Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation
Mary Hongying Cheng, She Zhang, Rebecca A Porritt, Magali Noval Rivas, Lisa Paschold, Edith Willscher, Mascha Binder, Moshe Arditi, Ivet Bahar, Mary Hongying Cheng, She Zhang, Rebecca A Porritt, Magali Noval Rivas, Lisa Paschold, Edith Willscher, Mascha Binder, Moshe Arditi, Ivet Bahar
Abstract
Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in children with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These children and adult patients with severe hyperinflammation present with a constellation of symptoms that strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to T cell receptors (TCRs) and/or major histocompatibility complex class II (MHCII) molecules. Here, using structure-based computational models, we demonstrate that the SARS-CoV-2 spike (S) glycoprotein exhibits a high-affinity motif for binding TCRs, and may form a ternary complex with MHCII. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in other SARS-related coronaviruses), which is highly similar in both sequence and structure to the bacterial superantigen staphylococcal enterotoxin B. This interaction between the virus and human T cells could be strengthened by a rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from an intercellular adhesion molecule (ICAM)-like motif shared between the SARS viruses from the 2003 and 2019 pandemics. A neurotoxin-like sequence motif on the receptor-binding domain also exhibits a high tendency to bind TCRs. Analysis of the TCR repertoire in adult COVID-19 patients demonstrates that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen activation. These data suggest that SARS-CoV-2 S may act as a superantigen to trigger the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.
Keywords: COVID-19; SARS-CoV-2 spike; TCR binding; superantigen; toxic shock syndrome.
Conflict of interest statement
Competing interest statement: Patent filing process has been started for short peptide sequences to neutralize the superantigenic fragment.
Copyright © 2020 the Author(s). Published by PNAS.
Figures
References
- Walls A. C. et al. ., Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181, 281–292.e6 (2020).
- Cristiani L. et al. ., Will children reveal their secret? The coronavirus dilemma. Eur. Respir. J. 55, 2000749 (2020).
- Tay M. Z., Poh C. M., Rénia L., MacAry P. A., Ng L. F. P., The trinity of COVID-19: Immunity, inflammation and intervention. Nat. Rev. Immunol. 20, 363–374 (2020).
- Vabret N. et al. .; Sinai Immunology Review Project , Immunology of COVID-19: Current state of the science. Immunity 52, 910–941 (2020).
- Riphagen S., Gomez X., Gonzalez-Martinez C., Wilkinson N., Theocharis P., Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 395, 1607–1608 (2020).
- Verdoni L. et al. ., An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study. Lancet 395, 1771–1778 (2020).
- Belhadjer Z. et al. ., Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation 142, 429–436 (2020).
- Low D. E., Toxic shock syndrome: Major advances in pathogenesis, but not treatment. Crit. Care Clin. 29, 651–675 (2013).
- Cook A., Janse S., Watson J. R., Erdem G., Manifestations of toxic shock syndrome in children, Columbus, Ohio, USA, 2010-20171. Emerg. Infect. Dis. 26, 1077–1083 (2020).
- Whittaker E. et al. .; PIMS-TS Study Group and EUCLIDS and PERFORM Consortia , Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA 324, 259–269 (2020).
- Li H., Llera A., Malchiodi E. L., Mariuzza R. A., The structural basis of T cell activation by superantigens. Annu. Rev. Immunol. 17, 435–466 (1999).
- Krakauer T., Staphylococcal superantigens: Pyrogenic toxins induce toxic shock. Toxins (Basel) 11, 178 (2019).
- Scherer M. T., Ignatowicz L., Winslow G. M., Kappler J. W., Marrack P., Superantigens: Bacterial and viral proteins that manipulate the immune system. Annu. Rev. Cell Biol. 9, 101–128 (1993).
- Choi Y. W. et al. ., Interaction of Staphylococcus aureus toxin “superantigens” with human T cells. Proc. Natl. Acad. Sci. U.S.A. 86, 8941–8945 (1989).
- Fraser J. D., Proft T., The bacterial superantigen and superantigen-like proteins. Immunol. Rev. 225, 226–243 (2008).
- Saline M. et al. ., The structure of superantigen complexed with TCR and MHC reveals novel insights into superantigenic T cell activation. Nat. Commun. 1, 119 (2010).
- Wrapp D. et al. ., Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367, 1260–1263 (2020).
- Kozakov D. et al. ., The ClusPro web server for protein-protein docking. Nat. Protoc. 12, 255–278 (2017).
- Hoffmann M. et al. ., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8 (2020).
- Changeux J.-P., Amoura Z., Rey F. A., Miyara M., A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications. C. R. Biol. 343, 33–39 (2020).
- Arad G. et al. ., Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock. PLoS Biol. 9, e1001149 (2011).
- Popugailo A., Rotfogel Z., Supper E., Hillman D., Kaempfer R., Staphylococcal and streptococcal superantigens trigger B7/CD28 costimulatory receptor engagement to hyperinduce inflammatory cytokines. Front. Immunol. 10, 942 (2019).
- Li Y. et al. ., Structure-based preliminary analysis of immunity and virulence of SARS coronavirus. Viral Immunol. 17, 528–534 (2004).
- Mateus J. et al. ., Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science, 10.1126/science.abd3871 (2020).
- Sekine T. et al. ., Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell, (2020).
- Korber B., et al. , Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2. bioRxiv:2020.2004.2029.069054 (15 June 2020).
- Zhan S. H., Deverman B. E., Chan Y. A., SARS-CoV-2 is well adapted for humans. What does this mean for re-emergence? bioRxiv:2020.2005.2001.073262 (21 May 2020).
- Schultheiß C. et al. ., Next-Generation sequencing of T and B cell receptor repertoires from COVID-19 patients showed signatures associated with severity of disease. Immunity 53, 442–455.e4 (2020).
- Del Valle D. M., et al. , An inflammatory cytokine signature helps predict COVID-19 severity and death. medRxiv:10.1101/2020.05.28.20115758 (30 May 2020).
- Li C. K. et al. ., T cell responses to whole SARS coronavirus in humans. J. Immunol. 181, 5490–5500 (2008).
- Nishi J.-I. et al. ., B cell epitope mapping of the bacterial superantigen staphylococcal enterotoxin B: The dominant epitope region recognized by intravenous IgG. J. Immunol. 158, 247–254 (1997).
- Whitfield S. J. C. et al. ., Interference of the T cell and antigen-presenting cell costimulatory pathway using CTLA4-Ig (abatacept) prevents Staphylococcal enterotoxin B pathology. J. Immunol. 198, 3989–3998 (2017).
- Krakauer T., Buckley M., Issaq H. J., Fox S. D., Rapamycin protects mice from staphylococcal enterotoxin B-induced toxic shock and blocks cytokine release in vitro and in vivo. Antimicrob. Agents Chemother. 54, 1125–1131 (2010).
- Larkin E. A., Stiles B. G., Ulrich R. G., Inhibition of toxic shock by human monoclonal antibodies against staphylococcal enterotoxin B. PLoS One 5, e13253 (2010).
- Dutta K. et al. ., Mechanisms mediating enhanced neutralization efficacy of staphylococcal enterotoxin B by combinations of monoclonal antibodies. J. Biol. Chem. 290, 6715–6730 (2015).
- Renn A., Fu Y., Hu X., Hall M. D., Simeonov A., Fruitful neutralizing antibody pipeline brings hope to defeat SARS-Cov-2. Trends Pharmacol. Sci., 10.1016/j.tips.2020.1007.1004 (2020).
- Ho M., Perspectives on the development of neutralizing antibodies against SARS-CoV-2. Antib. Ther. 3, 109–114 (2020).
- Yuan M. et al. ., A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science 368, 630–633 (2020).
- Ju B. et al. ., Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature 584, 115–119 (2020).
- Hansen J. et al. ., Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 369, 1010–1014 (2020).
- Shi R. et al. ., A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature 579, 270–273 (2020).
- Chi X. et al. ., A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science 369, 650–655 (2020).
- Pinto D. et al. ., Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 583, 290–295 (2020).
- Cao Y. et al. ., Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell 182, 73–84.e16 (2020).
- Zost S. J. et al. ., Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 584, 443–449 (2020).
- Grifoni A. et al. ., Targets of T Cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 181, 1489–1501.e15 (2020).
- Weisberg S. P., et al. , Antibody responses to SARS-CoV2 are distinct in children with MIS-C compared to adults with COVID-19. medRxiv: (14 July 2020).
- Nguyen A. et al. ., Human leukocyte antigen susceptibility map for SARS-CoV-2. J. Virol. 94, e00510–e00520 (2020).
- LeClaire R. D., Bavari S., Human antibodies to bacterial superantigens and their ability to inhibit T-cell activation and lethality. Antimicrob. Agents Chemother. 45, 460–463 (2001).
- McGann V. G., Rollins J. B., Mason D. W., Evaluation of resistance to staphylococcal enterotoxin B: Naturally acquired antibodies of man and monkey. J. Infect. Dis. 124, 206–213 (1971).
- Tirado S. M. C., Yoon K.-J., Antibody-dependent enhancement of virus infection and disease. Viral Immunol. 16, 69–86 (2003).
- Xu Y. et al. ., Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat. Med. 26, 502–505 (2020).
- Waterhouse A. et al. ., SWISS-MODEL: Homology modelling of protein structures and complexes. Nucleic Acids Res. 46, W296–W303 (2018).
- Song W., Gui M., Wang X., Xiang Y., Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog. 14, e1007236 (2018).
- Zhang Y., Skolnick J., The protein structure prediction problem could be solved using the current PDB library. Proc. Natl. Acad. Sci. U.S.A. 102, 1029–1034 (2005).
- Peitsch M. C., Protein modeling by E-mail. Bio/technology 13, 658–660 (1995).
- Jo S., Kim T., Iyer V. G., Im W., CHARMM-GUI: A web-based graphical user interface for CHARMM. J. Comput. Chem. 29, 1859–1865 (2008).
- Xue L. C., Rodrigues J. P., Kastritis P. L., Bonvin A. M., Vangone A., PRODIGY: A web server for predicting the binding affinity of protein-protein complexes. Bioinformatics 32, 3676–3678 (2016).
- Simnica D. et al. ., High-throughput immunogenetics reveals a lack of physiological T cell clusters in patients with autoimmune cytopenias. Front. Immunol. 10, 1897 (2019).
- Simnica D. et al. ., T cell receptor next-generation sequencing reveals cancer-associated repertoire metrics and reconstitution after chemotherapy in patients with hematological and solid tumors. OncoImmunology 8, e1644110 (2019).
- Young A. E., Thornton K. L., Toxic shock syndrome in burns: Diagnosis and management. Arch. Dis. Child. Educ. Pract. Ed. 92, ep97-ep100 (2007).
- Matsuda Y. et al. ., Early and definitive diagnosis of toxic shock syndrome by detection of marked expansion of T-cell-receptor VBeta2-positive T cells. Emerg. Infect. Dis. 9, 387–389 (2003).
- Bracci L., Ballas S. K., Spreafico A., Neri P., Molecular mimicry between the rabies virus glycoprotein and human immunodeficiency virus-1 GP120: Cross-reacting antibodies induced by rabies vaccination. Blood 90, 3623–3628 (1997).
- Papageorgiou A. C., Tranter H. S., Acharya K. R., Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 A resolution: Implications for superantigen recognition by MHC class II molecules and T-cell receptors. J. Mol. Biol. 277, 61–79 (1998).
Source: PubMed