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Pre-existing cross-reactivity to SARS-CoV-2 may occur in absence of prior viral exposure. However, this has been difficult to quantify at the population level due to a lack of reliably defined seroreactivity thresholds. Using an orthogonal antibody testing approach, we estimated that ~0.6% of non-triaged adults from the greater Vancouver area, Canada between May 17th and June 19th 2020 showed clear evidence of a prior SARS-CoV-2 infection, after adjusting for false-positive and false-negative test results. Using a highly sensitive multiplex assay and positive/negative thresholds established in infants in whom maternal antibodies have waned, we determine that more than 90% of uninfected adults showed antibody reactivity against the spike, receptor-binding domain (RBD), N-terminal domains (NTD) or the nucleocapsid (N) protein from SARS-CoV-2. This sero-reactivity was evenly distributed across age and sex, correlated with circulating coronaviruses reactivity, and was partially outcompeted by soluble circulating coronaviruses’ spike. Using a custom SARS-CoV-2 peptide mapping array, we found that this antibody reactivity broadly mapped to spike, and to conserved non-structural viral proteins. We conclude that most adults display pre-existing antibody cross-reactivity against SARS-CoV-2, which further supports investigation of how this may impact the clinical severity of COVID-19 or SARS-CoV-2 vaccine responses.
Abdelilah Majdoubi, Christina Michalski, Sarah E. O’Connell, Sarah Dada, Sandeep R. Narpala, Jean P. Gelinas, Disha Mehta, Claire Cheung, Dirk F.H. Winkler, Manjula Basappa, Aaron C. Liu, Matthias Görges, Vilte E. Barakauskas, Michael A. Irvine, Jennifer Mehalko, Dominic Esposito, Inna Sekirov, Agatha N. Jassem, David M. Goldfarb, Steven Pelech, Daniel C. Douek, Adrian B. McDermott, Pascal M Lavoie
Total views: 36528
Multiple organ failure in sepsis is a progressive failure of several interdependent organ systems. Liver dysfunction occurs early during sepsis and is directly associated with patient death; however, the underlying mechanism of liver dysfunction is unclear. Platelet transfusion benefits patients with sepsis, and inhibition of complement activation protects liver function in septic animals. Herein, we explored the potential link between platelets, complement activation, and liver dysfunction in sepsis. We found that deletion of platelet C-type lectin-like receptor 2 (CLEC-2) exacerbated liver dysfunction in early sepsis. Platelet CLEC-2–deficient mice exhibited higher complement activation, more severe complement attack in the liver, and lower plasma levels of complement inhibitors at early time points after E. coli infection. Circulating monocytes expressed the CLEC-2 ligand podoplanin in early sepsis, and podoplanin binding induced release of complement inhibitors from platelets. Injection of complement inhibitors released from platelets reduced complement attack and attenuated liver dysfunction in septic mice. These findings indicate a new function of platelets in the regulation of complement activation during sepsis.
Zhanli Xie, Bojing Shao, Christopher Hoover, Michael McDaniel, Jianhua Song, Miao Jiang, Zhenni Ma, Fei Yang, Jingjing Han, Xia Bai, Changgeng Ruan, Lijun Xia
Total views: 9862
Background: COVID-19 is more benign in children compared to adults for unknown reasons. This contrasts with other respiratory viruses where disease manifestations are often more severe in children. We hypothesize that a more robust early innate immune response to SARS-CoV-2 protects against severe disease. Methods: Clinical outcomes, SARS-CoV-2 viral copies and cellular gene expression were compared in nasopharyngeal swabs obtained at the time of presentation to the Emergency Department from 12 children and 27 adults using bulk RNA sequencing and quantitative reverse transcription PCR. Total protein, cytokines and anti-SARS-CoV-2 IgG and IgA were quantified in nasal fluid. Results: SARS-CoV-2 copies, ACE2 and TMPRSS2 gene expression were similar in children and adults, but children displayed higher expression of genes associated with interferon signaling, NLRP3 inflammasome, and other innate pathways. Higher levels of IFN-α2, IFN-γ, IP-10, IL-8, and IL-1β protein were detected in nasal fluid in children versus adults. Children also expressed higher levels of genes associated with immune cells whereas expression of those associated with epithelial cells did not differ in children versus adults. Anti-SARS-CoV-2 IgA and IgG were detected at similar levels in nasal fluid from both groups. None of the children required supplemental oxygen whereas 7 adults did (p=0.03); four adults died. Conclusions: These findings provide direct evidence of a more vigorous early mucosal immune response in children compared to adults and suggest that this contributes to favorable clinical outcomes.
Carl A. Pierce, Sharlene Sy, Benjamin Galen, Doctor Y. Goldstein, Erika P. Orner, Marla J. Keller, Kevan C. Herold, Betsy C. Herold
Total views: 2907
Limitations of checkpoint inhibitor cancer immunotherapy include induction of autoimmune syndromes and resistance of many cancers. Since CD318, a novel CD6 ligand, is associated with the aggressiveness and metastatic potential of human cancers, we tested the effect of an anti-CD6 monoclonal antibody, UMCD6, on killing of cancer cells by human lymphocytes. UMCD6 augmented killing of breast, lung, and prostate cancer cells through direct effects on both CD8+ T cells and NK cells, increasing cancer cell death and lowering cancer cell survival in vitro more robustly than monoclonal antibody checkpoint inhibitors that interrupt the programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) axis. UMCD6 also augmented in vivo killing by human peripheral blood lymphocytes of a human breast cancer line xenotransplanted into immunodeficient mice. Mechanistically, UMCD6 upregulated the expression of the activating receptor NKG2D and downregulated expression of the inhibitory receptor NKG2A on both NK cells and CD8+ T cells, with concurrent increases in perforin and granzyme B production. The combined capability of an anti-CD6 monoclonal antibody to control autoimmunity through effects on CD4+ lymphocyte differentiation while enhancing killing of cancer cells through distinct effects on CD8+ and NK cells opens a potential new approach to cancer immunotherapy that would suppress rather than instigate autoimmunity.
Jeffrey H. Ruth, Mikel Gurrea-Rubio, Kalana S. Athukorala, Stephanie M. Rasmussen, Daniel P. Weber, Peggy M. Randon, Rosemary J. Gedert, Matthew E. Lind, M. Asif Amin, Phillip L. Campbell, Pei-Suen Tsou, Yang Mao-Draayer, Qi Wu, Thomas M. Lanigan, Venkateshwar G. Keshamouni, Nora G. Singer, Feng Lin, David A. Fox
Total views: 1790
Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti–SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response.
Michele L. Donato, Steven Park, Melissa Baker, Robert Korngold, Alison Morawski, Xue Geng, Ming Tan, Andrew Ip, Stuart Goldberg, Scott Rowley, Kar Chow, Emily Brown, Joshua Zenreich, Phyllis McKiernan, Kathryn Buttner, Anna Ullrich, Laura Long, Rena Feinman, Andrea Ricourt, Marlo Kemp, Mariefel Vendivil, Hyung Suh, Bindu Balani, Cristina Cicogna, Rani Sebti, Abdulla Al-Khan, Steven Sperber, Samit Desai, Stacey Fanning, Danit Arad, Ronaldo Go, Elizabeth Tam, Keith Rose, Sean Sadikot, David Siegel, Martin Gutierrez, Tatyana Feldman, Andre Goy, Andrew Pecora, Noa Biran, Lori Leslie, Alfred Gillio, Sarah Timmapuri, Michele Boonstra, Sam Singer, Sukhdeep Kaur, Ernest Richards, David S. Perlin
Total views: 1494
The early COVID-19 pandemic was characterized by rapid global spread. In Maryland and Washington, DC, United States, more than 2500 cases were reported within 3 weeks of the first COVID-19 detection in March 2020. We aimed to use genomic sequencing to understand the initial spread of SARS-CoV-2 — the virus that causes COVID-19 — in the region. We analyzed 620 samples collected from the Johns Hopkins Health System during March 11–31, 2020, comprising 28.6% of the total cases in Maryland and Washington, DC. From these samples, we generated 114 complete viral genomes. Analysis of these genomes alongside a subsampling of over 1000 previously published sequences showed that the diversity in this region rivaled global SARS-CoV-2 genetic diversity at that time and that the sequences belong to all of the major globally circulating lineages, suggesting multiple introductions into the region. We also analyzed these regional SARS-CoV-2 genomes alongside detailed clinical metadata and found that clinically severe cases had viral genomes belonging to all major viral lineages. We conclude that efforts to control local spread of the virus were likely confounded by the number of introductions into the region early in the epidemic and the interconnectedness of the region as a whole.
Peter M. Thielen, Shirlee Wohl, Thomas Mehoke, Srividya Ramakrishnan, Melanie Kirsche, Oluwaseun Falade-Nwulia, Nídia S. Trovão, Amanda Ernlund, Craig Howser, Norah Sadowski, C. Paul Morris, Mark Hopkins, Matthew Schwartz, Yunfan Fan, Victoria Gniazdowski, Justin Lessler, Lauren Sauer, Michael C. Schatz, Jared D. Evans, Stuart C. Ray, Winston Timp, Heba H. Mostafa
Total views: 1206
In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have the potential to propagate inflammation and microvascular thrombosis — including in the lungs of patients with acute respiratory distress syndrome. We now report that sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and citrullinated histone H3 (Cit-H3); the latter 2 are specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute-phase reactants, including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.
Yu Zuo, Srilakshmi Yalavarthi, Hui Shi, Kelsey Gockman, Melanie Zuo, Jacqueline A. Madison, Christopher Blair, Andrew Weber, Betsy J. Barnes, Mikala Egeblad, Robert J. Woods, Yogendra Kanthi, Jason S. Knight
Total views: 1166
Complexity of lung microenvironment and changes in cellular composition during disease make it exceptionally hard to understand molecular mechanisms driving development of chronic lung diseases. Although recent advances in cell type–resolved approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a versatile workflow that allows storage of lung tissue with high viability, permits thorough sample quality check before cell isolation, and befits sequencing-based profiling. We demonstrate that cryopreservation enables isolation of multiple cell types from both healthy and diseased lungs. Basal cells from cryopreserved airways retain their differentiation ability, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for omics profiling of lung cells. Moreover, we obtained high-quality single-cell RNA-sequencing data of cells from cryopreserved human lungs, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our workflow is well suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to viable human tissue.
Maria Llamazares-Prada, Elisa Espinet, Vedrana Mijošek, Uwe Schwartz, Pavlo Lutsik, Raluca Tamas, Mandy Richter, Annika Behrendt, Stephanie T. Pohl, Naja P. Benz, Thomas Muley, Arne Warth, Claus Peter Heußel, Hauke Winter, Jonathan J. M. Landry, Felix J.F. Herth, Tinne C.J. Mertens, Harry Karmouty-Quintana, Ina Koch, Vladimir Benes, Jan O. Korbel, Sebastian M. Waszak, Andreas Trumpp, David M. Wyatt, Heiko F. Stahl, Christoph Plass, Renata Z. Jurkowska
Total views: 1091
Ventilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in which the close apposition of respiratory epithelium and endothelial cells of the pulmonary microvascular enables efficient gas exchange. Morphogenesis of the alveoli initiates at late gestation in humans and the early postnatal period in the mouse. Alveolar septation is directed by complex signaling interactions among multiple cell types. Here, we demonstrate that IGF1 receptor gene (Igf1r) expression by a subset of pulmonary fibroblasts is required for normal alveologenesis in mice. Postnatal deletion of Igf1r caused alveolar simplification, disrupting alveolar elastin networks and extracellular matrix without altering myofibroblast differentiation or proliferation. Moreover, loss of Igf1r impaired contractile properties of lung myofibroblasts and inhibited myosin light chain (MLC) phosphorylation and mechanotransductive nuclear YAP activity. Activation of p-AKT, p-MLC, and nuclear YAP in myofibroblasts was dependent on Igf1r. Pharmacologic activation of AKT enhanced MLC phosphorylation, increased YAP activation, and ameliorated alveolar simplification in vivo. IGF1R controls mechanosignaling in myofibroblasts required for lung alveologenesis.
Hua He, John Snowball, Fei Sun, Cheng-Lun Na, Jeffrey A. Whitsett
Total views: 1067
Functional dyspepsia (FD) is associated with chronic gastrointestinal distress and with anxiety and depression. Here, we hypothesized that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. Using a previously validated rat model of FD characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior, we found that vagal activity — in response to gastric distention — was increased in FD rats. The FD phenotype was associated with gastric mast cell hyperplasia and increased expression of corticotrophin-releasing factor (Crh) and decreased brain-derived neurotrophic factor genes in the central amygdala. Subdiaphragmatic vagotomy reversed these changes and restored affective behavior to that of controls. Vagotomy partially attenuated pain responses to gastric distention, which may be mediated by central reflexes in the periaqueductal gray, as determined by local injection of lidocaine. Ketotifen, a mast cell stabilizer, reduced vagal hypersensitivity, normalized affective behavior, and attenuated gastric hyperalgesia. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in Crh signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors. Together, these results support a “bottom-up” pathway involving the gut-brain axis in the pathogenesis of both gastric pain and psychiatric comorbidity in FD.
Zachary A. Cordner, Qian Li, Liansheng Liu, Kellie L. Tamashiro, Aditi Bhargava, Timothy H. Moran, Pankaj Jay Pasricha
Total views: 804