Publications by authors named "Jessica Tsui"

13 Publications

  • Page 1 of 1

Global absence and targeting of protective immune states in severe COVID-19.

Nature 2021 Jan 25. Epub 2021 Jan 25.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs) across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.
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http://dx.doi.org/10.1038/s41586-021-03234-7DOI Listing
January 2021

SCENITH: A Flow Cytometry-Based Method to Functionally Profile Energy Metabolism with Single-Cell Resolution.

Cell Metab 2020 Dec;32(6):1063-1075.e7

Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France; Institute for Research in Biomedicine (iBiMED) and Ilidio Pinho Foundation, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal; International Associated Laboratory (LIA) CNRS "Mistra", 13288 Marseille Cedex 9, France.

Energetic metabolism reprogramming is critical for cancer and immune responses. Current methods to functionally profile the global metabolic capacities and dependencies of cells are performed in bulk. We designed a simple method for complex metabolic profiling called SCENITH, for single-cell energetic metabolism by profiling translation inhibition. SCENITH allows for the study of metabolic responses in multiple cell types in parallel by flow cytometry. SCENITH is designed to perform metabolic studies ex vivo, particularly for rare cells in whole blood samples, avoiding metabolic biases introduced by culture media. We analyzed myeloid cells in solid tumors from patients and identified variable metabolic profiles, in ways that are not linked to their lineage or their activation phenotype. SCENITH's ability to reveal global metabolic functions and determine complex and linked immune-phenotypes in rare cell subpopulations will contribute to the information needed for evaluating therapeutic responses or patient stratification.
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http://dx.doi.org/10.1016/j.cmet.2020.11.007DOI Listing
December 2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

bioRxiv 2020 Oct 29. Epub 2020 Oct 29.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.

One Sentence Summary: In severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.
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http://dx.doi.org/10.1101/2020.10.28.359935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605559PMC
October 2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

Res Sq 2020 Oct 28. Epub 2020 Oct 28.

Department of Pathology, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, CA 94143-0511, USA.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a wholeblood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferonstimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and autodirected antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.
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http://dx.doi.org/10.21203/rs.3.rs-97042/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605560PMC
October 2020

EMP2 Is a Novel Regulator of Stemness in Breast Cancer Cells.

Mol Cancer Ther 2020 08 25;19(8):1682-1695. Epub 2020 May 25.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Little is known about the role of epithelial membrane protein-2 (EMP2) in breast cancer development or progression. In this study, we tested the hypothesis that EMP2 may regulate the formation or self-renewal of breast cancer stem cells (BCSC) in the tumor microenvironment. analysis of gene expression data demonstrated a correlation of EMP2 expression with known metastasis-related genes and markers of cancer stem cells (CSC) including aldehyde dehydrogenase (ALDH). In breast cancer cell lines, EMP2 overexpression increased and EMP2 knockdown decreased the proportion of stem-like cells as assessed by the expression of the CSC markers CD44/CD24, ALDH activity, or by tumor sphere formation. , upregulation of EMP2 promoted tumor growth, whereas knockdown reduced the ALDH CSC population as well as retarded tumor growth. Mechanistically, EMP2 functionally regulated the response to hypoxia through the upregulation of HIF-1α, a transcription factor previously shown to regulate the self-renewal of ALDH CSCs. Furthermore, in syngeneic mouse models and primary human tumor xenografts, mAbs directed against EMP2 effectively targeted CSCs, reducing the ALDH population and blocking their tumor-initiating capacity when implanted into secondary untreated mice. Collectively, our results show that EMP2 increases the proportion of tumor-initiating cells, providing a rationale for the continued development of EMP2-targeting agents.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415657PMC
August 2020

Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4 T Cell Immunity.

Cell 2019 04 4;177(3):556-571.e16. Epub 2019 Apr 4.

Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

Differentiation of proinflammatory CD4 conventional T cells (T) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4 T, but then fail to support antitumor CD4 T differentiation. Regulatory T cell (T) depletion enhanced their capacity to elicit strong CD4 T responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to T predicts protective ICOS PD-1 CD4 T phenotypes and survival. Further, in melanoma patients with low T abundance, intratumoral cDC2 density alone correlates with abundant CD4 T and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4 T abundance and controls tumor growth.
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http://dx.doi.org/10.1016/j.cell.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954108PMC
April 2019

Analysis of pulmonary features and treatment approaches in the COPA syndrome.

ERJ Open Res 2018 Apr 27;4(2). Epub 2018 Jun 27.

Dept of Medicine, Division of Pulmonary and Critical Care, University of California San Francisco, San Francisco, CA, USA.

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment.
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http://dx.doi.org/10.1183/23120541.00017-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019741PMC
April 2018

Type I interferon pathway activation in COPA syndrome.

Clin Immunol 2018 02 10;187:33-36. Epub 2017 Oct 10.

Clinica Pediatrica e Reumatologia, Istituto Giannina Gaslini, Genova, Italy. Electronic address:

Mutations of the COPA gene cause an immune dysregulatory disease characterised by polyarticular arthritis and progressive interstitial lung disease with pulmonary haemorrhages. We report the case of a young girl that presented at age 3 with polyarticular arthritis, chronic cough and high titer rheumatoid factor. Radiologic imaging showed interstitial lung disease with tree-in-a-bud nodules and air-filled cysts. Targeted genetic analysis of COPA gene showed the reported c.698G>A mutation. The patient was lost to follow up for 3years during which therapy was discontinued with the development of joint damage and deformities. Analysis of peripheral blood showed activation of type 1 interferon pathway, which was also confirmed in 4 previously reported COPA patients. Our observations underline the importance of early treatment in COPA disease to avoid loss of joint function. Furthermore, our results suggest a role for type 1 interferon in disease pathogenesis opening the possibility for targeted therapeutic approaches.
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http://dx.doi.org/10.1016/j.clim.2017.10.001DOI Listing
February 2018

Epithelial membrane protein-2 (EMP2) promotes angiogenesis in glioblastoma multiforme.

J Neurooncol 2017 Aug 9;134(1):29-40. Epub 2017 Jun 9.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, 90095, USA.

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and is associated with an extremely poor clinical prognosis. One pathologic hallmark of GBM is excessive vascularization with abnormal blood vessels. Extensive investigation of anti-angiogenic therapy as a treatment for recurrent GBM has been performed. Bevacizumab, a monoclonal anti-vascular endothelial growth factor A (VEGF-A), suggests a progression-free survival benefit but no overall survival benefit. Developing novel anti-angiogenic therapies are urgently needed in controlling GBM growth. In this study, we demonstrate tumor expression of epithelial membrane protein-2 (EMP2) promotes angiogenesis both in vitro and in vivo using cell lines from human GBM. Mechanistically, this pro-angiogenic effect of EMP2 was partially through upregulating tumor VEGF-A levels. A potential therapeutic effect of a systemic administration of anti-EMP2 IgG1 on intracranial xenografts was observed resulting in both significant reduction of tumor load and decreased tumor vasculature. These results suggest the potential for anti-EMP2 IgG1 as a promising novel anti-angiogenic therapy for GBM. Further investigation is needed to fully understand the molecular mechanisms how EMP2 modulates GBM pathogenesis and progression and to further characterize anti-EMP2 therapy in GBM.
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http://dx.doi.org/10.1007/s11060-017-2507-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695892PMC
August 2017

Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation.

Am J Respir Crit Care Med 2012 Nov 30;186(9):866-76. Epub 2012 Aug 30.

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5642, USA.

Rationale: Extracellular matrix (ECM) is a dynamic tissue that contributes to organ integrity and function, and its regulation of cell phenotype is a major aspect of cell biology. However, standard in vitro culture approaches are of unclear physiologic relevance because they do not mimic the compositional, architectural, or distensible nature of a living organ. In the lung, fibroblasts exist in ECM-rich interstitial spaces and are key effectors of lung fibrogenesis.

Objectives: To better address how ECM influences fibroblast phenotype in a disease-specific manner, we developed a culture system using acellular human normal and fibrotic lungs.

Methods: Decellularization was achieved using treatment with detergents, salts, and DNase. The resultant matrices can be sectioned as uniform slices within which cells were cultured.

Measurements And Main Results: We report that the decellularization process effectively removes cellular and nuclear material while retaining native dimensionality and stiffness of lung tissue. We demonstrate that lung fibroblasts reseeded into acellular lung matrices can be subsequently assayed using conventional protocols; in this manner we show that fibrotic matrices clearly promote transforming growth factor-β-independent myofibroblast differentiation compared with normal matrices. Furthermore, comprehensive analysis of acellular matrix ECM details significant compositional differences between normal and fibrotic lungs, paving the way for further study of novel hypotheses.

Conclusions: This methodology is expected to allow investigation of important ECM-based hypotheses in human tissues and permits future scientific exploration in an organ- and disease-specific manner.
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http://dx.doi.org/10.1164/rccm.201204-0754OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530219PMC
November 2012

Control of fibroblast fibronectin expression and alternative splicing via the PI3K/Akt/mTOR pathway.

Exp Cell Res 2010 Oct 13;316(16):2644-53. Epub 2010 Jul 13.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Fibronectin (FN), a ubiquitous glycoprotein that plays critical roles in physiologic and pathologic conditions, undergoes alternative splicing which distinguishes plasma FN (pFN) from cellular FN (cFN). Although both pFN and cFN can be incorporated into the extracellular matrix, a distinguishing feature of cFN is the inclusion of an alternatively spliced exon termed EDA (for extra type III domain A). The molecular steps involved in EDA splicing are well-characterized, but pathways influencing EDA splicing are less clear. We have previously found an obligate role for inhibition of the tumor suppressor phosphatase and tensin homologue on chromosome 10 (PTEN), the primary regulator of the PI3K/Akt pathway, in fibroblast activation. Here we show TGF-beta, a potent inducer of both EDA splicing and fibroblast activation, inhibits PTEN expression and activity in mesenchymal cells, corresponding with enhanced PI3K/Akt signaling. In pten(-/-) fibroblasts, which resemble activated fibroblasts, inhibition of Akt attenuated FN production and decreased EDA alternative splicing. Moreover, inhibition of mammalian target of rapamycin (mTOR) in pten(-/-) cells also blocked FN production and EDA splicing. This effect was due to inhibition of Akt-mediated phosphorylation of the primary EDA splicing regulatory protein SF2/ASF. Importantly, FN silencing in pten(-/-) cells resulted in attenuated proliferation and migration. Thus, our results demonstrate that the PI3K/Akt/mTOR axis is instrumental in FN transcription and alternative splicing, which regulates cell behavior.
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http://dx.doi.org/10.1016/j.yexcr.2010.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2924943PMC
October 2010

Phosphatase and tensin homologue on chromosome 10 (PTEN) directs prostaglandin E2-mediated fibroblast responses via regulation of E prostanoid 2 receptor expression.

J Biol Chem 2009 Nov 6;284(47):32264-71. Epub 2009 Oct 6.

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.

Prostaglandin E(2) (PGE(2)) is an arachidonic acid metabolite that counters transforming growth factor-beta-induced fibroblast activation via E prostanoid 2 (EP2) receptor binding. Phosphatase and tensin homologue on chromosome 10 (PTEN) is a lipid phosphatase that, by antagonizing the phosphoinositol 3-kinase (PI3K) pathway, also inhibits fibroblast activation. Here, we show that PTEN directly regulates PGE(2) inhibition of fibroblast activation by augmenting EP2 receptor expression. The increase in collagen production and alpha-smooth muscle actin expression observed in fibroblasts in which PTEN is deficient was resistant to the usual suppressive effects of PGE(2). This was due to marked down-regulation of EP2, a G(s) protein-coupled receptor (GPCR) that mediates the inhibitory actions of this prostanoid via cAMP. pten(-/-) or PTEN-inhibited fibroblasts in which the PI3K pathway was blocked demonstrated a restoration of EP2 receptor expression, due to augmented gene transcription and mRNA instability. Importantly, restoration of the balance between PI3K and PTEN reestablished the inhibitory effect of PGE(2) on fibroblast activation. No such influence of PTEN was observed on alternative E prostanoid GPCRs. Moreover, our studies identified a positive feedback loop in which cAMP signaling enhanced EP2 receptor expression, independent of PTEN. Therefore, our findings indicate that PTEN regulates the antifibrotic effects of PGE(2) by a specific and permissive effect on EP2 receptor expression. Further, our data imply that cAMP signaling circumvents EP2 down-regulation in pten-deficient cells to restore EP2 receptor expression. This is the first description, to our knowledge, of PI3K/PTEN balance directing GPCR expression, and provides a novel mechanism for cellular effects of PTEN.
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http://dx.doi.org/10.1074/jbc.M109.004796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781639PMC
November 2009

An essential role for fibronectin extra type III domain A in pulmonary fibrosis.

Am J Respir Crit Care Med 2008 Mar 20;177(6):638-45. Epub 2007 Dec 20.

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, 6301 MSRB III/0642, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0642, USA.

Rationale: Tissue fibrosis is considered a dysregulated wound-healing response. Fibronectin containing extra type III domain A (EDA) is implicated in the regulation of wound healing. EDA-containing fibronectin is deposited during wound repair, and its presence precedes that of collagen.

Objectives: To investigate the role of EDA-containing fibronectin in lung fibrogenesis.

Methods: Primary lung fibroblasts from patients with idiopathic pulmonary fibrosis or from patients undergoing resection for lung cancer were assessed for EDA-containing fibronectin and alpha-smooth muscle actin (alpha-SMA) expression. Mice lacking the EDA domain of fibronectin and their wild-type littermates were challenged with the bleomycin model of lung fibrosis. Primary lung fibroblasts from these mice were assayed in vitro to determine the contribution of EDA-containing fibronectin to fibroblast phenotypes.

Measurements And Main Results: Idiopathic pulmonary fibrosis lung fibroblasts produced markedly more EDA-containing fibronectin and alpha-SMA than control fibroblasts. EDA-null mice failed to develop significant fibrosis 21 days after bleomycin challenge, whereas wild-type controls developed the expected increase in total lung collagen. Histologic analysis of EDA-null lungs after bleomycin showed less collagen and fewer alpha-SMA-expressing myofibroblasts compared with that observed in wild-type mice. Failure to develop lung fibrosis in EDA-null mice correlated with diminished activation of latent transforming growth factor (TGF)-beta and decreased lung fibroblast responsiveness to active TGF-beta in vitro.

Conclusions: The data show that EDA-containing fibronectin is essential for the fibrotic resolution of lung injury through TGF-beta activation and responsiveness, and suggest that EDA-containing fibronectin plays a critical role in tissue fibrogenesis.
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http://dx.doi.org/10.1164/rccm.200708-1291OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267338PMC
March 2008