Issue published July 1, 2021 Previous issue | Next issue
- Volume 131, Issue 13
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On the cover: SARS-CoV-2 infection in nasal multiciliated epithelial cells
Ahn et al. demonstrate that nasal multiciliated epithelial cells are a target for SARS-CoV-2 infection and replication in the upper airway during the early stages of COVID-19. The cover image shows that SARS-CoV-2 nucleocapsid protein (dark pink) is detected solely in nasal acetylated-α-tubulin+ (green) multiciliated or dying epithelial cells in an early stage of COVID-19 patient. ECAM+ epithelial cells are shown in (blue); nuclei are stained with DAPI (gray).
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Review Series
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Abstract
The gut-brain axis (GBA) refers to the complex interactions between the gut microbiota and the nervous, immune, and endocrine systems, together linking brain and gut functions. Perturbations of the GBA have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target. While research in the area is still in its infancy, a number of studies revealed that pwMS are more likely to exhibit altered microbiota, altered levels of short chain fatty acids and secondary bile products, and increased intestinal permeability. However, specific microbes and metabolites identified across studies and cohorts vary greatly. Small clinical and preclinical trials in pwMS and mouse models, in which microbial composition was manipulated through the use of antibiotics, fecal microbiota transplantation, and probiotic supplements, have provided promising outcomes in preventing CNS inflammation. However, results are not always consistent, and large-scale randomized controlled trials are lacking. Herein, we give an overview of how the GBA could contribute to MS pathogenesis, examine the different approaches tested to modulate the GBA, and discuss how they may impact neuroinflammation and demyelination in the CNS.
Authors
Laura Ghezzi, Claudia Cantoni, Gabriela V. Pinget, Yanjiao Zhou, Laura Piccio
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Neurodegenerative disorders (NDs) affect essential functions not only in the CNS, but also cause persistent gut dysfunctions, suggesting that they have an impact on both CNS and gut-innervating neurons. Although the CNS biology of NDs continues to be well studied, how gut-innervating neurons, including those that connect the gut to the brain, are affected by or involved in the etiology of these debilitating and progressive disorders has been understudied. Studies in recent years have shown how CNS and gut biology, aided by the gut-brain connecting neurons, modulate each other’s functions. These studies underscore the importance of exploring the gut-innervating and gut-brain connecting neurons of the CNS and gut function in health, as well as the etiology and progression of dysfunction in NDs. In this Review, we discuss our current understanding of how the various gut-innervating neurons and gut physiology are involved in the etiology of NDs, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, to cause progressive CNS and persistent gut dysfunction.
Authors
Alpana Singh, Ted M. Dawson, Subhash Kulkarni
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Commentaries
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Abstract
Fibromyalgia syndrome (FMS) is a highly prevalent, debilitating disease with heterogeneous symptoms of widespread pain and tenderness, fatigue, sleep disturbance, and impaired cognition. The cause of FMS is unknown, but the clinical constellation of symptoms and abnormalities in the neuroendocrine system, autonomic nervous system, and sleep implicate the nervous system in its pathogenesis. In this issue of the JCI, Goebel, Krock, et al. identified antibodies from patients with FMS that produce FMS in mice by binding to satellite glial cells (SGCs), which envelope sensory neurons. Because antibodies harvested from patients with FMS, but not controls, stimulated SGCs to an activated state known to mediate chronic pain by augmenting neuronal activity, these findings reveal a pivotal role for autoreactive IgG in the pathophysiology of FMS. These important findings pave a pathway to study mechanism-based experimental therapeutics targeting IgG titers or antibody binding to SGCs underlying the neuroimmune dysfunction of FMS.
Authors
Kevin J. Tracey
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The biphasic wound-healing response in the heart after myocardial infarction involves an initial inflammatory phase followed by a more prolonged period of inflammation resolution, tissue repair, and scar formation. Infiltrating proinflammatory Ly6Chi monocytes and monocyte-derived macrophages are key drivers of the inflammatory phase and are also the source of the locally generated reparative macrophages that promote inflammation resolution. In this issue of the JCI, Sicklinger et al. from the Leuschner laboratory uncover a salutary role for cardiac basophils in this process. The authors demonstrated that basophils promote healing and proper scar formation and also limit late cardiac remodeling by augmenting reparative macrophages in the infarcted heart, in part via basophil-derived enhancement of cardiac IL-4 and IL-13 levels. These findings underscore the potentially disproportionate (relative to cell numbers) yet essential biological effects of immune cells of low abundance on cardiac repair and remodeling, related in part to amplification of downstream macrophage responses via secreted cytokines.
Authors
Sumanth D. Prabhu
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Pregnant patients with COVID-19 are more likely to require intensive care and die compared with noninfected pregnant women. While the consequences of COVID-19 disease in pregnancy prompted many health care organizations to support vaccination in pregnancy, vaccine effects for mother and infant remained unclear. In this issue of the JCI, Beharier and Mayo et al. explored maternal and neonatal responses to the Pfizer BNT162b2 SARS-CoV-2 mRNA vaccine. The authors examined blood samples from women and cord blood of neonates following childbirth. Samples were stratified into three groups: vaccine recipients, unvaccinated participants with past positive SARS-CoV-2 test, and unvaccinated participants without prior infection. Vaccinated mothers and mothers with previous infection generated and transferred protective IgG antibodies across the placenta. This study provides evidence to support the safety and efficacy of COVID-19 vaccination in pregnancy with protection to the neonate against infection, outlining clear vaccine benefits for both maternal and child health.
Authors
Irina Burd, Tomoshige Kino, James Segars
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Research Articles
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Abstract
The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6Clo macrophages toward increased numbers of inflammatory Ly6Chi monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6Chi monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/α-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels.
Authors
Florian Sicklinger, Ingmar Sören Meyer, Xue Li, Daniel Radtke, Severin Dicks, Moritz P. Kornadt, Christina Mertens, Julia K. Meier, Kory J. Lavine, Yunhang Zhang, Tim Christian Kuhn, Tobias Terzer, Jyoti Patel, Melanie Boerries, Gabriele Schramm, Norbert Frey, Hugo A. Katus, David Voehringer, Florian Leuschner
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B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicted by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may substantially contribute to its leukemogenesis. Here, we have integrated genome-wide DNA methylome and transcriptome data from 69 patients with de novo MLL-rearranged leukemia (MLLr) and non-MLLr iB-ALL leukemia uniformly treated according to the Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control in normal hematopoietic cells. DNA methylation, gene expression, and gene coexpression network analyses segregated MLLr away from non-MLLr iB-ALL and identified a coordinated and enriched expression of the AP-1 complex members FOS and JUN and RUNX factors in MLLr iB-ALL, consistent with the significant enrichment of hypomethylated CpGs in these genes. Integrative methylome-transcriptome analysis identified consistent cancer cell vulnerabilities, revealed a robust iB-ALL–specific gene expression–correlating dmCpG signature, and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Finally, pharmacological inhibition or functional ablation of AP-1 dramatically impaired MLLr-leukemic growth in vitro and in vivo using MLLr-iB-ALL patient–derived xenografts, providing rationale for new therapeutic avenues in MLLr-iB-ALL.
Authors
Juan Ramón Tejedor, Clara Bueno, Meritxell Vinyoles, Paolo Petazzi, Antonio Agraz-Doblas, Isabel Cobo, Raúl Torres-Ruiz, Gustavo F. Bayón, Raúl F. Pérez, Sara López-Tamargo, Francisco Gutierrez-Agüera, Pablo Santamarina-Ojeda, Manuel Ramírez-Orellana, Michela Bardini, Giovanni Cazzaniga, Paola Ballerini, Pauline Schneider, Ronald W. Stam, Ignacio Varela, Mario F. Fraga, Agustín F. Fernández, Pablo Menéndez
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Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2- and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1α in astrocytes, resulting in increased VEGF production and expression of a “hypoxic” program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1α target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non–cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.
Authors
Miguel Alejandro Lopez-Ramirez, Catherine Chinhchu Lai, Shady Ibrahim Soliman, Preston Hale, Angela Pham, Esau J. Estrada, Sara McCurdy, Romuald Girard, Riya Verma, Thomas Moore, Rhonda Lightle, Nicholas Hobson, Robert Shenkar, Orit Poulsen, Gabriel G. Haddad, Richard Daneman, Brendan Gongol, Hao Sun, Frederic Lagarrigue, Issam A. Awad, Mark H. Ginsberg
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Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell–like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.
Authors
Sylvain Carras, Dimitri Chartoire, Sylvain Mareschal, Maël Heiblig, Antoine Marçais, Rémy Robinot, Mirjam Urb, Roxane M. Pommier, Edith Julia, Amel Chebel, Aurélie Verney, Charlotte Bertheau, Emilie Bardel, Caroline Fezelot, Lucien Courtois, Camille Lours, Alyssa Bouska, Sunandini Sharma, Christine Lefebvre, Jean-Pierre Rouault, David Sibon, Anthony Ferrari, Javeed Iqbal, Laurence de Leval, Philippe Gaulard, Alexandra Traverse-Glehen, Pierre Sujobert, Mathieu Blery, Gilles Salles, Thierry Walzer, Emmanuel Bachy, Laurent Genestier
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Clinical immunotherapy approaches are lacking efficacy in the treatment of glioblastoma (GBM). In this study, we sought to reverse local and systemic GBM-induced immunosuppression using the Helicobacter pylori neutrophil-activating protein (NAP), a potent TLR2 agonist, as an immunostimulatory transgene expressed in an oncolytic measles virus (MV) platform, retargeted to allow viral entry through the urokinase-type plasminogen activator receptor (uPAR). While single-agent murine anti-PD1 treatment or repeat in situ immunization with MV-s-NAP-uPA provided modest survival benefit in MV-resistant syngeneic GBM models, the combination treatment led to synergy with a cure rate of 80% in mice bearing intracranial GL261 tumors and 72% in mice with CT-2A tumors. Combination NAP-immunovirotherapy induced massive influx of lymphoid cells in mouse brain, with CD8+ T cell predominance; therapeutic efficacy was CD8+ T cell dependent. Inhibition of the IFN response pathway using the JAK1/JAK2 inhibitor ruxolitinib decreased PD-L1 expression on myeloid-derived suppressor cells in the brain and further potentiated the therapeutic effect of MV-s-NAP-uPA and anti-PD1. Our findings support the notion that MV strains armed with bacterial immunostimulatory antigens represent an effective strategy to overcome the limited efficacy of immune checkpoint inhibitor–based therapies in GBM, creating a promising translational strategy for this lethal brain tumor.
Authors
Eleni Panagioti, Cheyne Kurokawa, Kimberly Viker, Arun Ammayappan, S. Keith Anderson, Sotiris Sotiriou, Kyriakos Chatzopoulos, Katayoun Ayasoufi, Aaron J. Johnson, Ianko D. Iankov, Evanthia Galanis
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Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. In genetic FGFR-knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Transcriptome analyses of BGJ398-treated cells and histological and expression analyses of mouse and human synovial sarcoma tumors revealed prevalent expression of two ETS factors and FGFR targets, ETV4 and ETV5. We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. Upon ETV4 and ETV5 knockdown, we observed a striking upregulation of DUX4 and its transcriptional targets that activate the zygotic genome and drive the atrophy program in facioscapulohumeral dystrophy patients. In addition to demonstrating the importance of inhibiting all three FGFRs, the current findings reveal potential nodes of attack for the cancer with the discovery of ETV4 and ETV5 as appropriate biomarkers and molecular targets, and activation of the embryonic DUX4 pathway as a promising approach to block synovial sarcoma tumors.
Authors
Joanna DeSalvo, Yuguang Ban, Luyuan Li, Xiaodian Sun, Zhijie Jiang, Darcy A. Kerr, Mahsa Khanlari, Maria Boulina, Mario R. Capecchi, Juha M. Partanen, Lin Chen, Tadashi Kondo, David M. Ornitz, Jonathan C. Trent, Josiane E. Eid
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The role of PI3K and Hippo signaling in chronic pancreatitis (CP) pathogenesis is unclear. Therefore, we assessed the involvement of these pathways in CP by examining the PI3K and Hippo signaling components PTEN and SAV1, respectively. We observed significant decreases in pancreatic PTEN and SAV1 levels in 2 murine CP models: repeated cerulein injection and pancreatic ductal ligation. Additionally, pancreas-specific deletion of Pten and Sav1 (DKO) induced CP in mice. Pancreatic connective tissue growth factor (CTGF) was markedly upregulated in both CP models and DKO mice, and pancreatic CCAAT/enhancer-binding protein-α (CEBPA) expression was downregulated in the CP models. Interestingly, in pancreatic acinar cells (PACs), CEBPA knockdown reduced PTEN and SAV1 and increased CTGF levels in vitro. Furthermore, CEBPA knockdown in PACs induced acinar-to-ductal metaplasia and activation of cocultured macrophages and pancreatic stellate cells. These results were mitigated by CTGF inhibition. CP in DKO mice was also ameliorated by Ctgf gene deletion, and cerulein-induced CP was alleviated by antibody-mediated CTGF neutralization. Finally, we observed significantly decreased PTEN, SAV1, and CEBPA and increased CTGF levels in human CP tissues compared with nonpancreatitis tissues. Taken together, our results indicate that dysregulation of PI3K and Hippo signaling induces CP via CTGF upregulation.
Authors
Takeshi Tamura, Takahiro Kodama, Katsuhiko Sato, Kazuhiro Murai, Teppei Yoshioka, Minoru Shigekawa, Ryoko Yamada, Hayato Hikita, Ryotaro Sakamori, Hirofumi Akita, Hidetoshi Eguchi, Randy L. Johnson, Hideki Yokoi, Masashi Mukoyama, Tomohide Tatsumi, Tetsuo Takehara
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Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.
Authors
Andreas Goebel, Emerson Krock, Clive Gentry, Mathilde R. Israel, Alexandra Jurczak, Carlos Morado Urbina, Katalin Sandor, Nisha Vastani, Margot Maurer, Ulku Cuhadar, Serena Sensi, Yuki Nomura, Joana Menezes, Azar Baharpoor, Louisa Brieskorn, Angelica Sandström, Jeanette Tour, Diana Kadetoff, Lisbet Haglund, Eva Kosek, Stuart Bevan, Camilla I. Svensson, David A. Andersson
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Background The evolutionary pressure of endemic malaria and other erythrocytic pathogens has shaped variation in genes encoding erythrocyte structural and functional proteins, influencing responses to hemolytic stress during transfusion and disease.Methods We sought to identify such genetic variants in blood donors by conducting a genome-wide association study (GWAS) of 12,353 volunteer donors, including 1,406 African Americans, 1,306 Asians, and 945 Hispanics, whose stored erythrocytes were characterized by quantitative assays of in vitro osmotic, oxidative, and cold-storage hemolysis.Results GWAS revealed 27 significant loci (P < 5 × 10–8), many in candidate genes known to modulate erythrocyte structure, metabolism, and ion channels, including SPTA1, ALDH2, ANK1, HK1, MAPKAPK5, AQP1, PIEZO1, and SLC4A1/band 3. GWAS of oxidative hemolysis identified variants in genes encoding antioxidant enzymes, including GLRX, GPX4, G6PD, and SEC14L4 (Golgi-transport protein). Genome-wide significant loci were also tested for association with the severity of steady-state (baseline) in vivo hemolytic anemia in patients with sickle cell disease, with confirmation of identified SNPs in HBA2, G6PD, PIEZO1, AQP1, and SEC14L4.Conclusions Many of the identified variants, such as those in G6PD, have previously been shown to impair erythrocyte recovery after transfusion, associate with anemia, or cause rare Mendelian human hemolytic diseases. Candidate SNPs in these genes, especially in polygenic combinations, may affect RBC recovery after transfusion and modulate disease severity in hemolytic diseases, such as sickle cell disease and malaria.
Authors
Grier P. Page, Tamir Kanias, Yuelong J. Guo, Marion C. Lanteri, Xu Zhang, Alan E. Mast, Ritchard G. Cable, Bryan R. Spencer, Joseph E. Kiss, Fang Fang, Stacy M. Endres-Dighe, Donald Brambilla, Mehdi Nouraie, Victor R. Gordeuk, Steve Kleinman, Michael P. Busch, Mark T. Gladwin, the National Heart, Lung, and Blood Institute (NHLBI) Recipient Epidemiology Donor Evaluation Study–III (REDS-III) program
×Abstract
The 4 serotypes of dengue virus (DENV1–4) are mosquito-borne flaviviruses that infect humans. Live attenuated tetravalent DENV vaccines are at different phases of clinical testing. DENV vaccine developers have relied on neutralizing antibodies (NAbs) as a correlate of protection. A leading tetravalent vaccine (Dengvaxia) stimulated NAbs to the 4 DENV serotypes, yet overall vaccine efficacy was low in children who were DENV seronegative at baseline before vaccination. We compared the properties of (a) NAbs induced by WT DENV1 or DENV3 infections, which are strongly correlated with protection from repeat infections, and (b) NAbs induced by Dengvaxia in individuals who subsequently experienced DENV1 or DENV3 breakthrough infections. WT infections induced NAbs that recognized epitopes unique (type specific) to each serotype, whereas the vaccine stimulated qualitatively different NAbs that recognized epitopes conserved (crossreactive) between serotypes. Our results indicate that, among children who were DENV-seronegative at baseline, unbalanced replication of the DENV type 4 vaccine component in the tetravalent vaccine stimulates Abs capable of crossneutralizing DENV1 and DENV3 in vitro, but not protecting in vivo. In DENV-seronegative individuals who are vaccinated, we propose that type-specific NAbs are a better correlate of protection than total levels of NAbs.
Authors
Sandra Henein, Cameron Adams, Matthew Bonaparte, Janice M. Moser, Alina Munteanu, Ralph Baric, Aravinda M. de Silva
×Abstract
The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at the cellular level is not fully defined. Unlike recent single-cell RNA-Seq analyses indicating uniformly low mRNA expression of SARS-CoV-2 entry–related host molecules in all nasal epithelial cells, we show that the protein levels are relatively high and that their localizations are restricted to the apical side of multiciliated epithelial cells. In addition, we provide evidence in patients with COVID-19 that SARS-CoV-2 is massively detected and replicated within the multiciliated cells. We observed these findings during the early stage of COVID-19, when infected ciliated cells were rapidly replaced by differentiating precursor cells. Moreover, our analyses revealed that SARS-CoV-2 cellular tropism was restricted to the nasal ciliated versus oral squamous epithelium. These results imply that targeting ciliated cells of the nasal epithelium during the early stage of COVID-19 could be an ideal strategy to prevent SARS-CoV-2 propagation.
Authors
Ji Hoon Ahn, JungMo Kim, Seon Pyo Hong, Sung Yong Choi, Myung Jin Yang, Young Seok Ju, Young Tae Kim, Ho Min Kim, MD Tazikur Rahman, Man Ki Chung, Sang Duk Hong, Hosung Bae, Chang-Seop Lee, Gou Young Koh
×Abstract
BACKGROUND SARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19 in small-scale cohort studies. The mechanisms behind this association remain elusive.METHODS We evaluated the relationship between SARS-CoV-2 viremia, disease outcome, and inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using a quantitative reverse transcription PCR–based platform. Proteomic data were generated with Proximity Extension Assay using the Olink platform.RESULTS This study included 300 participants with nucleic acid test–confirmed COVID-19. Plasma SARS-CoV-2 viremia levels at the time of presentation predicted adverse disease outcomes, with an adjusted OR of 10.6 (95% CI 4.4–25.5, P < 0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and 3.9 (95% CI 1.5–10.1, P = 0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, and endothelium/vasculature, and alterations in coagulation pathways.CONCLUSION These results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.FUNDING Mark and Lisa Schwartz; the National Institutes of Health (U19AI082630); the American Lung Association; the Executive Committee on Research at Massachusetts General Hospital; the Chan Zuckerberg Initiative; Arthur, Sandra, and Sarah Irving for the David P. Ryan, MD, Endowed Chair in Cancer Research; an EMBO Long-Term Fellowship (ALTF 486-2018); a Cancer Research Institute/Bristol Myers Squibb Fellowship (CRI2993); the Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH awards UL1TR001102 and UL1TR002541-01); and by the Harvard University Center for AIDS Research (National Institute of Allergy and Infectious Diseases, 5P30AI060354).
Authors
Yijia Li, Alexis M. Schneider, Arnav Mehta, Moshe Sade-Feldman, Kyle R. Kays, Matteo Gentili, Nicole C. Charland, Anna L.K. Gonye, Irena Gushterova, Hargun K. Khanna, Thomas J. LaSalle, Kendall M. Lavin-Parsons, Brendan M. Lilley, Carl L. Lodenstein, Kasidet Manakongtreecheep, Justin D. Margolin, Brenna N. McKaig, Blair A. Parry, Maricarmen Rojas-Lopez, Brian C. Russo, Nihaarika Sharma, Jessica Tantivit, Molly F. Thomas, James Regan, James P. Flynn, Alexandra-Chloé Villani, Nir Hacohen, Marcia B. Goldberg, Michael R. Filbin, Jonathan Z. Li
×Abstract
Seasonal influenza vaccination elicits a diminished adaptive immune response in the elderly, and the mechanisms of immunosenescence are not fully understood. Using Ig-Seq, we found a marked increase with age in the prevalence of cross-reactive (CR) serum antibodies that recognize both the H1N1 (vaccine-H1) and H3N2 (vaccine-H3) components of an egg-produced split influenza vaccine. CR antibodies accounted for 73% ± 18% of the serum vaccine responses in a cohort of elderly donors, 65% ± 15% in late middle-aged donors, and only 13% ± 5% in persons under 35 years of age. The antibody response to non-HA antigens was boosted by vaccination. Recombinant expression of 19 vaccine-H1+H3 CR serum monoclonal antibodies (s-mAbs) revealed that they predominantly bound to non-HA influenza proteins. A sizable fraction of vaccine-H1+H3 CR s-mAbs recognized with high affinity the sulfated glycans, in particular sulfated type 2 N-acetyllactosamine (Galβ1-4GalNAcβ), which is found on egg-produced proteins and thus unlikely to contribute to protection against influenza infection in humans. Antibodies against sulfated glycans in egg-produced vaccine had been identified in animals but were not previously characterized in humans. Collectively, our results provide a quantitative basis for how repeated exposure to split influenza vaccine correlates with unintended focusing of serum antibody responses to non-HA antigens that may result in suboptimal immunity against influenza.
Authors
Jiwon Jung, Sophia T. Mundle, Irina V. Ustyugova, Andrew P. Horton, Daniel R. Boutz, Svetlana Pougatcheva, Ponraj Prabakaran, Jonathan R. McDaniel, Gregory R. King, Daechan Park, Maria D. Person, Congxi Ye, Bing Tan, Yuri Tanno, Jin Eyun Kim, Nicholas C. Curtis, Joshua DiNapoli, Simon Delagrave, Ted M. Ross, Gregory C. Ippolito, Harry Kleanthous, Jiwon Lee, George Georgiou
×Abstract
BACKGROUND The significant risks posed to mothers and fetuses by COVID-19 in pregnancy have sparked a worldwide debate surrounding the pros and cons of antenatal SARS-CoV-2 inoculation, as we lack sufficient evidence regarding vaccine effectiveness in pregnant women and their offspring. We aimed to provide substantial evidence for the effect of the BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection.METHODS A multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 study groups: vaccinated (n = 86); PCR-confirmed SARS-CoV-2 infected during pregnancy (n = 65), and unvaccinated noninfected controls (n = 62). Maternal and fetal blood samples were collected from parturients prior to delivery and from the umbilical cord following delivery, respectively. Sera IgG and IgM titers were measured using the Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD, and N).RESULTS The BNT162b2 mRNA vaccine elicits strong maternal humoral IgG response (anti-S and RBD) that crosses the placenta barrier and approaches maternal titers in the fetus within 15 days following the first dose. Maternal to neonatal anti-COVID-19 antibodies ratio did not differ when comparing sensitization (vaccine vs. infection). IgG transfer ratio at birth was significantly lower for third-trimester as compared with second trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group.CONCLUSION Antenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.FUNDING Israel Science Foundation and the Weizmann Institute Fondazione Henry Krenter.
Authors
Ofer Beharier, Romina Plitman Mayo, Tal Raz, Kira Nahum Sacks, Letizia Schreiber, Yael Suissa-Cohen, Rony Chen, Rachel Gomez-Tolub, Eran Hadar, Rinat Gabbay-Benziv, Yuval Jaffe Moshkovich, Tal Biron-Shental, Gil Shechter-Maor, Sivan Farladansky-Gershnabel, Hen Yitzhak Sela, Hedi Benyamini-Raischer, Nitzan D. Sela, Debra Goldman-Wohl, Ziv Shulman, Ariel Many, Haim Barr, Simcha Yagel, Michal Neeman, Michal Kovo
×Abstract
BACKGROUND Although convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data from randomized controlled trials that support its efficacy are limited.METHODS We conducted a randomized, double-blind, controlled trial among adults hospitalized with severe and critical COVID-19 at 5 sites in New York City (USA) and Rio de Janeiro (Brazil). Patients were randomized 2:1 to receive a single transfusion of either convalescent plasma or normal control plasma. The primary outcome was clinical status at 28 days following randomization, measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population.RESULTS Of 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to receive normal control plasma. At 28 days, no significant improvement in the clinical scale was observed in participants randomized to convalescent plasma (OR 1.50, 95% confidence interval [CI] 0.83–2.68, P = 0.180). However, 28-day mortality was significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 [12.6%] versus 18/73 [24.6%], OR 0.44, 95% CI 0.22–0.91, P = 0.034). The median titer of anti–SARS-CoV-2 neutralizing antibody in infused convalescent plasma units was 1:160 (IQR 1:80–1:320). In a subset of nasopharyngeal swab samples from Brazil that underwent genomic sequencing, no evidence of neutralization-escape mutants was detected.CONCLUSION In adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant improvement in day 28 clinical status. However, convalescent plasma was associated with significantly improved survival. A possible explanation is that survivors remained hospitalized at their baseline clinical status.TRIAL REGISTRATION ClinicalTrials.gov, NCT04359810.FUNDING Amazon Foundation, Skoll Foundation.
Authors
Max R. O’Donnell, Beatriz Grinsztejn, Matthew J. Cummings, Jessica E. Justman, Matthew R. Lamb, Christina M. Eckhardt, Neena M. Philip, Ying Kuen Cheung, Vinay Gupta, Esau João, Jose Henrique Pilotto, Maria Pia Diniz, Sandra Wagner Cardoso, Darryl Abrams, Kartik N. Rajagopalan, Sarah E. Borden, Allison Wolf, Leon Claude Sidi, Alexandre Vizzoni, Valdilea G. Veloso, Zachary C. Bitan, Dawn E. Scotto, Benjamin J. Meyer, Samuel D. Jacobson, Alex Kantor, Nischay Mishra, Lokendra V. Chauhan, Elizabeth F. Stone, Flavia Dei Zotti, Francesca La Carpia, Krystalyn E. Hudson, Stephen A. Ferrara, Joseph Schwartz, Brie A. Stotler, Wen-Hsuan W. Lin, Sandeep N. Wontakal, Beth Shaz, Thomas Briese, Eldad A. Hod, Steven L. Spitalnik, Andrew Eisenberger, Walter I. Lipkin
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