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In-Press Preview

In-Press Preview Articles
Battle for supremacy: nucleic acid interactions between viruses and cells
Since the COVID-19 pandemic swept across the globe, researchers have been trying to understand its origin, life cycle, and pathogenesis. There is a striking variability in the phenotypic response...
Published December 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI144227.
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Review In-Press Preview

Battle for supremacy: nucleic acid interactions between viruses and cells

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Since the COVID-19 pandemic swept across the globe, researchers have been trying to understand its origin, life cycle, and pathogenesis. There is a striking variability in the phenotypic response to infection with SARS-CoV-2 that may reflect differences in host genetics and/or immune response. It is known that the human epigenome is influenced by ethnicity, age, lifestyle, and environmental factors, including previous viral infections. This review will examine the influence of viruses on the host epigenome. We will describe general lessons and methodologies that can be used to understand how the virus evades the host immune response. We will consider how variation in the epigenome may contribute to heterogeneity in the response to SARS-CoV-2 and may identify a precision medicine approach to treatment.

Authors

Elizabeth J. Hennessy, Garret A. FitzGerald

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ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation
Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia Telangiectasia Mutated (ATM) protein plays a central role in sensing DNA double strand breaks...
Published December 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI139333.
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Research In-Press Preview Oncology

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation

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Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia Telangiectasia Mutated (ATM) protein plays a central role in sensing DNA double strand breaks and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance immune checkpoint blockade (ICB) therapy. However, the molecular mechanism involved is not clearly elucidated. Here we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA and activation of the cGAS/STING pathway. Genetic depletion of ATM in murine cancer cells significantly delayed tumor growth in syngeneic mouse hosts in a T-cell dependent manner. Furthermore, chemical inhibition of ATM significantly potentiated anti-PD1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating TFAM, which led to mitochondrial DNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits for ICB therapy. Our study therefore provides strong evidence that ATM may serve both as a therapeutic target and a biomarker to enable ICB therapy

Authors

Mengjie Hu, Min Zhou, Xuhui Bao, Dong Pan, Meng Jiao, Xinjian Liu, Fang Li, Chuan-Yuan Li

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Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency
Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy and malignancy. Somatic reversion refers to the...
Published December 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI142434.
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Research In-Press Preview Immunology Infectious disease

Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency

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Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to bi-allelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterised by severe bacterial, viral and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic and cellular features of three patients with bi-allelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared to typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further non-redundant functions of DOCK8 in human lymphocyte biology. Lastly, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.

Authors

Bethany A. Pillay, Mathieu Fusaro, Paul E. Gray, Aaron Luke Statham, Leslie Burnett, Liliana Bezrodnik, Alisa Kane, Winnie W. Y. Tong, Chrystelle Abdo, Sarah Winter, Samuel Chevalier, Romain Levy, Cécile Masson, Yohann Schmitt, Christine Bole-Feysot, Marion Malphettes, Elizabeth Macintyre, Jean-Pierre de Villartay, John B. Ziegler, Joanne M. Smart, Jane Peake, Asghar Aghamohammadi, Lennart Hammarström, Hassan Abolhassani, Capucine Picard, Alain Fischer, Sylvain Latour, Benedicte Neven, Stuart Tangye, Cindy S. Ma

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Biomarkers of inflammation and repair in kidney disease progression
Introduction: Acute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision-making, more accurate information regarding risk of long-term...
Published December 8, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI139927.
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Clinical Medicine In-Press Preview Inflammation Nephrology

Biomarkers of inflammation and repair in kidney disease progression

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Introduction: Acute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision-making, more accurate information regarding risk of long-term progression to kidney failure is required. Methods: We enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein-1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression. Results: Higher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis. Conclusions: Biomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression. Funding: National Institutes of Health grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01HL085757, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, R01DK093771, K01DK120783, P30DK079310, P30DK114809.

Authors

Jeremy Puthumana, Heather Thiessen-Philbrook, Leyuan Xu, Steven G. Coca, Amit X. Garg, Jonathan Himmelfarb, Pavan K. Bhatraju, Talat Alp Ikizler, Edward Siew, Lorraine B. Ware, Kathleen D. Liu, Alan S. Go, James S. Kaufman, Paul L. Kimmel, Vernon M. Chinchilli, Lloyd Cantley, Chirag R. Parikh

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Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice
Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no cure. Using conditional knockout mice, we found that ablation of the genomic organizer Special AT-rich sequence-binding...
Published December 3, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI135711.
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Research In-Press Preview Hematology

Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice

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Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no cure. Using conditional knockout mice, we found that ablation of the genomic organizer Special AT-rich sequence-binding protein-1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T-cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T-cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T-cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition), restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with Mycosis fungoides/Sézary syndrome, a set of incurable diseases.

Authors

Carly M. Harro, Jairo Perez-Sanz, Tara Lee Costich, Kyle K. Payne, Carmen M. Anadon Galindo, Ricardo A. Chaurio, Subir Biswas, Gunjan Mandal, Kristen E. Rigolizzo, Kimberly B. Sprenger, Jessica A. Mine, Louise Showe, Xiaoqing Yu, Kebin Liu, Paulo C. Rodriguez, Javier Pinilla-Ibarz, Lubomir Sokol, Jose R. Conejo-Garcia

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Generating evidence for therapeutic effects: the need for well-conducted randomized trials
In this viewpoint, Robert Califf, former commissioner of the U.S. Food and Drug Administration, and colleagues reflect on how to approach questions about which patient treatments and strategies...
Published December 3, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI146391.
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Viewpoint In-Press Preview

Generating evidence for therapeutic effects: the need for well-conducted randomized trials

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In this viewpoint, Robert Califf, former commissioner of the U.S. Food and Drug Administration, and colleagues reflect on how to approach questions about which patient treatments and strategies work, particularly in light of the tremendous pressure on the government and biomedical research enterprise to quickly develop safe, effective therapies during the SARS-CoV-2 pandemic.

Authors

Robert M. Califf, Lesley H. Curtis, Robert A. Harrington, Adrian F. Hernandez, Eric D. Peterson

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The use of observational research to inform clinical practice
Randomized controlled trials are the preferred design for the analysis of health-related interventions. In this Viewpoint, Nigel Paneth and Michael Joyner discuss circumstances when randomized...
Published December 3, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI146392.
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Viewpoint In-Press Preview

The use of observational research to inform clinical practice

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Randomized controlled trials are the preferred design for the analysis of health-related interventions. In this Viewpoint, Nigel Paneth and Michael Joyner discuss circumstances when randomized controlled trials might not be feasible and the criteria that should be used when considering applying observational data medicine.

Authors

Nigel Paneth, Michael Joyner

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TREM-1 orchestrates Angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm
The triggering receptor expressed on myeloid cells-1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our...
Published December 1, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI142468.
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Research In-Press Preview Inflammation Vascular biology

TREM-1 orchestrates Angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm

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The triggering receptor expressed on myeloid cells-1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of Angiotensin (Ang) II-induced AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalizes with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2 and Mmp9 mRNA expression, and led to a decreased macrophage content, due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L up-regulation and promoted pro-inflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII Receptor Type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared to patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in human.

Authors

Marie Vandestienne, Yujiao Zhang, Icia Santos-Zas, Rida Al-Rifai, Jeremie Joffre, Andreas Giraud, Ludivine Laurans, Bruno Esposito, Florence Pinet, Patrick Bruneval, Juliette Raffort, Fabien Lareyre, Jose Vilar, Amir Boufenzer, Lea Guyonnet, Coralie L. Guerin, Eric Clauser, Jean-Sébastien Silvestre, Sylvie Lang, Laurie Soulat-Dufour, Alain Tedgui, Ziad Mallat, Soraya Taleb, Alexandre Boissonnas, Marc Derive, Giulia Chinetti, Hafid Ait-Oufella

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The vascular landscape of human cancer
Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anti-cancer target. However, only a fraction of cancer patients benefits from angiogenesis...
Published December 1, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI136655.
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Research In-Press Preview Angiogenesis Oncology

The vascular landscape of human cancer

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Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anti-cancer target. However, only a fraction of cancer patients benefits from angiogenesis inhibitors. Whether anti-angiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric – the Endothelial Index (EI) – to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypo-vascular tumors, enabling the classification of human tumors into six vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular hub genes. EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Our studies thus provide an unbiased picture of human tumor vasculature which may enable more precise deployment of anti-angiogenesis therapy.

Authors

Benjamin M. Kahn, Alfredo Lucas, Rohan Alur, Maximilian D. Wengyn, Gregory W. Schwartz, Jinyang Li, Kathryn Sun, H. Carlo Maurer, Kenneth P. Olive, Robert B. Faryabi, Ben Stanger

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Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model
Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGEL2 gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The...
Published November 24, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI144450.
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Research In-Press Preview Neuroscience

Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model

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Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGEL2 gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We ask whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin can alleviate the disabilities of social behavior. We used Magel2 knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We find that the activation of vasopressin neurons and its projections in the lateral septum are inappropriate to perform a social habituation/discrimination task. Mechanistically, the lack of vasopressin impedes the deactivation of somatostatin neurons in the lateral septum, which predicts social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identifies vasopressin in the lateral septum as a key factor in the pathophysiology.

Authors

Amélie M. Borie, Yann Dromard, Gilles Guillon, Aleksandra Olma, Maurice Manning, Françoise Muscatelli, Michel G. Desarmenien, Freddy Jeanneteau

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Myeloid cell-targeted STAT3 inhibition sensitizes head and neck cancers to radiotherapy and T cell-mediated immunity
The tumor microenvironment affects the outcome of radiotherapy against head and neck squamous cell carcinoma (HNSCC). We recently found that tolerogenic myeloid cells accumulate in circulation of...
Published November 24, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI137001.
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Research In-Press Preview Immunology Oncology

Myeloid cell-targeted STAT3 inhibition sensitizes head and neck cancers to radiotherapy and T cell-mediated immunity

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The tumor microenvironment affects the outcome of radiotherapy against head and neck squamous cell carcinoma (HNSCC). We recently found that tolerogenic myeloid cells accumulate in circulation of HNSCC patients undergoing radiotherapy. Here, we analyzed tumor-containing lymph nodes biopsies collected from these patients. After two-weeks of radiotherapy, we found an increase in tumor-associated macrophages (TAMs) with activated STAT3, while CD8 T-cells were reduced as detected using multiplex IHC. Gene expression profiling indicated upregulation of M2 macrophage-related genes (CD163, CD206), immunosuppressive mediators (ARG1, LIF, TGFB1) and Th2 cytokines (IL4, IL5) in irradiated tumors. We next validated STAT3 as a potential target in human HNSCC-associated TAMs, using UM-SCC1 xenotransplants in humanized mice. Local injections of myeloid cell-targeted STAT3 antisense oligonucleotide (CpG-STAT3ASO) activated human DCs/macrophages, promoted CD8 T-cell recruitment and thereby arrested UM-SCC1 tumor growth. Furthermore, CpG-STAT3ASO synergized with tumor irradiation against syngeneic HPV+ mEERL and HPV– MOC2 HNSCC tumors in mice, triggering tumor regression and/or extending animal survival. The antitumor immune responses were CD8+ and CD4+ T-cell-dependent and associated with the activation of antigen-presenting cells (DCs/M1 macrophages) and increased CD8+ to regulatory T-cell ratio. Our observations suggest that targeted inhibition of STAT3 in tumor-associated myeloid cells augments the efficacy of radiotherapy against HNSCC.

Authors

Dayson Moreira, Sagus Sampath, Haejung Won, Seok Voon White, Yu-Lin Su, Marice Alcantara, Chongkai Wang, Peter P. Lee, Ellie Maghami, Erminia Massarelli, Marcin Kortylewski

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Does common cold coronavirus infection protect against severe SARS-CoV2 disease?
The coronavirus disease 2019 (COVID 19) pandemic continues to cause morbidity and mortality. Since severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the cause for COVID...
Published November 20, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI144807.
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Commentary In-Press Preview

Does common cold coronavirus infection protect against severe SARS-CoV2 disease?

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The coronavirus disease 2019 (COVID 19) pandemic continues to cause morbidity and mortality. Since severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the cause for COVID 19, some have questioned whether exposure to seasonal common cold coronaviruses (CCCs) could provide tangible protection against SARS-CoV-2 infection or disease. In this issue of the JCI, Sager, et al. examined SARS-CoV-2 infections and outcomes from patients previously tested for CCC as part of a comprehensive respiratory panel using PCR and were segregated into negative (CCC–) or positive (CCC+) exposure. No differences were seen between groups in terms of susceptibility to SARS-CoV-2 infection. However, hospitalized patients with a documented history of CCC+ infection had lower rates of ICU admissions and higher rates of survival than hospitalized CCC– patients. While these findings are associative and not causative, they highlight evidence suggesting that previous CCC+ infection may influence the disease course of SARS-CoV-2 infection.

Authors

David K. Meyerholz, Stanley Perlman

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SARS-CoV-2 B cell receptor signatures in risk populations
Many individuals possess B cells capable of recognizing epitopes on the spike glycoprotein of SARS-CoV-2. In this issue of the JCI, Paschold and Simnica et al. interrogated the frequency of...
Published November 20, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI144685.
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Commentary In-Press Preview

SARS-CoV-2 B cell receptor signatures in risk populations

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Many individuals possess B cells capable of recognizing epitopes on the spike glycoprotein of SARS-CoV-2. In this issue of the JCI, Paschold and Simnica et al. interrogated the frequency of SARS-CoV-2–specific B cell receptor rearrangements in healthy subjects based on age and cancer status. The authors found that, while SARS-CoV-2–specific antibody signatures can be identified in the repertoires of young, healthy individuals, such sequences are less frequent in elderly subjects or cancer patients. Overall, this study sheds light on B cell repertoire restrictions that might lead to an unfavorable clinical course of COVID-19 infection in risk populations.

Authors

Andrew I. Flyak

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The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury
ABSTRACTIndividuals harboring the loss-of-function (LOF) proprotein convertase subtilising/kexin type 9 Gln152His variation (PCSK9Q152H) have low circulating low-density lipoprotein (LDL)...
Published November 19, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI128650.
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Research In-Press Preview Hepatology Vascular biology

The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

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ABSTRACTIndividuals harboring the loss-of-function (LOF) proprotein convertase subtilising/kexin type 9 Gln152His variation (PCSK9Q152H) have low circulating low-density lipoprotein (LDL) cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of pro-PCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes where it would be expected to contribute to ER storage disease (ERSD); a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9Q152H variation. We report that PCSK9Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than to induce them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress-driven conditions of the liver. In summary, we have uncovered a co-chaperone function for PCSK9Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.

Authors

Paul F. Lebeau, Hanny Wassef, Jae Hyun Byun, Khrystyna Platko, Brandon Ason, Simon Jackson, Joshua Dobroff, Susan Shetterly, William G. Richards, Ali A. Al-Hashimi, Kevin D. Won, Majambu Mbikay, Annik Prat, An Tang, Guillaume Paré, Renata Pasqualini, Nabil G. Seidah, Wadih Arap, Michel Chretien, Richard C. Austin

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Extracellular traps released by antimicrobial TH17 cells contribute to host defense
TH17 cell subpopulations have been defined that contribute to inflammation and homeostasis, yet the characteristics of TH17 cells that contribute to host defense against infection are not clear. To...
Published November 19, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI141594.
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Research In-Press Preview Immunology

Extracellular traps released by antimicrobial TH17 cells contribute to host defense

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TH17 cell subpopulations have been defined that contribute to inflammation and homeostasis, yet the characteristics of TH17 cells that contribute to host defense against infection are not clear. To elucidate the antimicrobial machinery of the TH17 subset, we studied the response to Cutibacterium acnes, a skin commensal that is resistant to IL-26, the only known TH17 secreted protein with direct antimicrobial activity. We generated C. acnes-specific antimicrobial TH17 clones (AMTH17) with varying antimicrobial activity against C. acnes, which we correlated by RNA-seq to the expression of transcripts encoding proteins that contribute to antimicrobial activity. Additionally, we validated that AMTH17-mediated killing of C. acnes as well as bacterial pathogens, was dependent on the secretion of granulysin, granzyme B, perforin and histone H2B. We found that AMTH17s can release fibrous structures composed of DNA decorated with the histone H2B that entangle C. acnes that we call T cell extracellular traps (TETs). Within acne lesions, H2B and IL-17 colocalized in CD4+ T cells, in proximity to TETs in the extracellular space composed of DNA decorated with H2B. This study identifies a functionally distinct subpopulation of TH17 cells with an ability to form TETs containing secreted antimicrobial proteins that capture and kill bacteria.

Authors

George W. Agak, Alice Mouton, Rosane Teles, Thomas A. Weston, Marco Morselli, Priscila R. Andrade, Matteo Pellegrini, Robert L. Modlin

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BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of healthcare workers
BACKGROUND. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused over one million deaths worldwide, thus there is an urgent need to develop preventive and therapeutic strategies....
Published November 19, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI145157.
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Clinical Medicine In-Press Preview COVID-19 Vaccines

BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of healthcare workers

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BACKGROUND. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused over one million deaths worldwide, thus there is an urgent need to develop preventive and therapeutic strategies. The anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) demonstrates non-specific protective innate immune-boosting effects. Here, we determined if history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a retrospective observational study of a diverse cohort of health care workers (HCWs). METHODS. We assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, including BCG vaccination status and pre-existing demographic and clinical characteristics, from an observational cohort of HCWs in a multi-site Los Angeles healthcare organization. We used multi-variate analysis to estimate if history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion. RESULTS. Of the 6,201 HCWs, 29.6% reported a history of BCG vaccination whereas 68.9% did not receive BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as incidence of self-reported clinical symptoms associated with COVID-19 were significantly decreased among HCWs with a history of BCG vaccination compared to those without BCG vaccination. After adjusting for age and sex, we found that history of BCG vaccination, but not meningococcal, pneumococcal or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion. CONCLUSIONS. History of BCG vaccination was associated with decreased seroprevalence of anti-SARS-CoV-2 IgG and reduced reported COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized prospective clinical trials of BCG vaccination are urgently needed to confirm if BCG vaccination can induced a protective effect against SARS-CoV2 infection. FUNDING. This work was supported by the National Institutes of Health, National Cancer Institute (U54 CA26059) and the Erika J. Glazer Family Foundation. Key words: SARS-CoV-2, COVID-19, Bacillus Calmette-Guérin, BCG, anti-SARS-CoV-2 IgG, healthcare workers, trained immunity.

Authors

Magali Noval Rivas, Joseph E. Ebinger, Min Wu, Nancy Sun, Jonathan Braun, Kimia Sobhani, Jennifer E. Van Eyk, Susan Cheng, Moshe Arditi

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Bone marrow adipogenic lineage precursors (MALPs) promote osteoclastogenesis in bone remodeling and pathologic bone loss
Bone is maintained by coupled activities of bone-forming osteoblasts/osteocytes and bone-resorbing osteoclasts. Alterations in this relationship can lead to pathologic bone loss, such as...
Published November 18, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI140214.
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Research In-Press Preview Bone Biology

Bone marrow adipogenic lineage precursors (MALPs) promote osteoclastogenesis in bone remodeling and pathologic bone loss

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Abstract

Bone is maintained by coupled activities of bone-forming osteoblasts/osteocytes and bone-resorbing osteoclasts. Alterations in this relationship can lead to pathologic bone loss, such as osteoporosis. It is well known that osteogenic cells support osteoclastogenesis via production of RANKL. Interestingly, our recently identified bone marrow mesenchymal cell population—marrow adipogenic lineage precursors (MALPs) that form a multi-dimensional cell network in bone—was computationally demonstrated to be the most interactive with monocyte-macrophage lineage cells through high and specific expression of several osteoclast regulatory factors, including RANKL. Using an adipocyte-specific Adipoq-Cre to label MALPs, we demonstrated that mice with RANKL deficiency in MALPs have a drastic increase in trabecular bone mass in long bones and vertebrae starting from 1 month of age, while their cortical bone appears normal. This phenotype was accompanied by diminished osteoclast number and attenuated bone formation at the trabecular bone surface. Reduced RANKL signaling in calvarial MALPs abolished osteolytic lesions after lipopolysaccharide (LPS) injections. Furthermore, in ovariectomized mice, elevated bone resorption was partially attenuated by RANKL deficiency in MALPs. In summary, our studies identified MALPs as a critical player in controlling bone remodeling during normal bone metabolism and pathological bone loss in a RANKL-dependent fashion.

Authors

Wei Yu, Leilei Zhong, Lutian Yao, Yulong Wei, Tao Gui, Ziqing Li, Hyunsoo Kim, Nicholas Holdreith, Xi Jiang, Wei Tong, Nathaniel A. Dyment, Xiaowei Sherry Liu, Shuying Yang, Yongwon Choi, Jaimo Ahn, Ling Qin

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TLR3 controls constitutive IFN-b antiviral immunity in human fibroblasts and cortical neurons
Human herpes simplex virus-1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway resulting in impairment of central nervous system (CNS) cell-intrinsic antiviral immunity....
Published November 18, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI134529.
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Research In-Press Preview Immunology Infectious disease

TLR3 controls constitutive IFN-b antiviral immunity in human fibroblasts and cortical neurons

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Abstract

Human herpes simplex virus-1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway resulting in impairment of central nervous system (CNS) cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-a/b induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-b protein, thereby also constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-b secretion and ISGs mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro, and by which the human central nervous system prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-b immunity, rather than viral recognition triggering an amplification of IFN-a/b production.

Authors

Daxing Gao, Michael J. Ciancanelli, Peng Zhang, Oliver Harschnitz, Vincent Bondet, Mary Hasek, Jie Chen, Xin Mu, Yuval Itan, Aurélie Cobat, Vanessa Sancho-Shimizu, Benedetta Bigio, Lazaro Lorenzo, Gabriele Ciceri, Jessica L. McAlpine, Esperanza Anguiano, Emmanuelle Jouanguy, Damien Chaussabel, isabelle Meyts, Michael S. Diamond, Laurent Abel, Sun Hur, Gregory A. Smith, Luigi D. Notarangelo, Darragh Duffy, Lorenz Studer, Jean-Laurent Casanova, Shen-Ying Zhang

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A CRISPR view of the 2020 Nobel Prize in Chemistry
Katherine Uyhazi and renowned gene therapy pioneer Jean Bennett share their perspective on the 2020 Nobel Prize in Chemistry awarded to Emmanuelle Charpentier and Jennifer Doudna for their...
Published November 17, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI145214.
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A CRISPR view of the 2020 Nobel Prize in Chemistry

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Abstract

Katherine Uyhazi and renowned gene therapy pioneer Jean Bennett share their perspective on the 2020 Nobel Prize in Chemistry awarded to Emmanuelle Charpentier and Jennifer Doudna for their discovery of the CRISPR/Cas9 genetic scissors that have revolutionized genome editing.

Authors

Katherine E. Uyhazi, Jean Bennett

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Congenital heart disease risk loci identified by genome-wide association study in European patients
Genetic factors undoubtedly affect the development of congenital heart disease (CHD), but still remain ill-defined. We sought to identify genetic risk factors associated with CHD and to accomplish...
Published November 17, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI141837.
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Research In-Press Preview Cardiology Genetics

Congenital heart disease risk loci identified by genome-wide association study in European patients

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Abstract

Genetic factors undoubtedly affect the development of congenital heart disease (CHD), but still remain ill-defined. We sought to identify genetic risk factors associated with CHD and to accomplish functional analysis of single nucleotide polymorphisms (SNP)-carrying genes. We performed a genome-wide association study of 4,034 Caucasian CHD patients and 8,486 healthy controls. One SNP on chromosome 5q22.2 reached genome-wide significance across all CHD phenotypes and was also indicative for septal defects. One region on chromosome 20p12.1 pointing to the MACROD2 locus identified four highly significant SNPs in patients with transposition of the great arteries (TGA). Three highly significant risk variants on chromosome 17q21.32 within the GOSR2 locus were detected in patients with anomalies of thoracic arteries and veins (ATAV). Genetic variants associated with ATAV are suggested to influence expression of WNT3, and variant rs870142 related to septal defects is proposed to influence expression of MSX1. The expression of all four genes was analyzed during cardiac differentiation of human and murine induced pluripotent stem cells in vitro and by single-cell RNAseq analyses of developing murine and human hearts. Our data show that MACROD2, GOSR2, WNT3 and MSX1 play an essential functional role in heart development at the embryonic and newborn stage.

Authors

Harald Lahm, Meiwen Jia, Martina Dreßen, Felix F. M. Wirth, Nazan Puluca, Ralf Gilsbach, Bernard Keavney, Julie Cleuziou, Nicole Beck, Olga Bondareva, Elda Dzilic, Melchior Burri, Karl C. König, Johannes A. Ziegelmüller, Claudia Abou-Ajram, Irina Neb, Zhong Zhang, Stefanie A. Doppler, Elisa Mastantuono, Peter Lichtner, Gertrud Eckstein, Jürgen Hörer, Peter Ewert, James R. Priest, Lutz Hein, Rüdiger Lange, Thomas Meitinger, Heather J. Cordell, Bertram Müller-Myhsok, Markus Krane

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