Author: Robert Lee (---.vnnyca.adelphia.net)
Date: 05-22-03 20:52
SARS E2-spike Protein Contains a Superantigen Between Residues 690 through 1050
Author: (C) 2003 Robert E. Lee, M.S., M.S.W., L.C.S.W., Ph.D.
Abstract
Lee (2003) observed that SARS coronavirus employs a CD13 pathway to attack peripheral monocytes and macrophages and is likely to initiate FcgammaR and that the coronavirus is causing a fatal hyperimmune reaction in HLA-DR individuals. The present study continues this investigation with the observation that SARS E2-spike protein contains a superantigen between residues 690 through 1050 of the SARS E2-spike protein that also has relationship to T-cell Receptor alpha-beta V chain protein. Implications of the findings are discussed and multiple sequence alignments are provided. The study provides further evidence that SARS coronavirus is initiating a graft-vs-host disease, supporting Lee’s earlier work, and that the superantigen in SARS coronavirus is mimicking T-cell Receptor alpha-beta V protein.
Introduction
Lee (2003) indicated SARS E2-spike protein likely uses a CD13 pathway to attack monocytes in initial infection and also indicated SARS coronavirus likely to initiate an FcgammaR response provoking a profound proinflammatory response and subsequent hyperimmune disorder [1]. The present paper provides further evidence to support the likelihood of this FcgammaR response and attempts to identify the mechanism of its activation.
Region 690 through 1050 of SARS coronavirus E2-spike protein contains amino acids that are highly likely to be a superantigen. Multiple sequence alignment of this region of SARS coronavirus E2-spike protein with various T-cell receptor alpha-beta V chain proteins reveals a statistically significant alignment (p < .01) between the E2-spike protein and, for example, 1BWMA protein, a T-cell Receptor alpha-beta V chain structure. Figure 1 (below) shows a wire rendition of the 1BWMA structure with only-unique to SARS E2 and no other human coronavirus amino acids highlighted in yellow (on left) against an IBWMA structure with only-unique to HuCovOC43/HuCov229E and not SARS-coronavirus amino acids (on right). Figure 2 (click here) is the detailed multiple sequence alignment
of the SARS E2-spike protein with the 1BWMA protein.
A Monte Carlo method was used to determine the expected number of hits in the multiple sequence alignment that would occur by chance alone. Results of the Monte Carlo modeling indicated a Mean (m) of 14.66 matches with a standard deviation of 3.32 matches by chance alone. As can be seen in Figure 2, there are 45 direct hits in the SARS E2-spike protein/1BWMA protein multiple sequence alignment; there are 58 closely related hits; there are 44 distant-but-related matches. There is an important statistically significant relationship existing between 1BWMA protein and SARS E2-spike protein (Z= 9.1, p<.01). It would appear a reasonable conclusion that SARS E2-spike protein is composed of amino acids that are, between residues 690 to about 1050 of the SARS E2-spike protein, very like T-cell receptor alpha-beta V chain amino acids. This similarity of structure between SARS E2-spike protein and a host of other T-cell Receptor alpha-beta V chains is conserved in multiple sequence alignments (data not shown).
What is this relationship given that SARS E2-spike protein region 690 to about 1050 and T-cell Receptor alpha-beta V chain proteins are showing statistically significant similarity? How do these amino acids exist in the structure of 1BWMA? How might these amino acids, as they are in both agents, be functioning in SARS E2-spike protein?
Answers to the questions posited above are seemingly discovered in a comparison of the section of SARS E2-spike protein (690 through about 1050 residues) with 1BWMA (T-cell Receptor alpha-beta V chain protein) and two superantigen proteins. Figure 3 (click here) is a multiple sequence alignment showing a comparision between SARS E2-spike protein (selected region), 1BWMA protein, and Mouse Mammary Tumor Virus superantigen. Figure 4 (click here) is a multiple sequence aligment showing a comparison between SARS E2-spike protein (selected region), 1BWMA protein, and Mycoplasma arthriditis superantigen. Inspection of the two figures shows there is a remarkable amount of similarity between the selected region of SARS E2-spike protein, T-cell Receptor alpha-beta V chain protein, and the respective superantigens.
As can be observed in the multiple sequence alignments (Figure 3 and Figure 4) there is a remarkable conservation of structure existing between the selected region (690 through about 1050 residues) of SARS E2-spike protein, 1BWMA (T-cell Receptor alpha-beta V chain protein), and the respective superantigens. The number of matches for Mouse Mammary Tumor Virus superantigen in comparison to either 1BWMA or SARS E2-spike protein amino acid selected region matches was 33 (Z=5.52, p < .01). Number of matches for Mycoplasma arthriditis superantigen in comparison to either 1BWMA or SARS E2-spike protein amino acid selected region matches was 28 (Z=4.01, p < .01)
Discussion
Implications of the above observation include the following:
• SARS E2-spike protein region 690 through 1050 residues contains amino acids that statistically significantly match T-cell Receptor alpha-beta V chain protein amino acids.
• SARS E2-spike protein region 690 through 1050 residues contains amino acids that statistically significantly match Mouse Mammary Tumor Virus superantigen protein amino acids.
• SARS E2-spike protein region 690 through 1050 residues contains amino acids that statistically significantly match Mycoplasma arthriditis superantigen protein amino acids.
• Mouse Mammary Tumor Virus superantigen protein amino acids show important relationship to T-cell Receptor alpha-beta V chain protein amino acids and SARS E2-spike protein amino acids.
• Mycoplasma arthriditis superantigen protein amino acids show important relationship to T-cell Receptor alpha-beta V chain protein amino acids and SARS E2-spike protein amino acids.
• The superantigen protein amino acids, at least two members of the superantigen family investigated here, show important relationship with the T-cell Receptor alpha-beta V chain protein amino acids.
• As SARS E2-spike protein amino acids appear to more closely resemble T-cell Receptor alpha-beta V chain protein amino acids than do either of the two investigated superantigens, it is entirely possible that superantigens can be indexed in their potency as they more closely resemble T-cell Receptor alpha-beta V chain protein amino acids.
• Finally, it appears that SARS E2-spike protein region 690 through 1050 residues contains a superantigen that is a better mimick of T-cell Receptor alpha-beta V chain protein amino acids than either Mouse Mammary Tumor Virus superantigen protein amino acids or Mycoplasma arthriditis superantigen amino acids.
It is significant, should it be confirmed by others, that SARS E2-spike protein contains a superantigen. Moreover, the implications of the observation appear to be likely to have impact on study of coronavirus E2-spike proteins, generally, SARS E2-spike protein specifically, as well as the relationship of T-cell Receptor alpha-beta V chain proteins and their relationship to superantigens.
Finding that SARS E2-spike protein amino acids region 690 though 1050 residues is likely to be a superantigen conforms with research of others concerning relationship of superantigens and T-cell activity in relationship to autoimmune disorders. Fournel et al. (1993) discussed possible implications of effect of a superantigen and its inhibition regarding selective clonal deletion of autoreactive T cells by administration of anti-CD4 mAbs in patients with auto-immune diseases [2]. More particularly, in regard to the present discussion, Marcinkiewicz et al. (1998), in a study concerning Kawasaki Syndrome, reported “mechanisms of action have been proposed to account for the immunomodulatory effects of IVIG in Kawasaki and other immune-mediated diseases: (i) functional blockade of Fc receptor on monocytes/macrophages; (ii) modulation of the production of cytokines and cytokine antagonists; (iii) inhibition of complement mediated damage; (iv) neutralisation of bacterial toxins by specific antibodies; (v) neutralisation of circulating autoantibodies by complementary (e.g. anti-idiotypic) antibodies in IVIG.” [3] Of interest in Marcinkiewicz’s et al. work is the likelihood that SARS disease, while completely different from Kawasaki Syndrome, is using a similar methodology in causing disease, i.e., Fc gamma Receptors on monocytes/macrophates, induction of cytokines, causing compliment-mediated damage, possessing here a viral and not bacterial toxin (though related to Mycoplasma arthriditis superantigen), resulting in a graft-vs-host disease process. In this case of SARS disease, the superantigen appears to be significantly mimicking T-cell Receptor alpha-beta V chain protein.
This study has implications for further investigation of graft-vs-host disease, coronavirus E2-spike protein mimickry of T-cell Receptor alpha-beta V protein, superantigens expressed via viral vectoring; relationship of viral superantigens to bacterial superantigens, etc., and, most significantly, further understanding of the SARS coronavirus and the hyperimmune disease it causes.
Dr. Robert E. Lee, M.S., M.S.W., L.C.S.W., Ph.D.
May 22, 2003
References:
1. Lee RE: SARS Coronavirus Appears to be an FcgammaR Agent, Causing an Hyperimmune Response via a CD13 pathway - Implication for Therapeutic Interventions. JOIMR 2003;1(1):2 [Publisher FullText]
2. Fournel S, Morel P, Revillard JP, Lizard G, Bonnefoy-Berard N: Inhibition of human T cell response to staphylococcal enterotoxin B by prior ligation of surface CD4 molecules. Cell Immunol 1993 Aug;150(1):194-204 [PubMed Abstract]
3. Marcinkiewicz J, Szymanowska Z, Mazurek A: Immunoregulatory mechanisms of action of intravenous gammaglobulin in Kawasaki syndrome. Przegl Lek 1998;55(11):611-3 [PubMed Abstract]
Keywords
coronavirus
SARS
E2-spike protein
cytokine
FcgammaR
aminopeptidase N
immunology
1BWMA protein
T-cell Receptor alpha-beta V Superantigen
Acknowledgements
I would like to thank Dr. Brian Foley and Dr. Alan Cantwell for their support, friendship, and guidance through the years.
Competing Interests
None declared.
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