytokine storms and ARDS. Preliminary clinical and laboratory studies suggest Boswellia's potential as an anti-inflammatory and antiviral agent. Laboratory experiments corroborated these findings, demonstrating that cultures infected with 229e virus, as measured by qPCR. Boswellia extracts also decreased viral RNA levels by up to 75% without adverse effects on cell viability and inhibited TMPRSS2 activity, a key protease for viral entry. These findings underscore Boswellia's therapeutic potential, combining anti-inflammatory and antiviral mechanisms, and support further investigation into its use as a complementary treatment for COVID-19.