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Molecular similarities between antigenic sites in the SARS-CoV-2 receptor binding domain and antigenic determinants of fifteen pathogenic bacterial, malaria, and viral species

Molecular similarity can be defined as the theoretical explanation for sequence similarities (mainly in antigens) between two (or more) organisms. In this study, the author from India employed an integrative approach to identify antigenic sites in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) receptor binding domain (RBD) and to evaluate the molecular similarities of antigenic sites predicted in the SARS-CoV-2 S RBD with proteins/antigens from other different organisms.

The author emphasized that computational biology approaches for epitope prediction, identification, and analysis are well-developed and have been proven highly successful in predicting and identifying both weak and strong antibody epitopes.

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, namely the spike (S), envelope (E), nucleocapsid (N), and membrane (M) protein. The S protein appears to be a major pathogenic factor that contributes to the unique pathogenesis of SARS-CoV-2. The S protein is a glycosylated homotrimer with each monomer composed of subunits S1 and S2, separated by host cell proteases. The S1 domain comprises the N-terminal domain (NTD), the receptor binding domain (RBD) with a receptor binding motif (RBM), and two C-terminal domains. The RBD in the S1 subunit recognizes human angiotensin-converting enzyme 2 receptor (ACE2) and is responsible for attachment to host cells.

About the study

The author used an integrated approach that included the identification of potential antigenic sites and antigenic determinants in SARS-CoV-2 RBD based on its primary sequence and 3-dimensional structure.

Results

The SARS-CoV-2 spike RBD was found to be highly antigenic with nine potential surface antigenic sites. Seven of nine antigenic sites in the SARS-CoV-2 S protein showed molecular similarities with 54 antigenic determinants found in fifteen pathogenic bacteria, parasites, and viruses, namely in twelve pathogenic bacterial species (Mycobacterium tuberculosis, Mycobacterium leprae, Bacillus anthracis, Borrelia burgdorferi, Clostridium perfringens, Clostridium tetani, Helicobacter Pylori, Listeria monocytogenes, Staphylococcus aureus, Streptococcus pyogenes, Vibrio cholerae and Yersinia pestis), two malarial parasites (Plasmodium falciparum and Plasmodium knowlesi) and influenza virus A.

Table from the original article of Dakal TC. List of antigenic proteins from different pathogenic microorganisms and virus showing sequence similarity with predicted antigenic sites’ sequence in SARS-CoV-2 spike RBD.

S.No

UniProt ID

Protein Name

Protein

Description

Organisms

1

O33084

ESXB_MYCLE

ESAT-6-like protein EsxB

Mycobacterium leprae (strain TN)

2

P01556

CHTB_VIBCH

Cholera enterotoxin subunit B

Vibrio cholerae serotype O1 (strain ATCC 39315/El Tor Inaba N16961)

3

P01558

ELTB_CLOPF

Heat-labile enterotoxin B chain

Clostridium perfringens

4

P02893

CSP_PLAFA

Circumsporozoite protein

Plasmodium falciparum

5

P02894

CSP_PLAKH

Circumsporozoite protein

Plasmodium knowlesi (strain H)

6

P03438

HEMA_I000X

Hemagglutinin

Influenza A virus
(strain A/X-31 H3N2)

7

P03449

HEMA_I71A1

Hemagglutinin

Influenza A virus
(strain A/Memphis/1/1971 H3N2)

8

P03452

HEMA_I34A1

Hemagglutinin

Influenza A virus
(strain A/Puerto Rico/8/1934 H1N1)

9

P03453

HEMA_177AB

Hemagglutinin

Influenza A virus (strain A/USSR/90/1977 H1N1)

10

P03459

HEMA_I34A0

Hemagglutinin

Influenza A virus
(strain A/Fowl plague virus/Rostock/8/1934 H7N1)

11

P03466

NCAP_I34A1

Nucleoprotein

Influenza A virus
(strain A/Puerto Rico/8/1934 H1N1)

12

P04923

CRA_PLAFA

Circumsporozoite protein-related antigen

Plasmodium falciparum

13

P04926

EXP1_PLAFA

Malaria protein EXP-1

Plasmodium falciparum

14

P04934

MSP1_PLAFC

Merozoite surface protein 1

Plasmodium falciparum (isolate Camp/Malaysia)

15

P04958

TETX_CLOTE

Tetanus toxin

Clostridium tetani
(strain Massachusetts/E88)

16

P08089

M6B_STRPY

M protein, serotype 6

Streptococcus pyogenes

17

P09621

CH10_MYCTU

10 kDa chaperonin

Mycobacterium tuberculosis
(strain ATCC 25618/H37Rv)

18

P09621

CH10_MYCTO

10 kDa chaperonin

Mycobacterium tuberculosis
(strain CDC 1551/Oshkosh)

19

P0A0L2

ETXA_STAAU

Enterotoxin type A

Staphylococcus aureus

20

P0A4V2

A85A_MYCTU

Diacylglycerol

acyltransferase

Mycobacterium tuberculosis
(strain ATCC 25618/H37Rv)

21

P0A4V2

A85A_MYCTO

Diacylglycerol

acyltransferase

Mycobacterium tuberculosis
(strain CDC 1551/Oshkosh)

22

P0A550

DPO1_MYCTU

DNA polymerase I

Mycobacterium tuberculosis
(strain ATCC 25618/H37Rv)

23

P0A550

DPO1_MYCTO

DNA polymerase I

Mycobacterium tuberculosis
(strain CDC 1551/Oshkosh)

24

P0A564

ESXA_MYCTU

6 kDa early secretory antigenic target

Mycobacterium tuberculosis
(strain ATCC 25,618 / H37Rv)

25

P0A564

ESXA_MYCTO

6 kDa early secretory antigenic tar

Mycobacterium tuberculosis
(strain CDC 1551/Oshkosh)

26

P0A5J0

LPQH_MYCTU

Lipoprotein LpqH

Mycobacterium tuberculosis
(strain ATCC 25618/H37Rv)

27

P0A5J0

LPQH_MYCTO

Lipoprotein LpqH

Mycobacterium tuberculosis
(strain CDC 1551/Oshkosh)

28

P0A5Q4

MP64_MYCTU

Immunogenic protein MPT64

Mycobacterium tuberculosis
(strain ATCC 25618/H37Rv)

29

P0A5Q4

MP64_MYCTO

Immunogenic protein MPT64

Mycobacterium tuberculosis
(strain CDC 1551/Oshkosh)

30

P11089

FLA1_BORBU

Flagellar filament 41 kDa core protein

Borrelia burgdorferi
(strain ATCC 35210/B31/CIP 102532/DSM 4680)

31

P13423

PAG_BACAN

Protective antigen

Bacillus anthracis

32

P13830

RESA_PLAFF

Ring-infected erythrocyte surface antigen

Plasmodium falciparum (isolate FC27/Papua New Guinea)

33

P14013

OSPA_BORBU

Outer surface protein A

Borrelia burgdorferi
(strain ATCC 35210/B31/CIP 102532/DSM 4680)

34

P14013

OSPA_BORBN

Outer surface protein A

Borrelia burgdorferi
(strain N40)

35

P14013

OSPA_BORBZ

Outer surface protein A

Borrelia burgdorferi
(strain ZS7)

36

P14916

URE23_HELPY

Urease subunit alpha

Helicobacter pylori
(strain ATCC 700392/26695) (Campylobacter pylori)

37

P15712

PSTS1_MYCTU

Phosphate-binding protein PstS 1

Mycobacterium tuberculosis
(strain ATCC 25618/H37Rv)

38

P15712

PSTS1_MYCTO

Phosphate-binding protein PstS 1

Mycobacterium tuberculosis
(strain CDC 1551/Oshkosh)

39

P15917

LEF_BACAN

Lethal factor

Bacillus anthracis

40

P16893

TRAP_PLAFA

Thrombospondin-related anonymous protein

Plasmodium falciparum

41

P19214

EBA1_PLAFC

Erythrocyte-binding antigen 175

Plasmodium falciparum (isolate Camp/Malaysia)

42

P21171

P60_LISMO

Probable endopeptidase p60

Listeria monocytogenes serovar 1/2a (strain ATCC BAA-679/EGD-e)

43

P23024

TCPA_VIBCL

Toxin coregulated pilin

Vibrio cholera

44

P24301

CH10_MYCLE

10 kDa chaperonin

Mycobacterium leprae (strain TN)

45

P25893

46

P26948

CAF1_YERPE

F1 capsule antigen

Yersinia pestis

47

P31951

A85B_MYCLE

Diacylglycerol

acyltransferase

Mycobacterium leprae (strain TN)

48

P31952

A85B_MYCTA

Diacylglycerol

acyltransferase

Mycobacterium tuberculosis
(strain ATCC 25177/H37Ra)

49

P31952

A85B_MYCTU

Diacylglycerol

acyltransferase

Mycobacterium tuberculosis
(strain ATCC 25618/H37Rv)

50

P31952

A85B_MYCTO

Diacylglycerol

acyltransferase

Mycobacterium tuberculosis
(strain CDC 1551/Oshkosh)

51

Q07337

OSPC_BORBU

Outer surface protein C

Borrelia burgdorferi
(strain ATCC 35210/B31/CIP 102532/DSM 4680)

52

Q25893

Q25893_PLAFA

Liver stage antigen-1

Plasmodium falciparum

53

Q9U0P0

Q9U0P0_PLAFA

Liver stage antigen-3

Plasmodium falciparum

54

Q60153

TCPA_VIBCL

Toxin coregulatedpilin

Vibrio cholerae serotype O1 (strain ATCC 39315/El Tor Inaba N16961)

 

 

Most of the antigenic determinants found in pathogenic microorganisms that showed molecular similarity to the RBD’s antigenic sites were toxins and factors with a diverse functional role in pathogens. The antigenic determinants predicted from Mycobacterium tuberculosis play a role in immune recognition escape and ensure persistence in the host body, possibly in the latent stage. 10-kDa co-chaperonin (cpn10) led in vitro to bone weakness and fragility, while the MPT64 is involved in the persistence and survival of pathogens in host cells and tissues.

The antigenic sequences predicted from malaria parasites were circumsporozoite protein-related antigen, malaria protein EXP-1, thrombospondin-related anonymous protein, liver stage antigens -1 and -3, erythrocyte-binding antigen 175, and ring-infected erythrocyte surface antigen. The circumsporozoite proteins play an important role in the invasion of liver cells in humans. The antigenic determinants predicted from Bacillus anthracis are two of the three proteins that form the anthrax toxin. Five antigenic determinants were predicted from spirochete Borrelia burgdorferi. The antigenic sequences predicted from Clostridium perfrigens and Clostridium tetani were toxin proteins, as well as the enterotoxin A from Staphylococcus aureus, M protein from Streptococcus pyogenes, and toxins from Vibrio cholerae. Two proteins predicted from Mycobacterium leprae play a role in bacterial virulence and act as chaperones to prevent membrane lysis. One predicted antigenic site in SARS-CoV-2 RBD had molecular similarity with antigenic determinant from Yersisnia pestis, a capsule-like antigen, fraction 1 (F1) which has been implicated to be involved in the ability of bacteria to prevent uptake by macrophages. Certain antigenic determinants from influenza virus A play a role in the assembly of newly budded virions.

Interestingly, a study that examined the association between the cross-reactivity to SARS-CoV-2 S protein/RBD and exposure to Plasmodium falciparum infection in 741 pre-pandemic samples from eight malaria-endemic and non-endemic countries showed that people with confirmed acute malaria had more pronounced cross-reactivity than those previously exposed to malaria but without acute Plasmodium falciparum infection. Also, IgM but not IgG cross-reactivity was higher among uninfected individuals exposed to infection in malaria-endemic areas than among people from non-endemic settings. Importantly, there was no cross-reactivity between acute Plasmodium falciparum infection and other human coronaviruses or other SARS-CoV-2 proteins. (Lapidus, S et al. Plasmodium infection is associated with cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein. Sci Rep 2022; 12, 22175.)   https://doi.org/10.1038/s41598-022-26709-7

Plasmodium falciparum

The author of the present study stated that the findings of the molecular similarities between antigenic sites in the SARS-CoV-2 RBD and antigenic determinants of fifteen pathogens (bacterial, malarial, and viral species) are seriously alarming because their presence makes the SARS-CoV-2 more pathogenic than any other previously known coronavirus. Especially, antigenic determinants unique to SARS-CoV-2. As all seven predicted antigenic sites in SARS-CoV-2 RBD had molecular similarity with antigenic determinants from Mycobacterium tuberculosis and Plasmodium falciparum, the author suggested that COVID-19 patients should have at least symptoms of these two diseases.

The researcher also stated that the presence of antigenic determinants of the SARS-CoV-2 RBD which display molecular similarity with highly potent antigenic determinants found in fifteen pathogenic microorganisms might explain numerous pathophysiological complications, like exacerbated innate and adaptive immune responses leading to hyper-activation of B-cells, T-cells (both cytotoxic T-cells and T-helper cells), dendritic cells, natural killer cells, and macrophage/monocyte lineage cells, the excessive release of cytokines that adversely affect numerous vital organs and multiple organ failure. 

The author also speculated that individuals previously infected with or immunized/vaccinated against malaria, tuberculosis (TB), or other diseases caused by fifteen microorganisms with molecular similarities between their antigenic determinants and SARS-CoV-2 RBD, are expected to display a considerable degree of resistance against SARS-CoV-2 infection. One possible explanation is that the memory B or T cells previously generated by these microorganisms would be reactivated upon SARS-CoV-2 infection due to the similar antigenic specificity and common antigenic determinants in both. In addition, he suggested that the over-representation of antigenic determinants from Mycobacterium tuberculosis and Plasmodium falciparum in all antigenic sites suggests that anti-malarial and anti-TB drugs can be clinically beneficial for COVID-19 treatment. 

This article was published in Immunobiology.

Journal Reference

Dakal TC. Antigenic sites in SARS-CoV-2 spike RBD show molecular similarity with pathogenic antigenic determinants and harbors peptides for vaccine development Immunobiology 2021 Sep; 226(5): 152091. (Open Access)  https://www.sciencedirect.com/science/article/pii/S0171298521000395

 

 

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