The immunopathology of COVID-19 remains enigmatic, exhibiting immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSC) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied blood and airways of COVID-19 patients across disease severity at multiple timepoints. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of COVID-19 patients compared to controls. M-MDSCs isolated from COVID-19 patients suppressed T cell proliferation and IFNg production partly via an arginase-1 (Arg-1) dependent mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. COVID-19 patients had fewer T cells, and displayed downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expand in blood of COVID-19 patients, suppress T cells and strongly associate with disease severity, suggesting a role for M-MDSCs in the dysregulated COVID-19 immune response.
Sara Falck-Jones, Sindhu Vangeti, Meng Yu, Ryan Falck-Jones, Alberto Cagigi, Isabella Badolati, Björn Österberg, Maximilian Julius Lautenbach, Eric Ahlberg, Ang Lin, Rico Lepzien, Inga Szurgot, Klara Lenart, Fredrika Hellgren, Holden T. Maecker, Jörgen Sälde, Jan Albert, Niclas Johansson, Max Bell, Karin Lore, Anna Färnert, Anna Smed-Sörensen
Characterization of the T cell response in individuals who recover from SARS-CoV-2 infection is critical to understand its contribution to protective immunity. A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 COVID-19 convalescent individuals. T cells were evaluated using a 28-marker phenotypic panel, and findings were modelled against time from diagnosis, humoral and inflammatory responses. There were 132 SARS-CoV-2-specific CD8+ T cell responses detected across six different HLAs, corresponding to 52 unique epitope reactivities. CD8+ T cell responses were detected in almost all convalescent individuals and were directed against several structural and non-structural target epitopes from the entire SARS-CoV-2 proteome. A unique phenotype for SARS-CoV-2-specific T cells was observed that was distinct from other common virus-specific T cells detected in the same cross-sectional sample and characterized by early differentiation kinetics. Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem-cell and transitional memory states, subsets, which may be key to developing durable protection.
Hassen Kared, Andrew D. Redd, Evan M. Bloch, Tania S. Bonny, Hermi R. Sumatoh, Faris Kairi, Daniel Carbajo, Brian Abel, Evan W. Newell, Maria Bettinotti, Sarah E. Benner, Eshan U. Patel, Kirsten Littlefield, Oliver Laeyendecker, Shmuel Shoham, David Sullivan, Arturo Casadevall, Andrew Pekosz, Alessandra Nardin, Michael Fehlings, Aaron AR Tobian, Thomas C. Quinn
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.
Magali Noval Rivas, Joseph E. Ebinger, Min Wu, Nancy Sun, Jonathan Braun, Kimia Sobhani, Jennifer E. Van Eyk, Susan Cheng, Moshe Arditi
BACKGROUND Corticosteroids are widely used in patients with COVID 19, although their benefit-to-risk ratio remains controversial.METHODS Patients with severe COVID-19–related acute respiratory distress syndrome (ARDS) were included from December 29, 2019 to March 16, 2020 in 5 tertiary Chinese hospitals. Cox proportional hazards and competing risks analyses were conducted to analyze the impact of corticosteroids on mortality and SARS–CoV-2 RNA clearance, respectively. We performed a propensity score (PS) matching analysis to control confounding factors.RESULTS Of 774 eligible patients, 409 patients received corticosteroids, with a median time from hospitalization to starting corticosteroids of 1.0 day (IQR 0.0–3.0 days) . As compared with usual care, treatment with corticosteroids was associated with increased rate of myocardial (15.6% vs. 10.4%, P = 0.041) and liver injury (18.3% vs. 9.9%, P = 0.001), of shock (22.0% vs. 12.6%, P < 0.001), of need for mechanical ventilation (38.1% vs. 19.5%, P < 0.001), and increased rate of 28-day all-cause mortality (44.3% vs. 31.0%, P < 0.001). After PS matching, corticosteroid therapy was associated with 28-day mortality (adjusted HR 1.46, 95% CI 1.01–2.13, P = 0.045). High dose (>200 mg) and early initiation (≤3 days from hospitalization) of corticosteroid therapy were associated with a higher 28-day mortality rate. Corticosteroid use was also associated with a delay in SARS–CoV-2 coronavirus RNA clearance in the competing risk analysis (subhazard ratio 1.59, 95% CI 1.17–2.15, P = 0.003).CONCLUSION Administration of corticosteroids in severe COVID-19–related ARDS is associated with increased 28-day mortality and delayed SARS–CoV-2 coronavirus RNA clearance after adjustment for time-varying confounders.FUNDING None.
Jiao Liu, Sheng Zhang, Xuan Dong, Zhongyi Li, Qianghong Xu, Huibin Feng, Jing Cai, Sisi Huang, Jun Guo, Lidi Zhang, Yizhu Chen, Wei Zhu, Hangxiang Du, Yongan Liu, Tao Wang, Limin Chen, Zhenliang Wen, Djillali Annane, Jieming Qu, Dechang Chen
SARS-CoV-2 causes a wide spectrum of clinical manifestations and significant mortality. Studies investigating underlying immune characteristics are needed to understand disease pathogenesis and inform vaccine design. In this study, we examined immune cell subsets in hospitalized and non-hospitalized individuals. In hospitalized patients, many adaptive and innate immune cells were decreased in frequency compared to healthy and convalescent individuals, with the exception of B lymphocytes which increased. Our findings show increased frequencies of T-cell activation markers (CD69, Ox40, HLA-DR and CD154) in hospitalized patients, with other T-cell activation/exhaustion markers (CD25, PD-L1 and TIGIT) remaining elevated in hospitalized and non-hospitalized individuals. B cells had a similar pattern of activation/exhaustion, with increased frequency of CD69 and CD95 during hospitalization, followed by an increase in PD1 frequencies in non-hospitalized individuals. Interestingly, many of these changes were found to increase over time in non-hospitalized longitudinal samples, suggesting a prolonged period of immune dysregulation following SARS-CoV-2 infection. Changes in T-cell activation/exhaustion in non-hospitalized patients were found to positively correlate with age. Severely infected individuals had increased expression of activation and exhaustion markers. These data suggest a prolonged period of immune dysregulation following SARS-CoV-2 infection highlighting the need for additional studies investigating immune dysregulation in convalescent individuals.
Jacob K. Files, Sushma Boppana, Mildred D. Perez, Sanghita Sarkar, Kelsey E. Lowman, Kai Qin, Sarah Sterrett, Eric Carlin, Anju Bansal, Steffanie Sabbaj, Dustin M. Long, Olaf Kutsch, James Kobie, Paul Goepfert, Nathaniel Erdmann
A considerable fraction of B cells recognize SARS-CoV-2 with germline-encoded elements of their B cell receptor resulting in the production of neutralizing and non-neutralizing antibodies. We found that antibody sequences from different discovery cohorts shared biochemical properties and could be retrieved across validation cohorts confirming the stereotyped character of this naive response in COVID-19. While neutralizing antibody sequences were found independently of disease severity in line with serological data, individual non-neutralizing antibody sequences were associated with fatal clinical courses suggesting detrimental effects of these antibodies. We mined 200 immune repertoires of healthy individuals and 500 of patients with blood or solid cancers - all acquired prior to the pandemic - for SARS-CoV-2 antibody sequences. While the largely unmutated B cell rearrangements occurred in a substantial fraction of immune repertoires from young and healthy individuals, these sequences were less likely found in individuals over 60 years of age and in cancer. This reflects B cell repertoire restriction in aging and cancer and may to a certain extent explain the different clinical COVID-19 courses observed in these risk groups. Future studies will have to address if this stereotyped B cell response to SARS-CoV-2 emerging from unmutated antibody rearrangements will create long-lived memory.
Lisa Paschold, Donjete Simnica, Edith Willscher, Maria J.G.T. Vehreschild, Jochen Dutzmann, Daniel G. Sedding, Christoph Schultheiß, Mascha Binder
Four different endemic coronaviruses (eCoVs) are etiologic agents for the seasonal “common cold,” and these eCoVs share extensive sequence homology with human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we show that individuals with as compared to without a relatively recent documented eCoV were tested at greater frequency for respiratory infections but had similar rate of SARS-CoV-2 acquisition. Importantly, the patients with a previously detected eCoV had less severe coronavirus disease-2019 (COVID-19) illness. Our observations suggest that pre-existing immune responses against endemic human coronaviruses can mitigate disease manifestations from SARS-CoV-2 infection.
Manish Sagar, Katherine Reifler, Michael Rossi, Nancy S. Miller, Pranay Sinha, Laura White, Joseph P. Mizgerd
BACKGROUND. Serological assays are of critical importance to investigate correlates of response and protection in COVID-19, to define previous exposure to SARS-CoV-2 in populations and to verify the development of an adaptive immune response in infected individuals. METHODS. We studied 509 confirmed COVID-19 patients from the San Raffaele Hospital of Milan and 480 pre-pandemic organ donor sera collected in 2010-2012. Using fluid-phase luciferase immune precipitation (LIPS) assays, we characterized IgG, IgM, IgA antibodies to the spike Receptor Binding Domain (RBD), S1+S2, nucleocapsid, and ORF6 to 10 of SARS-CoV-2, to the HCoV-OC43 and HCoV-HKU1 betacoronaviruses spike S2, and the H1N1Ca2009 flu virus hemagglutinin. Sequential samples at 1 and 3 months post-hospital discharge were also tested in 95 patients for SARS-CoV-2 RBD antibodies. RESULTS. Antibodies developed rapidly against multiple SARS-CoV-2 antigens in 95% of patients by 4 weeks post-symptoms onset and IgG to the RBD increased until the 3rd month of follow-up. We observed a major synchronous expansion of antibodies to the HCoV-OC43 and HCoV-HKU1 spike S2. A likely co-infection with influenza was neither linked to a more severe presentation of the disease nor to a worse outcome. Of the measured antibody responses positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival. CONCLUSIONS. The measurement of antibodies to selected epitopes of SARS-CoV-2 antigens can offer a more accurate assessment of the humoral response in patients and its impact on survival. The presence of partially cross-reactive antibodies with other betacoronoviruses is likely to impact on serological assay specificity and interpretation.
Massimiliano Secchi, Elena Bazzigaluppi, Cristina Brigatti, Ilaria Marzinotto, Cristina Tresoldi, Patrizia Rovere-Querini, Andrea Poli, Antonella Castagna, Gabriella Scarlatti, Alberto Zangrillo, Fabio Ciceri, Lorenzo Piemonti, Vito Lampasona
BACKGROUND. Understanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell therapy (CAR-T) at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations. METHODS. We retrospectively investigated patients diagnosed between March 15th and May 7th, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available. RESULTS. We identified 77 SARS-CoV-2 + cellular therapy recipients (Allo = 35, Auto = 37, CAR-T = 5; median time from cellular therapy 782 days (IQR 354,1611). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of non-rebreather or higher oxygen requirement and death (n events = 25/77) included number of co-morbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host-disease was not identified among Allo subjects. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients. CONCLUSION. In this series of Allo, Auto, and CAR-T recipients, we report overall favorable clinical outcomes for COVID-19 patients without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the anti-viral response and immune reconstitution. FUNDING. NIH P01 CA23766, NIH/NCI P30 CA008748.
Gunjan L. Shah, Susan DeWolf, Yeon Joo Lee, Roni Tamari, Parastoo B. Dahi, Jessica A. Lavery, Josel D. Ruiz, Sean M. Devlin, Christina Cho, Jonathan U. Peled, Ioannis Politikos, Michael Scordo, N. Esther Babady, Tania Jain, Santosha Vardhana, Anthony F. Daniyan, Craig S. Sauter, Juliet N. Barker, Sergio A. Giralt, Cheryl Goss, Peter Maslak, Tobias M. Hohl, Mini Kamboj, Lakshmi Ramanathan, Marcel R.M. van den Brink, Esperanza B. Papadopoulos, Genovefa A. Papanicolaou, Miguel-Angel Perales
Background: Marked progress is achieved in understanding the physiopathology of COVID-19 that caused global pandemics. However, CD4+ T cell population that is critical for antibody response in COVID-19 is poorly understood. Methods: In this study, we provided a comprehensive analysis of peripheral CD4+ T cells of 13 COVID-19 convalescent patients, as defined as confirmed free of SARS-CoV-2 for 2-4 weeks, using flow cytometry, magnetic chemiluminescence enzyme antibody immunoassay and correlated the data with clinical characteristics. Results: We observed that relative to healthy individuals, convalescent patients displayed an altered peripheral CD4+ T cell spectrum. Specifically, consistent with other viral infections, cTFH1 cell associated with SARS-CoV-2 targeting antibodies, which was found to skew with disease severity as more severe individuals showed higher frequency of TEM and TFH-EM cells but a lower frequency of TCM, TFH-CM and TNaive cells, relative to mild and moderate patients. Interestingly, higher frequency of cTFH-EM cells correlated with lower number of recorded admission blood oxygen level in convalescent patients. These observations might constitute residual effects by which COVID-19 can impact the homeostasis of CD4+ T cells in the long-term and explain the highest ratio of class-switched virus-specific antibody producing individuals found in our severe COVID-19 cohort. Conclusion: Together, our study demonstrated close connection between CD4+ T cells and antibody production in COVID-19 convalescents.Funding: This study was supported by Six Talent Peaks Project in Jiangsu Province and the National Natural Science Foundation of China (NSFC) grants 81970759.
Fang Gong, Yaping Dai, Ting Zheng, Liang Cheng, Dan Zhao, Hao Wang, Min Liu, Hao Pei, Tengchuan Jin, Di Yu, Pengcheng Zhou
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