The editors of JCI and JCI Insight have revised the editorial process to address the impact of the COVID-19 pandemic on the global research community. Highlights:
Several COVID-19 studies have focused on neuropathology. In this issue of the JCI, Qin, Wu, and Chen, et al. focused specifically on people whose acute infection lacked obvious neurological involvement. Severely infected patients showed abnormal grey matter volumes, white matter diffusion, and cerebral blood flow compared with healthy controls and those with mild infection. The data remain associative rather than mechanistic, but correlations with systemic immune markers suggest effects of inflammation, hypercoagulation, or other aspects of disease severity. Mechanistic research is warranted. Given the lack of obvious neurological symptoms, neurocognitive assessments were not performed, but the findings suggest that such assessments may be warranted in severely affected patients, even without obvious symptoms. Further, studying CNS involvement of other disorders with overlapping pathophysiologies, such as inflammation, coagulation, hypoxia, or direct viral infection may reveal the causes for COVID-19 related neuropathology.
Amit Mahajan, Graeme F. Mason
Multisystem Inflammatory Syndrome in Children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vβ-chains results in Vβ-skewing, whereby T cells with specific Vβ-chains and diverse antigen specificity are overrepresented in the TCR repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR Βeta Variable gene (TRBV)11-2, with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and CDR3 length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion showed HLA class I allele restriction to HLA-I A02, C35 and C04, indicating a novel mechanism for CDR3-independent T cell expansion. In silico modelling indicated that polyacidic residues in the Vβ chain encoded by TRBV11-2 strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.
Rebecca A. Porritt, Lisa Paschold, Magali Noval Rivas, Mary Hongying Cheng, Lael M. Yonker, Harsha Chandnani, Merrick Lopez, Donjete Simnica, Christoph Schultheiß, Chintda Santiskulvong, Jennifer van Eyk, John K. McCormick, Alessio Fasano, Ivet Bahar, Mascha Binder, Moshe Arditi
Dysregulated immune profiles have been described in symptomatic SARS-CoV-2-infected patients. Whether the reported immune alterations are specific to SARS-CoV-2 infection or also triggered by other acute illnesses remains unclear. We performed flow cytometry analysis on fresh peripheral blood from a consecutive cohort of i) patients hospitalized with acute SARS-CoV-2 infection; ii) patients of comparable age/sex hospitalized for other acute disease (SARS-CoV-2 negative); and iii) healthy controls. Using both data-driven and hypothesis-driven analyses, we found several dysregulations in immune cell subsets (e.g., decreased proportion of T cells) that are similarly associated with acute SARS-CoV-2 infection and non-COVID-19 related acute illnesses. In contrast, we identified specific differences in myeloid and lymphocyte subsets that are associated with SARS-CoV-2 status (e.g., elevated proportion of ICAM-1+ mature/activated neutrophils, ALCAM+ monocytes, and CD38+CD8+ T cells). A subset of SARS-CoV-2-specific immune alterations correlated with disease severity, disease outcome at 30 days and mortality. Our data provide an understanding of the immune dysregulation that are specifically associated with SARS-CoV-2 infection among acute care hospitalized patients. Our study lays the foundation for the development of specific biomarkers to stratify SARS-CoV-2+ patients at risk of unfavorable outcome and uncover candidate molecules to investigate from a therapeutic perspective.
Rose-Marie Rébillard, Marc Charabati, Camille Grasmuck, Abdelali Filali-Mouhim, Olivier Tastet, Nathalie Brassard, Audrey Daigneault, Lyne Bourbonnière, Sai Priya Anand, Renaud Balthazard, Guillaume Beaudoin-Bussières, Romain Gasser, Mehdi Benlarbi, Ana Carmena Moratalla, Yves Carpentier Solorio, Marianne Boutin, Negar Farzam-kia, Jade Descôteaux-Dinelle, Antoine Philippe Fournier, Elizabeth M. Gowing, Annemarie Laumaea, Hélène Jamann, Boaz Lahav, Guillaume Goyette, Florent Lemaître, Victoria Hannah Mamane, Jérémie Prévost, Jonathan Richard, Karine Thai, Jean-François Cailhier, Nicolas Chomont, Andrés Finzi, Michaël Chassé, Madeleine Durand, Nathalie Arbour, Daniel E. Kaufmann, Alexandre Prat, Catherine Larochelle
Peter J. Hotez
The coronavirus disease 2019 (COVID-19) rapidly progressed to a global pandemic. Although patients totally recover from COVID-19 pneumonia, long-term effects on the brain still need to be explored. Here, two subtypes (mild type-MG and severe type-SG) with no specific neurological manifestations at the acute stage and no obvious lesions on the conventional MRI three months after discharge were recruited. Changes in gray matter morphometry, cerebral blood flow (CBF) and white matter (WM) microstructure were investigated using MRI. The relationship between brain imaging measurements and inflammation markers were further analyzed. Compared with healthy controls, the decrease in cortical thickness/CBF, and the changes in WM microstructure were observed to be more severe in the SG than MG, especially in the frontal and limbic systems. Furthermore, changes in brain microstructure, CBF and tracts parameters were significantly correlated with inflammatory markers. The indirect injury related to inflammatory storm may damage the brain, that led to these interesting observations. There are also other likely potential causes, such as hypoxemia and dysfunction of vascular endothelium, et al. The abnormalities in these brain areas need to be monitored in the process of complete recovery, which could help clinicians to understand the potential neurological sequelae of COVID-19.
Yuanyuan Qin, Jinfeng Wu, Tao Chen, Jia Li, Guiling Zhang, Di Wu, Yiran Zhou, Ning Zheng, Aoling Cai, Qin Ning, Anne Manyande, Fuqiang Xu, Jie Wang, Wenzhen Zhu
Arturo Casadevall, Jeffrey P. Henderson, Michael J. Joyner, Liise-anne Pirofski
Multiple studies have shown loss of severe acute respiratory syndrome coronavirus 2–specific (SARS-CoV-2–specific) antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from coronavirus disease 2019 (COVID-19). However, memory B cells (MBCs) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multidimensional flow cytometric analysis of S protein receptor binding domain–specific (S-RBD–specific) MBCs in cohorts of ambulatory patients with COVID-19 with mild disease (n = 7), and hospitalized patients with moderate to severe disease (n = 7), at a median of 54 days (range, 39–104 days) after symptom onset. We detected S-RBD–specific class-switched MBCs in 13 of 14 participants, failing only in the individual with the lowest plasma levels of anti–S-RBD IgG and neutralizing antibodies. Resting MBCs (rMBCs) made up the largest proportion of S-RBD–specific MBCs in both cohorts. FCRL5, a marker of functional memory on rMBCs, was more dramatically upregulated on S-RBD–specific rMBCs after mild infection than after severe infection. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD–specific, class-switched rMBCs that resemble germinal center–derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell–mediated immunity against SARS-CoV-2 after mild or severe disease.
Clinton O. Ogega, Nicole E. Skinner, Paul W. Blair, Han-Sol Park, Kirsten Littlefield, Abhinaya Ganesan, Santosh Dhakal, Pranay Ladiwala, Annukka A.R. Antar, Stuart C. Ray, Michael J. Betenbaugh, Andrew Pekosz, Sabra L. Klein, Yukari C. Manabe, Andrea L. Cox, Justin R. Bailey
SARS-CoV-2 (CoV2) antibody therapies, including COVID-19 convalescent plasma (CCP), monoclonal antibodies, and hyperimmune globulin, are among the leading treatments for individuals with early COVID-19 infection. The functionality of convalescent plasma varies greatly, but the association of antibody epitope specificities with plasma functionality remains uncharacterized. We assessed antibody functionality and reactivities to peptides across the CoV2 and the 4 endemic human coronavirus (HCoV) genomes in 126 CCP donations. We found strong correlation between plasma functionality and polyclonal antibody targeting of CoV2 spike protein peptides. Antibody reactivity to many HCoV spike peptides also displayed strong correlation with plasma functionality, including pan-coronavirus cross-reactive epitopes located in a conserved region of the fusion peptide. After accounting for antibody cross-reactivity, we identified an association between greater alphacoronavirus NL63 antibody responses and development of highly neutralizing antibodies against CoV2. We also found that plasma preferentially reactive to the CoV2 spike receptor binding domain (RBD), versus the betacoronavirus HKU1 RBD, had higher neutralizing titer. Finally, we developed a 2-peptide serosignature that identifies plasma donations with high anti-spike titer, but that suffer from low neutralizing activity. These results suggest that analysis of coronavirus antibody fine specificities may be useful for selecting desired therapeutics and understanding the complex immune responses elicited by CoV2 infection.
William R. Morgenlander, Stephanie N. Henson, Daniel R. Monaco, Athena Chen, Kirsten Littlefield, Evan M. Bloch, Eric Fujimura, Ingo Ruczinski, Andrew R. Crowley, Harini Natarajan, Savannah E. Butler, Joshua A. Weiner, Mamie Z. Li, Tania S. Bonny, Sarah E. Benner, Ashwin Balagopal, David Sullivan, Shmuel Shoham, Thomas C. Quinn, Susan H. Eshleman, Arturo Casadevall, Andrew D. Redd, Oliver Laeyendecker, Margaret E. Ackerman, Andrew Pekosz, Stephen J. Elledge, Matthew Robinson, Aaron A.R. Tobian, H. Benjamin Larman
BACKGROUND Circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA may represent a more reliable indicator of infection than nasal RNA, but quantitative reverse transcription PCR (RT-qPCR) lacks diagnostic sensitivity for blood samples.METHODS A CRISPR-augmented RT-PCR assay that sensitively detects SARS-CoV-2 RNA was employed to analyze viral RNA kinetics in longitudinal plasma samples from nonhuman primates (NHPs) after virus exposure; to evaluate the utility of blood SARS-CoV-2 RNA detection for coronavirus disease 2019 (COVID-19) diagnosis in adults cases confirmed by nasal/nasopharyngeal swab RT-PCR results; and to identify suspected COVID-19 cases in pediatric and at-risk adult populations with negative nasal swab RT-qPCR results. All blood samples were analyzed by RT-qPCR to allow direct comparisons.RESULTS CRISPR-augmented RT-PCR consistently detected SARS-CoV-2 RNA in the plasma of experimentally infected NHPs from 1 to 28 days after infection, and these increases preceded and correlated with rectal swab viral RNA increases. In a patient cohort (n = 159), this blood-based assay demonstrated 91.2% diagnostic sensitivity and 99.2% diagnostic specificity versus a comparator RT-qPCR nasal/nasopharyngeal test, whereas RT-qPCR exhibited 44.1% diagnostic sensitivity and 100% specificity for the same blood samples. This CRISPR-augmented RT-PCR assay also accurately identified patients with COVID-19 using one or more negative nasal swab RT-qPCR results.CONCLUSION Results of this study indicate that sensitive detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR permits accurate COVID-19 diagnosis, and can detect COVID-19 cases with transient or negative nasal swab RT-qPCR results, suggesting that this approach could improve COVID-19 diagnosis and the evaluation of SARS-CoV-2 infection clearance, and predict the severity of infection.TRIAL REGISTRATION ClinicalTrials.gov. NCT04358211.FUNDING Department of Defense, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the National Center for Research Resources.
Zhen Huang, Bo Ning, He S. Yang, Brady M. Youngquist, Alex Niu, Christopher J. Lyon, Brandon J. Beddingfield, Alyssa C. Fears, Chandler H. Monk, Amelie E. Murrell, Samantha J. Bilton, Joshua P. Linhuber, Elizabeth B. Norton, Monika L. Dietrich, Jim Yee, Weihua Lai, John W. Scott, Xiao-Ming Yin, Jay Rappaport, James E. Robinson, Nakhle S. Saba, Chad J. Roy, Kevin J. Zwezdaryk, Zhen Zhao, Tony Y. Hu
BACKGROUND Despite a rapidly growing body of literature on coronavirus disease 2019 (COVID-19), our understanding of the immune correlates of disease severity, course, and outcome remains poor.METHODS Using mass cytometry, we assessed the immune landscape in longitudinal whole-blood specimens from 59 patients presenting with acute COVID-19 and classified based on maximal disease severity. Hospitalized patients negative for SARS-CoV-2 were used as controls.RESULTS We found that the immune landscape in COVID-19 formed 3 dominant clusters, which correlated with disease severity. Longitudinal analysis identified a pattern of productive innate and adaptive immune responses in individuals who had a moderate disease course, whereas those with severe disease had features suggestive of a protracted and dysregulated immune response. Further, we identified coordinate immune alterations accompanying clinical improvement and decline that were also seen in patients who received IL-6 pathway blockade.CONCLUSION The hospitalized COVID-19 negative cohort allowed us to identify immune alterations that were shared between severe COVID-19 and other critically ill patients. Collectively, our findings indicate that selection of immune interventions should be based in part on disease presentation and early disease trajectory due to the profound differences in the immune response in those with mild to moderate disease and those with the most severe disease.FUNDING Benaroya Family Foundation, the Leonard and Norma Klorfine Foundation, Glenn and Mary Lynn Mounger, and the National Institutes of Health.
Hamid Bolouri, Cate Speake, David Skibinski, S. Alice Long, Anne M. Hocking, Daniel J. Campbell, Jessica A. Hamerman, Uma Malhotra, Jane H. Buckner, the Benaroya Research Institute COVID-19 Research Team