BACKGROUND. Antibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia. METHODS. We performed a randomized control trial (PennCCP2), in 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally-sourced CCP plus standard care vs. standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day WHO8 score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti-SARS-CoV-2 antibodies. RESULTS. 80 hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti-SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (MED (IQR) 10 (5.5,30) vs. 7 (2.75,12.25), p=0.037) and 28-day mortality (n=10, 26% vs. n=2, 5%; p=0.013). All other pre-specified outcome measures showed weak evidence towards benefit of CCP. CONCLUSIONS. Two units of locally-sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early. TRIAL REGISTRATION. ClinicalTrials.gov: NCT04397757 FUNDING. University of Pennsylvania.
Katharine J. Bar, Pamela A. Shaw, Grace H. Choi, Nicole Aqui, Andrew Fesnak, Jasper B. Yang, Haideliza Soto-Calderon, Lizette Grajales, Julie Starr, Michelle Andronov, Miranda Mastellone, Chigozie Amonu, Geoff Feret, Maureen DeMarshall, Marie Buchanan, Maria Caturla, James Gordon, Alan Wanicur, M. Alexandra Monroy, Felicity Mampe, Emily Lindemuth, Sigrid Gouma, Anne M. Mullin, Holly Barilla, Anastasiya Pronina, Leah Irwin, Raeann Thomas, Risa A. Eichinger, Faye Demuth, Eline T. Luning Prak, Jose L. Pascual, William R. Short, Michal A. Elovitz, Jillian Baron, Nuala J. Meyer, Kathleen O. Degnan, Ian Frank, Scott E. Hensley, Donald L. Siegel, Pablo Tebas
Bitter taste receptors (TAS2R) serve as warning sensors in the lingual system against ingestion of potential poisonous food. Here, we investigated the functional role of TAS2Rs in the human gut and focused on their potential to trigger an additional host defense pathway in the intestine. Human jejunal crypts, especially from obese subjects, responded to bitter agonists by inducing the release of antimicrobial peptides (α-defensin 5 and REG3A) but also regulated the expression of other innate immune factors (mucins, chemokines) that affected E. coli growth. The effect of aloin on E. coli growth and on the release of the mucus glycoprotein CLCA1, identified via proteomics, was affected by TAS2R43 amino acid/deletion polymorphisms and thus confirmed a role for TAS2R43. RNA sequencing uncovered that denatonium benzoate induced an NRF2-mediated nutrient stress response and an unfolded protein response that increased the expression of the mitokine GDF15 but also ADM2 and the LDLR, genes that are involved in anorectic signaling and lipid homeostasis. To conclude, TAS2Rs in the intestine provide a promising target for treating diseases that involve disturbances in the innate immune system and in body weight control. Polymorphisms in TAS2Rs may be valuable genetic markers to predict therapeutic responses.
Kathrin I. Liszt, Qiaoling Wang, Mona Farhadipour, Anneleen Segers, Theo Thijs, Linda Nys, Ellen Deleus, Bart Van der Schueren, Christopher Gerner, Benjamin Neuditschko, Laurens J. Ceulemans, Matthias Lannoo, Jan Tack, Inge Depoortere
Early initiation of antiretroviral therapy (ART) in acute HIV infection (AHI) is effective in limiting seeding of the HIV viral reservoir, but little is known about how the resultant decreased antigen load affects long-term antibody development after ART. We report here that Env-specific plasma antibody levels and antibody-dependent cellular cytotoxicity (ADCC) increased during the first 24 weeks of ART and correlated with antibody levels persisting after 48 weeks of ART. Participants treated in AHI stage 1 had lower Env-specific antibodies levels and ADCC activity on ART than those treated later. Importantly, participants who initiated ART after peak viremia in AHI developed elevated cross-clade ADCC responses detectable one year after ART initiation even though clinically undetectable viremia was reached by 24 weeks. These data suggest that there is more germinal center activity in the later stages of AHI and that antibody development continues in the absence of detectable viremia during the first year of suppressive ART. Development of therapeutic interventions that can enhance earlier development of germinal centers in AHI and antibodies after ART initiation could provide important protection against the viral reservoir that is seeded in early treated individuals.
Julie L. Mitchell, Justin Pollara, Kenneth Dietze, R. Whitney Edwards, Junsuke Nohara, Kombo F. N'guessan, Michelle Zemil, Supranee Buranapraditkun, Hiroshi Takata, Yifan Li, Roshell Muir, Eugene Kroon, Suteeraporn Pinyakorn, Shalini Jha, Sopark Manasnayakorn, Suthat Chottanapund, Pattarawat Thantiworasit, Peeriya Prueksakaew, Nisakorn Ratnaratorn, Bessara Nuntapinit, Lawrence Fox, Sodsai Tovanabutra, Dominic Paquin-Proulx, Lindsay Wieczorek, Victoria R. Polonis, Frank Maldarelli, Elias K. Haddad, Praphan Phanuphak, Carlo P. Sacdalan, Morgane Rolland, Nittaya Phanuphak, Jintanat Ananworanich, Sandhya Vasan, Guido Ferrari, Lydie Trautmann
Altered redox biology challenges all cells, with compensatory responses often determining a cell’s fate. When 15 lipoxygenase-1 (15LO1), a lipid peroxidizing enzyme abundant in asthmatic human airway epithelial cells (HAECs), binds phosphatidylethanolamine binding protein-1 (PEBP1), hydroperoxy-phospholipids, which drive ferroptotic cell death, are generated. Peroxidases, including glutathione peroxidase-4 (GPX4), metabolize hydroperoxy-phospholipids to hydroxy derivatives to prevent ferroptotic death, but consume reduced glutathione (GSH). The cystine transporter, SLC7A11, critically restores/maintains intracellular GSH. We hypothesized high 15LO1-PEBP1-GPX4 activity drives abnormal asthmatic redox biology, evidenced by lower bronchoalveolar lavage (BAL) fluid and intraepithelial cell GSH:oxidized GSH (GSSG), to enhance Type-2 (T2) inflammatory responses. GSH, GSSG (enzymatic assays), 15LO1, GPX4, SLC7A11 and T2 biomarkers (western blot and RNAseq) were measured in asthmatic and healthy control (HC) cells/fluids, with siRNA knockdown as appropriate. GSSG was higher and GSH:GSSG lower in asthmatic compared to HC BAL fluid, while intracellular GSH was lower in asthma. In vitro, T2 cytokine (IL-13) induced 15LO1 generated hydroperoxy-phospholipids, which lowered intracellular GSH and increased extracellular GSSG. Lowering GSH further by inhibiting SLC7A11 enhanced T2 inflammatory protein expression and ferroptosis. Ex vivo, redox imbalances corresponded to 15LO1 and SLC7A11 expression, T2 biomarkers and worsened clinical outcomes. Thus, 15LO1 pathway-induced redox biology perturbations worsen T2 inflammation and asthma control, supporting15LO1 as a therapeutic target.
Tadao Nagasaki, Alexander J. Schuyler, Jinming Zhao, Svetlana N. Samovich, Kazuhiro Yamada, Yanhan Deng, Scott P. Ginebaugh, Stephanie A. Christenson, Prescott G. Woodruff, John V. Fahy, John B. Trudeau, Detcho Stoyanovsky, Anuradha Ray, Yulia Y. Tyurina, Valerian E. Kagan, Sally E. Wenzel
Acute myocardial infarction (AMI) induces blood leukocytosis, which correlates inversely with patient survival. The molecular mechanisms leading to leukocytosis in the infarcted heart, remain poorly understood. Using an AMI mouse model, we identified gasdermin D (GSDMD) in activated leukocytes early in AMI. We demonstrated that GSDMD is required for enhanced early mobilization of neutrophils to the infarcted heart. Loss of GSDMD resulted in attenuated IL-1β release from neutrophils and subsequent decreased neutrophils and monocytes in the infarcted heart. Knockout of GSDMD in mice significantly reduced infarct size, improved cardiac function, and increased survival post AMI. Through a series of bone marrow transplantation studies and leukocytes depletion experiments, we further clarified that excessive bone marrow derived and GSDMD-dependent early neutrophil production and mobilization (24 hours post AMI), contributed to the detrimental immunopathology after AMI. Pharmacological inhibition of GSDMD also conferred cardioprotection post AMI, through reduction of scar size and enhancement of heart function. Our study provides new mechanistic insights into molecular regulation of neutrophil generation and mobilization after AMI, and supports GSDMD as a new target for improved ventricular remodeling and reduced heart failure after AMI.
Kai Jiang, Zizhuo Tu, Kun Chen, Yue Xu, Feng Chen, Sheng Xu, Tingting Shi, Jie Qian, Lan Shen, John Hwa, Dandan Wang, Yaozu Xiang
Chronic kidney disease (CKD) imposes a strong and independent risk for peripheral artery disease (PAD). While solutes retained in CKD patients (uremic solutes) inflict vascular damage, their role in PAD remain elusive. Here, we show that the dietary tryptophan-derived uremic solute including indoxyl sulfate (IS) and Kynurenine (Kyn), at concentrations corresponding to CKD patients suppressed β-catenin in several cell-types including microvascular endothelial cells (EC), inhibiting Wnt activity and proangiogenic Wnt targets in ECs. Mechanistic probing revealed that these uremic solutes downregulated β-catenin, dependent on serine 33 in its degron motif and through Aryl Hydrocarbon Receptor (AHR). Hindlimb ischemia in adenine-induced CKD and IS solute-specific mice models showed diminished β-catenin and VEGF-A in the capillaries and reduced capillary density, which correlated inversely with blood levels of IS and Kyn and AHR activity in ECs. An AHR inhibitor treatment normalized post-ischemic angiogenic response in CKD mice to a non-CKD level. In a prospective cohort of PAD patients, plasma levels of tryptophan metabolites and plasma’s AHR-inducing activity in ECs significantly increased the risk of future adverse limb events. This work uncovers tryptophan metabolites-AHR-β-catenin axis as a mediator of microvascular rarefaction in CKD patients and demonstrates its targetability for PAD in CKD models.
Nkiruka V. Arinze, Wenqing Yin, Saran Lotfollahzadeh, Marc Arthur Napoleon, Sean Richards, Joshua A. Walker, Mostafa Belghasem, Jonathan D. Ravid, Mohamed Hassan Kamel, Stephen A. Whelan, Norman Lee, Jeffrey J. Siracuse, Stephan Anderson, Alik Farber, David Sherr, Jean Francis, Naomi M. Hamburg, Nader Rahimi, Vipul C. Chitalia
Severe glomerular injury ultimately leads to tubulointerstitial fibrosis which determines patient outcome, but the immunological molecules connecting these two processes remain unresolved. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir–/–) kidney suffered more damage than in wild type kidneys. When interstitial immune cells were examined, the contact frequency of macrophages with infiltrated T cells increased, and the immunometabolic features of T cells changed to high oxidative phosphorylation and fatty acid metabolism and overproduction of interferon-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more interleukin-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against interferon-γ and interleukin-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., anti-neutrophil cytoplasmic autoantibody vasculitis), high VISTA expression in tubulointerstitial immune cells was associated with low tubulointerstitial fibrosis and good prognosis. Therefore, VISTA is a sentinel protein expressed in kidney macrophages that prevents tubulointerstitial fibrosis via the interferon-γ-interleukin-9 axis after acute antibody-mediated glomerular injury.
Min-Gang Kim, Donghwan Yun, Chae Lin Kang, Minki Hong, Juhyeon Hwang, Kyung Chul Moon, Chang Wook Jeong, Cheol Kwak, Dong Ki Kim, Kook-Hwan Oh, Kwon Wook Joo, Yon Su Kim, Dong-Sup Lee, Seung Seok Han
The increasing frequency of pathogenic coronaviruses in the human population has raised public health concerns about possible future pandemics. It is critical to understand whether immune responses to the current circulating coronaviruses provide protection against related viruses or those that may emerge in the future. In this issue of the JCI, Dangi, Palacio, et al. detail the extent of coronavirus cross-protection following both vaccination and natural infection and ultimately use murine models to highlight the mechanism behind this heterotypic immunity. This study provides insight into the possibility of a pan-coronavirus vaccine that could protect humans against future coronavirus outbreaks.
David J. Bean, Manish Sagar
Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet-induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared to their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 also inhibited hepatic insulin signaling by down-regulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.
Sijia He, Jiyoon Ryu, Juanhong Liu, Hairong Luo, Ying Lv, Paul R. Langlais, Jie Wen, Feng Dong, Zhe Sun, Wenjuan Xia, Jane L. Lynch, Ravindranath Duggirala, Bruce J. Nicholson, Mengwei Zang, Yuguang Shi, Fang Zhang, Feng Liu, Juli Bai, Lily Q. Dong
Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of non-healing diabetic foot ulcers (DFU). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here we report the intracellular accumulation of S. aureus in the epidermis of DFU with no clinical signs of infection due to marked suppression of Perforin-2. S. aureus residing within the epidermis of DFU triggers AIM2-inflammasome activation and pyroptosis. These findings were corroborated in mice lacking Perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in DFU patients undergoing standard of care. Increased AIM2-inflammasome and ASC-pyroptosome coupled with induction of IL-1β were found in non-healing when compared to healing DFU. Our findings reveal novel mechanism that includes Perforin-2 suppression, intracellular S. aureus accumulation and associated induction of pyroptosis that contribute to healing inhibition and prolonged inflammation in patients with DFU.
Irena Pastar, Andrew P. Sawaya, Jelena Marjanovic, Jamie L. Burgess, Natasa Strbo, Katelyn E. Rivas, Tongyu C. Wikramanayake, Cheyanne R. Head, Rivka C. Stone, Ivan Jozic, Olivera Stojadinovic, Eran Y. Kornfeld, Robert S. Kirsner, Hadar Lev-Tov, Marjana Tomic-Canic
The PRDM13 (PR Domain containing 13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia, normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the co-occurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.
Danielle E. Whittaker, Roberto Oleari, Louise C. Gregory, Polona Le Quesne Stabej, Hywel J. Williams, John G. Torpiano, Nancy Formosa, Mario J. Cachia, Daniel Field, Antonella Lettieri, Louise A. Ocaka, Alyssa J.J. Paganoni, Sakina H. Rajabali, Kimberley L.H. Riegman, Lisa B. De Martini, Taro Chaya, Iain C. Robinson, Takahisa Furukawa, Anna Cariboni, M. Albert Basson, Mehul T. Dattani
Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADC) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases.
Stephen P. Persaud, Julie K. Ritchey, Sena Kim, Sora Lim, Peter G. Ruminski, Matthew L. Cooper, Michael P. Rettig, Jaebok Choi, John F. DiPersio
Acute coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Disease Association (AARDA) Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10 to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.
Jason S. Knight, Roberto Caricchio, Jean Laurent Casanova, Alexis J. Combes, Betty Diamond, Sharon E. Fox, David A. Hanauer, Judith A. James, Yogendra Kanthi, Virginia Ladd, Puja Mehta, Aaron M. Ring, Ignacio Sanz, Carlo Selmi, Russell P. Tracy, Paul J. Utz, Catriona A. Wagner, Julia Y. Wang, W. Joseph McCune
Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between pro-inflammatory and pro-resolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several pro-resolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2×apolipoprotein E double KO background (hGPR32myc×Fpr2-/-×Apoe-/-), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2 and FOXP3. Atherosclerotic lesions, necrotic core and aortic inflammation were reduced in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice as compared to Fpr2-/-×Apoe-/- non-transgenic littermates. In a zymosan induced peritonitis model, the hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice had reduced inflammation at 4h and enhanced pro-resolving macrophage responses at 24h compared to non-transgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice but not in the Fpr2-/-×Apoe-/- non-transgenic littermates. Altogether these results provide the first evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo.
Hildur Arnardottir, Silke Thul, Sven-Christian Pawelzik, Glykeria Karadimou, Gonzalo Artiach, Alessandro L. Gallina, Victoria Mysdotter, Miguel Carracedo, Laura Tarnawski, April S. Caravaca, Roland Baumgartner, Daniel F.J. Ketelhuth, Peder S. Olofsson, Gabrielle Paulsson-Berne, Göran K. Hansson, Magnus Bäck
To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics which recapitulate antigen-specific T-cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently-tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent anti-viral activities. Intravenous injection of HIV or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens, respectively. Notably, these expanded HIV or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections, respectively, in the humanized mice providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.
Mengyan Li, Scott J. Garforth, Kaitlyn E. O’Connor, Hang Su, Danica M. Lee, Alev Celikgil, Rodolfo J. Chaparro, Ronald D. Seidel, R. Brad Jones, Ravit Arav-Boger, Steven C. Almo, Harris Goldstein
Genome-wide association studies (GWAS) involve testing genetic variants across the genomes of many individuals to identify genotype-phenotype associations. GWAS have enabled the identification of numerous genomic biomarkers in various complex human diseases including infectious ones. However, few of these studies are relevant for clinical practice or at the bedside. In this issue of the JCI, Nakanishi et al. characterized the clinical implications of a major genetic risk factor for COVID-19 severity and its age-dependent effect, using individual-level data in a large international multi-center consortium. This study indicates that a common COVID-19 genetic risk factor (rs10490770) associates with increased risks of morbidity and mortality, suggesting potential implications for future clinical risk management. How can the genomic biomarkers identified by GWAS be associated with the clinical outcomes of an infectious disease? In this commentary, we evaluate the advantages and limitations of this approach.
Vito Luigi Colona, Michela Bianocolella, Antonio Novelli, Giuseppe Novelli
Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitors (SSRIs) antidepressants correlates with body weight gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased body weight by enhancing food intake in healthy mice at two different time points and through two distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through the Htr1a receptor. Upon longer treatment Flx blunted Htr2c expression/signaling, decreased the phosphorylation of Creb and Stat3 and dampened the production of POMC/α-MSH in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (MC4R) by co-treating mice with Flx and lipocalin-2, an anorexigenic hormone signaling through this receptor, normalized feeding and body weight. Flx and other SSRIs also inhibit CREB/STAT3 phosphorylation in a human neuronal cell line suggesting that these non-canonical effects could also occur in long-term users of SSRIs. By defining the molecular basis of the long-term SSRIs-associated weight gain this study proposes a therapeutic strategy to counter it.
Maria Jose Ortuno, Marc Schneeberger, Anoj Ilanges, François Marchildon, Kyle Pellegrino, Jeffrey M. Friedman, Patricia Ducy
BACKGROUND. A long-held dream of scientists is to transfer information directly to the visual cortex of blind individuals, thereby restoring a rudimentary form of sight. However, no clinically available cortical visual prosthesis yet exists. METHODS.We implanted an intracortical microelectrode array consisting of 96 electrodes in the visual cortex of a 57-year-old person with complete blindness for a six- month period. We measured thresholds and the characteristics of the visual percepts elicited by intracortical microstimulation. RESULTS. Implantation and subsequent explantation of intracortical microelectrodes were carried out without complications. The mean stimulation threshold for single electrodes was 66.8 ± 36.5 μA. We consistently obtained high-quality recordings from visually deprived neurons and the stimulation parameters remained stable over time. Simultaneous stimulation via multiple electrodes were associated with a significant reduction in thresholds (p<0.001, ANOVA test) and evoked discriminable phosphene percepts, allowing the blind participant to identify some letters and recognize object boundaries. Furthermore, we observed a learning process that helped the subject to recognize complex patterns over time. CONCLUSIONS. Our results demonstrate the safety and efficacy of chronic intracortical microstimulation via a large number of electrodes in human visual cortex, showing its high potential for restoring functional vision in the blind. TRIAL REGISTRATION. ClinicalTrials.gov identifier NCT02983370. FUNDING. Funding was provided by grant RTI2018-098969-B-100 from the Spanish Ministerio de Ciencia Innovación y Universidades, by grant PROMETEO/2019/119 from the Generalitat Valenciana (Spain), by the Bidons Egara Research Chair of the University Miguel Hernández (Spain) and by the John Moran Eye Center of the University of Utah (US).
Eduardo Fernández, Arantxa Alfaro, Cristina Soto-Sánchez, Pablo González-López, Antonio M. Lozano Ortega, Sebastian Peña, María Dolores Grima, Alfonso Rodil, Bernardeta Gómez, Xing Chen, Pieter R. Roelfsema, John D. Rolston, Tyler S. Davis, Richard A. Normann
Immune checkpoint inhibitors (ICB) have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, gender specific differences in response to ICB have been observed with males getting more benefit than females, although the mechanism(s) underlying this difference are unknown. Mining published transcriptomic datasets, we determined that response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor (ERα) stimulate melanoma growth in murine models by skewing macrophage polarization towards an immune-suppressive state that promotes CD8+ T cell dysfunction/exhaustion and ICB resistance. This activity was not evident in mice harboring a macrophage specific depletion of ERα confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD) decreases tumor growth, stimulates adaptive immunity and increases the antitumor efficacy of ICBs. Further, a gene signature that reads on ER activity in macrophages predicted survival in ICB treated melanoma patients. These results highlight the importance of E2/ER as a regulator of intratumoral macrophage polarization; an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.
Binita Chakraborty, Jovita Byemerwa, Jonathan H. Shepherd, Corinne N. Haines, Robert Baldi, Weida Gong, Wen Liu, Debarati Mukherjee, Sandeep Artham, Felicia Lim, Yeeun Bae, Olivia Brueckner, Kendall Heetderks, Suzanne E. Wardell, Brent A. Hanks, Charles M. Perou, Ching-Yi Chang, Donald P. McDonnell
Although Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicit cross-protective immune responses against heterologous coronaviruses. In particular, we show that a Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1, confers robust heterologous protection against SARS-CoV-2 in mice. Similarly, prior coronavirus infections conferred heterologous protection against distinct coronaviruses. Cross-reactive immunity was also reported in Coronavirus Disease 2019 (COVID-19) patients and humans who received SARS-CoV-2 vaccines, and transfer of plasma from these individuals into mice improved protection against coronavirus challenges. These findings provide the first demonstration that coronavirus vaccines (and prior coronavirus infections) can confer broad protection against heterologous coronaviruses, providing a rationale for universal coronavirus vaccines.
Tanushree Dangi, Nicole Palacio, Sarah Sanchez, Mincheol Park, Jake Class, Lavanya Visvabharathy, Thomas Ciucci, Igor J. Koralnik, Justin M. Richner, Pablo Penaloza-MacMaster