ОРИГИНАЛЬНЫЕ СТАТЬИ 1 ORIGINAL PAPERS
DOI: 10.56871/RBR.2024.63.31.001
УДК [616.2+616.34]-036.21+578.834.1+579.8+577.112+547.96
СТРУКТУРНЫЕ БЕЛКИ ДЕЛЬТА-ВАРИАНТА SARS COV-2: ГОМОЛОГИЯ С ОППОРТУНИСТИЧЕСКИМИ БАКТЕРИЯМИ
© Александр Тимурович Марьянович1, Дмитрий Юрьевич Кормилец2
1 Северо-Западный государственный медицинский университет им. И.И. Мечникова. 195067, г. Санкт-Петербург, Пискаревский пр., 47
2 Военно-медицинская академия им. С.М. Кирова. 194044, Российская Федерация, г. Санкт-Петербург, ул. Академика Лебедева, 6
Контактная информация: Александр Тимурович Марьянович — д.б.н., профессор, заведующий кафедрой нормальной физиологии. E-mail: atm52@mail.ru ORCID: https://orcid.org/0000-0001-7482-3403 SPIN: 5957-2347
Для цитирования: Марьянович А.Т., Кормилец Д.Ю. Структурные белки дельта-варианта SARS CoV-2: гомология с оппортунистическими бактериями // Российские биомедицинские исследования. 2024. Т. 9. № 2. С. 5-17. DOI: https://doi.org/10.56871/RBR.2024.63.31.001
Поступила: 15.02.2024 Одобрена: 04.04.2024 Принята к печати: 20.05.2024
Резюме. Способность SARS CoV-2 уклоняться от иммунного ответа можно считать общепризнанной. Гомология белков коронавируса и человека может быть одним из механизмов иммунного уклонения. Дельта-вариант обязательно имеет структурные особенности, которые объясняют его специфические свойства. Целью нашего исследования было выяснить, изменяют ли мутации, произошедшие в структурных белках дельта-варианта, его гомологию с белками, присутствующими в организме человека, то есть собственно человеческими, бактериальными и пищевыми. Используя инструменты биоинформатики, мы обнаружили гомологию на уровне гептамеров между структурными белками дельта-варианта и белками человека, а также белками некоторых условно-патогенных бактерий верхних дыхательных путей, легких и кишечника. Белки шиповый (S) и мембранный (M) дельта-варианта имеют большое количество сходств (гомологичных соответствий) с перечисленными белками, причем наибольшее количество — в случае мутации S:A156,157;R158G. Причина, по которой дельта-вариант SARS CoV-2 обладает специфическими характеристиками, и прежде всего повышенной летальностью, скорее всего, кроется в мутации в положениях 156-158 шипового белка.
Ключевые слова: SARS CoV-2, дельта-вариант, шиповидный белок, оппортунистические бактерии, гомология
SARS COV-2 DELTA VARIANT STRUCTURAL PROTEINS: HOMOLOGY WITH OPPORTUNISTIC BACTERIA
© Alexander T. Maryanovich1, Dmitry Yu. Kormilets2
1 North-Western State Medical University named after I.I. Mechnikov. 47 Piskarevskiy ave., Saint Petersburg 195067 Russian Federation
2 Military Medical Academy named after S.M. Kirov. 6 Akademician Lebedev str., 194044 Saint Petersburg Russian Federation
Contact information: Alexander T. Maryanovich — Ph.D., D.Sc. (Biology), Professor, Head of Department of Normal Physiology. E-mail: atm52@mail.ru ORCID: https://orcid.org/0000-0001-7482-3403 SPIN: 5957-2347
For citation: Maryanovich AT, Kormilets DYu. SARS CoV-2 Delta variant structural proteins: homology with opportunistic bacteria. Russian Biomedical Research. 2024;9(2):5-17. DOI: https://doi.org/10.56871/RBR.2024.63.31.001
Received: 15.02.2024 Revised: 04.04.2024 Accepted: 20.05.2024
Abstract. The capacity of SARS CoV-2 for immune evasion can be considered universally recognized. Coronavirus and human protein homology may be one of the mechanisms of immune evasion. Delta variant necessarily has structural features that explain its specific qualities. The aim of our study is to find out whether mutations in the structural proteins of Delta variant change its homology with proteins present in the human body, i.e. human, bacterial and dietary. Using
bioinformatics tools we detected homology on the heptamer level between Delta variant structural proteins and human proteins as well as some opportunistic bacteria proteins of the upper respiratory tract, lung and gut. Delta variant spike (S) and membrane (M) proteins have a large number of similarities (homologous correspondences) with the listed proteins, with the S:A156,157;R158G mutation having the greatest amount. The reason why SARS CoV-2 Delta variant has specific characteristics, most importantly increased lethality, is most likely to be found in a mutation at positions 156-158 of spike protein.
Keywords: SARS CoV-2, Delta variant, spike protein, opportunistic bacteria, homology
INTRODUCTION
After a series of brilliant discoveries from Pasteur to Fleming and Waxman, mankind has learned to control most bacterial infections. Humans were able to create megalopolises with huge population densities. In response, nature had to put forward other limiting mechanisms less humanly controllable. The COVID-19 pandemic has become and will remain one of humanity's major concerns for the near future. The very important question is why and how this CoV could cause a pandemic [1]. Some mutation-induced structural substitutions in the N-terminal domain (NTD) of the SARS-CoV-2 S-protein lead to more efficient first contact and interaction with the upper airway epithelium [2].
The extraordinary virulence of Omicron variant (B.1.1.529) is now the main focus of researchers [3]. Nevertheless, it seems to us that in order to understand the causes of SARS CoV-2 lethality, the peculiarities of Delta variant (B.1.617.2) must be studied.
Using 3D models, the researchers can determine how the spike (S) protein binds to the ACE2 receptor [4]. The peculiarity of our approach is that we seek an explanation for the properties of coronavirus in the homology (commonality of short motifs) of virus proteins with human proteins. Recently we described dozens of homologous motifs in the primary structure of SARS CoV-2 and human proteins including proteins of olfactory and taste receptors [5]. Through mutations, the virus finds a way to avoid an immune response [6].
Molecular mimicry is considered a strategy used by many viruses to subvert and regulate antiviral immunity. For example, human cytomegalovirus has hijacked or developed a number of homologous sites that mimic immunomodulatory proteins encoded by the human body. These homologues encoded by the virus can contribute to the virus' evasion of immune clearance [7].
Following Joshua Lederberg's principle [8], we took into account not only proteins synthesized by the human body, but also those that originate from other genotypes and are constantly present in the macroorganism. These are the proteins of commensal and opportunistic bacteria of the upper respiratory tract, lung, oral cavity, and GI tract. We also analyzed the most common dietary proteins that are almost constantly present in the gut, namely those of the six world's most important cereal crops, i.e., Asian rice Oryza sativa, common wheat Triticum aestivum, maize Zea mays, common bean Phaseolus vulgaris, barley Hordeum vulgare, and sorghum Sorghum bicolor. We believed that the homology of the virus proteins with those of the named bacteria and
cereals helps coronavirus to avoid or reduce the primary immune response.
THE AIM OF OUR STUDY
The aim of our study is to find out whether mutations in the structural proteins of SARS CoV-2 Delta variant change its homology with proteins present in the human body, i.e. human, bacterial and dietary.
RESULTS
Spike glycoprotein
Wuhan-Hu spike glycoprotein (S protein) molecule consists of 1273 amino acid residues. In Delta variant, as a result of two deletions (E156A and F157A), S protein consists of 1271 amino acid residues and contains seven substitutions in nine positions, namely T19R, G142D, R158G, L452R, T478K, P681H, and D950N, numeration as in Wuhan-Hu variant [9].
S protein Delta variant, 1271 aa
mfvflvllplvssqcvnlRtrtqlppaytnsftrgvyyp
DKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGT KRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQ sllivnnatnvvikvcefqfcndpflD VYYHKNNKSWMES GVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREF VFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINI TRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRT FLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSN FRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRIS NCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSF VIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLD
skvggnynyRyrlfrksnlkpferdisteiyqagsKpcng
VEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPAT VCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQF GRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQ VAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGC LIGAEHVNNSYECDIPIGAGICASYQTQTNSRRRARSVAS QSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTK TSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQD KNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRS FIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFN GLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAA LQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIG KIQDSLSSTASALGKLQN VVNQNAQALNTLVKQLSS
NFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSL QTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDF CGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAI CHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNT FVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKN HTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNES LIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCC MTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
Hereinafter, motifs homologous with human proteins [5] are highlighted in red font. Amino acid residues substituted as a result of mutations are highlighted in large letters. The N-
terminal domain (NTD14_303) is highlighted in green. Receptor-binding domain (RBD317-539) is in gray italics. Receptor-binding motif RBM436-506 is underlined. Heptapeptide repeat sequence 1 (HR1910-982) is highlighted in blue. As a result of the double deletion A156 157, starting from G156, the numbering of positions in Delta variant does not correspond to the numbering in Wuhan-Hu.
Delta variant, as mentioned above, has a mutation S:P681H. The S protein motif sPRRARS680-686 homologous with a human protein has been replaced by a heptamer sHRRARS678-684, which has no homologues in mammals (Table 1).
Table 1
Homology of a SARS CoV-2 S protein to a human protein
Mutation Wuhan-Hu Delta
P681H* S protein heptamer Species Homologous protein heptamer S protein heptamer Species Homologous protein heptamer
sPRRARS680-686 Homo sapiens Hermansky-Pudlak syndrome 1 protein258-264 SHRRARS678-684 No homological heptamers in commensal
Wuhan-Hu Delta
Mutation S protein heptamer Species Homologous protein heptamer Localization in the human body S protein heptamer Species Homologous protein heptamer Localization in the human body
T19R vnlTtrt16.22 Escherichia coli BCE011_MS-01 Uncharacte-rized protein23-29 gut vnlRtrt16-22 Streptococcus mitis SK597 TnpX; Streptococcus salivarius (strain CCHSS3) Site-specific re- combinase275-281 nasopharynx, oral cavity, throat
nlTtrtq17-23 Enterococcus faecalis Helicase, RecD/TraA family755-761 gut nlRtrtq17-23 Subdoligranulum variabile Putative hydro- lase34-40 gut
G142D' ndpflGv,37,43 No homological heptamers in commensal or opportunistic bacteria NDPFLDV137.143 Pasteurella multocida subsp. multocida str Release factor glutamine methyl-transferase20-26 lung
Д156, 157; R158G efRvyss156,62 No homological heptamers in commensal or opportunistic bacteria ESGVYSS154,60 Lachnospira-ceae bacterium 7_1_58FAA Uncharacterized pratern^-^ gut
Escherichia coli UMEA 3609-1 Valine-tRNA ligase320-326 gut
FRVYSSA157,63 No homological heptamers in commensal or opportunistic bacteria SGVYSSA155,61 Fusobacterium sp. oral taxon 370 str. F0437 Hep/Hag repeat protein (Fragment^ oral cavity
RVYSSAN158,64 Bifidobacterium animalis subsp. lactis CNCM I-2494 Fibronectin-binding proteinig1,1g7 gut GVYSSAN«.« Bacillus sp. NRRL B-14911 Methylmalonyl-CoA mutase565-571 ?
*In Wuhan-Hu and Delta variants, the position numbering differs after position 156 as a result of the A156,157 deletions.
The heptamers of S protein that are homologous with the proteins of some commensal and opportunistic bacteria are listed in Table 2.
Table 2
The heptamers of S protein homologous with the proteins of some commensal and opportunistic bacteria
Endind of the table 2
Wuhan-Hu Delta
Mutation S protein heptamer Species Homologous protein heptamer Localization in the human body S protein heptamer Species Homologous protein heptamer Localization in the human body
Lactobacillus far-raginis JCM 14108 D-alanyl-D-alanine carboxypepti- dase149-155 gut
Fusobacterium nucleatum subsp. polymorphum F0401 Uncharacterized prOtein234.240 oral cavity
Prevotella saccha-rolytica F0055 Carbohydrate binding domain prate^^ oral cavity, upper respiratory tract, gut
human gut metagenome Glycoside hydrolase, family 25 (Fragment)395-401 gut
L452R No homological heptamers in commensal or opportunistic bacteria
T478K* No homological heptamers in commensal or opportunistic bacteria
P681H nsPrrar679-685 No homological heptamers in commensal or opportunistic bacteria NsHRRARg77-g83 Clostridium clostridioforme Uncharacterized proteinl16-122 gut
D950N' klqDvvn947-953 Prevotella salivae F0493 Peptidase M16 inactive domain protein918-924 oral cavity, gut klqNvvn^ Leptotrichia buc-calis (strain ATCC 14201 / DSM 1135 / JCM 12969 / NCTC 10249) GCN5-related N-acetyltrans- ferase 115-121 oral cavity
ÜVVNQNA950-956 No homological heptamers in commensal or opportunistic bacteria NvVNQNA948-954 Prevotella multisaccharivorax DSM 17128 Anaerobic ribonucleoside-triphosphate reductasem.i20 oral cavity, gut
*The same mutation has occurred in Omicron variant.
The heptamers of S protein that are homologous with the most common cereal proteins are listed in Table 3.
Table 3
The heptamers of S protein homologous with the most common cereal proteins
Mutation Wuhan-Hu Delta
S protein heptamer Species Homologous protein heptamer S protein heptamer Species Homologous protein heptamer
T19R SQCVNLT13.19 Oryza sativa Leucine Rich Repeat family protein, expressed520-526 sqcvnlR13-19 No most common cereal sample
vnlTtrt16-22 Oryza sativa BCE011_MS-01 Uncharacterized protein23.29 vnlRtrt16-22 No most common cereal sample
lTtrtql18-24 Triticum aestivum Uncharacterized protein888-894 lRtrtql18.24 No most common cereal sample
L452R LYRLFRK452-458 Oryza sativa subsp. indica Putative uncharacterized protein157.163 RYRLFRK450-456 No most common cereal sample
Zea mays Putative NAC domain transcription factor superfamily protein (Fragment)10(M06
Endind of the table 3
Wuhan-Hu Delta
Mutation S protein heptamer Species Homologous protein heptamer S protein heptamer Species Homologous protein heptamer
T478K* STPCNGV477.483 No most common cereal sample SKPCNGV475.481 Phaseolus vulgaris Uncharacterized protein59-65
sPRRARS680-686 Oryza sativa subsp. japonica 0s02g0817400 protein (Fragment)1-7 sHRRARS678-684 Oryza sativa subsp. japonica Expressed protein2g6-302
Zea mays Uncharacterized pro- tein58-64 Oryza sativa subsp. japonica Uncharacterized protein616-622
Hordeum vulgare Predicted protein (Fragment)^
PRRARSV681-687 Oryza sativa subsp. japonica Putative uncharacterized protein118-124 H RRARSV67g.685 No most common cereal sample
Zea mays Uncharacterized protein94-100
D950N* ALGKLQD844.950 Hordeum vulgare var. distichum Uncharacterized pro- tein123-129 algklqN842.848 No most commoncereal sample
LGKLQDV945.951 Hordeum vulgare var. distichum Uncharacterized protein96-102 lgklqNv843.849 No most common cereal sample
Oryza sativa subsp. indica Uncharacterized protein 248-254
Zea mays Protein lap4233-239
Golgi SNAP receptor complex member 175-81
GKLQDVVg46.g52 Zea mays Uncharacterized pro- tein388-394 GKLQNVV844-850 No most common cereal sample
*The same mutation has occurred in Omicron variant.
The heptamers of S protein that are homologous with some virus proteins are listed in Table 4.
Table 4
The heptamers of S protein homologous with some virus proteins
Mutation Wuhan-Hu Delta Comment
S protein heptamer Other virus Homologous protein heptamer S protein hep-tamer Other viruses Homologous protein hep-tamer
P681H QTQTNSP675.681 Human immunodeficiency virus 1 Protease (Fragment)2-7 QTQTNSH673.679 No virus proteins homology Homology with HIV-1 has disappeared
D950N* LQDVVNQg48.g54 No virus proteins homology LQNVVNQg46.g52 Human immunodeficiency virus 1 Envelope glycoprotein (Fragment)71-77 Homology with HIV-1 has appeared
* The same mutation has occurred in Omicron variant.
Membrane protein
M protein Delta variant, 222 aa
There are four mutations known in the membrane (M) protein mSdSNGTITVEELKKLLEQWNLVIGFLLlTWICLLQFAYANR Delta variant, namely A2S, F28L, V70L, and I82T [10]. NRFLYIIKLIFLWLLWPVTLACFVLAALyRINWITGGIATaMACLV
GLMWLSYFIASFRLFARTRSMWSFNPETNILLNVPLHGTILTRP The heptamers of M protein that are homologous with the LLESELVIGAVILRGHLRIAGHHLGRCDIKDLPKEITVATSRTLSY proteins of the commensal and opportunistic bacteria are listed YKLGASQRVAGDSGFAAYSRYRIGNYKLNTDHSSSSDNIALLVQ in Table 5.
Table 5
The heptamers of M protein homologous with the proteins of the commensal and opportunistic bacteria
Wuhan-Hu Delta
Mutation M protein heptamer Species Homologous protein heptamer Localization in the human body M protein heptamer Species Homologous protein heptamer Localization in the human body
A2S mAdsngt1-7 No homological heptamers in commensal or opportunistic bacteria mSdsngt1-7 No homological heptamers in commensal or opportunistic bacteria
Adsngti2-8 Lachnospiraceae bacterium 7_1_58FAA Uncharacterized protein252-258 gut Sdsngti2-8
F28L lvigflF22-28 Enterococcus faecalis R508 Putative ferrichrome transport system permease protein FhuG203-206 gut lvigfll22-28 Eubacterium ventriosum ATCC 27560 Putative K(+)-stimulated pyrophosphate-energized sodium pump573-579 gut
Enterococcus caccae ATCC BAA-1240 Uncharacterized protein 104-110 gut
Faecalibacterium sp. CAG:74 Binding-protein- dependent transport systems inner membrane component86-92 gut
Prevotella histicola F0411 Uncharacterized protein 15-21 gut
Lachnospiraceae bacterium 2_1_58FAA Uncharacterized protein65_71 gut
Escherichia coli ISC11 Putative cell envelope opacity-associated protein A42-48 gut
VIGFLFL23-29 Enterococcus flavescens ATCC 49996 Uncharacterized prateini28-i34 gut VIGFlLl23-29 Prevotella sp. oral taxon 472 str. F0295 Uncharacterized protein178.184 gut
Lachnospiraceae bacterium COE1 MATE efflux family protein112-118 gut Lactobacillus brevis ATCC 14869 = DSM 20054 Potassium uptake protein, TrkH family239-245 gut
Lactobacillus antri DSM 16041 Transporter, major facilitator family protein422-428 gut
Enterobacter cloacae subsp. cloacae (strain ATCC 13047/DSM 30054 / NBRC13535/ NCDC 279-56) Putative multidrug resistance protein MdtD183.189 gut
Lachnospiraceae bacterium 28-4 Uncharacterized protein^ gut
igflFlt24-30 Lachnospiraceae bacterium CAG.215 Transporter468-474 gut igflLlt24-30 Lactobacillus paracasei subsp. paracasei Lpp126 Oligopeptide transport system permease protein oppB9-15 oral cavity
Eubacterium nodatum ATCC 33099 TIGR02185 family protein43_49 oral cavity
Bacteroides uniformis dnLKV2 Uncharacterized protein737_743 gut
Escherichia coli 2845650 Uncharacterized protein13_19 gut
Prevotella sp. CAG:1320 Putative thol:disulfide interchange protein DsbD8.14 gut
Enterococcus faecalis 06-MB-DW-09 Putative transmembrane permease MsmF16-22 gut
gflFltw^, No homological heptamers in commensal or opportunistic bacteria gflLltw^-3, No homological heptamers in commensal or opportunistic bacteria
Endind of the table 5
Wuhan-Hu Delta
Mutation M protein heptamer Species Homologous protein heptamer Localization in the human body M protein heptamer Species Homologous protein heptamer Localization in the human body
flFltwu No homological heptamers in commensal or opportunistic bacteria flLltwi26-32 No homological heptamers in commensal or opportunistic bacteria
lFltwic27-33 No homological heptamers in commensal or opportunistic bacteria LLLTWIC27-33 Peptoniphilus sp. oral taxon 375 str. F0436 Na+/H+ antiporter family protein105-111 gut
FLTWICL28-34 No homological heptamers in commensal or opportunistic bacteria LLTWICL28-34 No homological heptamers in commensal or opportunistic bacteria
VraL cfvlaaVm-70 Enterobacter sp. Ag1 Formate dehydrogenase-O subunit gamma24-30 gut CFVLmLM-70 No homological heptamers in commensal or opportunistic bacteria
FVLAaVy65-7, No homological heptamers in commensal or opportunistic bacteria fvlaaLy65-7, Bacteroides dorei CL03T12C01 HAD hydrolase, family IA344-350 gut
vlaaVyr66-72 No homological heptamers in commensal or opportunistic bacteria vlaaLyrS6-72 Bifidobacterium longum subsp. infantis (strain ATCC 15697 1 DSM 20088 / JCM 1222 / NCTC11817 / S12) Putative ABC transporter permease component110-116 gut
Haemophilus parainfluenzae ATCC 33392 ABC transporter, permease protein121-127 upper respiratory tract, lung
laaVyru Lachnospiraceae bacterium 3_1_57FAA_CT1 Uncharacterized proteinl30-136 gut laaLyru Acinetobacter sp. CIP 101966 Uncharacterized protein18-24 oral cavity
aaVyrin68-74 Lautropia mirabilis ATCC 51599 Selenide, water dikinase56-62 oral cavity, upper respiratory aaLyrin68-74 Prevotella melaninogenica (strain ATCC 25845/ DSM 7089 / JCM 6325 / VPI2381 / B282) GN=HMPREF0659 A647 Hydrolase, NUDIX family54-60 upper respiratory
Lachnospiraceae bacterium JC7 Diguanylate cyclase (GGDEF) domain-containing protein (Precursor)114-120 gut Lactobacillus ruminis (strain ATCC 27782 / RF3) Conserved hypothetical YitT family protein gut
Bacteroides nordii CL02T12C05 Uncharacterized protein700-706 gut
aVyrinw69-75 No homological heptamers in commensal or opportunistic bacteria aLyrinw69-75 No homological heptamers in commensal or opportunistic bacteria
Vyrinwu No homological heptamers in commensal or opportunistic bacteria Lyrinwu No homological heptamers in commensal or opportunistic bacteria
I82T ITGGIA^ Ruminococcus obeum ATCC 29174 Ion channel143-149 gut ITGGIAT76-82 Enterococcus faecalis Dephospho-CoA kinase7-13 gut
Bacteroides sp. 3_1_19 Putative uncharacterized proteinl58-164 gut Clostridium asparagforme DSM 15981 ABC transporter, permease protein268-274 gut
tggiaIa77-83 No homological heptamers in commensal or opportunistic bacteria TGGIATA77-83 Veillonella sp. oral taxon 780 str. F0422 PrpF protein3,2-3,8 oral cavity
ggiaIam78-84 Enterobacteriaceae bacterium 9_2_54FAA Uncharacterized protein270-276 gut ggiaTam78-84 No homological heptamers in commensal or opportunistic bacteria
Eubacterium sulci ATCC 35585 Peptidase, M20/M25/ M40 family136-142 gut
Lactobacillus brevis subsp. gravesensis ATCC 27305 Transporter, major facilitator family protein42,-427 gut
giaIama79-85 Lachnospiraceae bacterium 10-1 Uncharacterized proteini48-154 gut giaTama79-85 Enterobacter aerogenes UCI48 Uncharacterized protein320-326 gut
iaIamac80-86 No homological heptamers in commensal or opportunistic bacteria IATAMAC80-86 No homological heptamers in commensal or opportunistic bacteria
aIamacl81-87 No homological heptamers in commensal or opportunistic bacteria aTamacl81-87 Lactobacillus paracasei subsp. paracasei CNCM I-4649 Class II aldolase/ adducin family proteinl01-107 oral cavity, gut
Iamaclv82-88 No homological heptamers in commensal or opportunistic bacteria Tamaclv82-88 No homological heptamers in commensal or opportunistic bacteria
*The same mutation has occurred in Omicron variant.
Membrane protein
There are four mutations known in the membrane (M) protein Delta variant, namely A2S, F28L, V70L, and I82T [10]. M protein Delta variant, 222 aa
mSdsngtitveelkklleqwnlvigflLltwicllqfayanrn rflyiikliflwllwpvtlacfvlaaLyrinwitggiaTamacl
VGLMWLSYFIASFRLFARTRSMWSFNPETNILLNVPLHGTILT
RPLLESELVIGAVILRGHLRIAGHHLGRCDIKDLPKEITVATSR TLSYYKLGASQRVAGDSGFAAYSRYRIGNYKLNTDHSSSSD NIALLVQ
The heptamers of M protein that are homologous with the proteins of the commensal and opportunistic bacteria are listed in Table 6.
Table 6
The heptamers of M protein homologous with the proteins of the commensal and opportunistic bacteria.
Wuhan-Hu Delta
Mutation M protein heptamer Species Homologous protein heptamer Loca lization in the human body M protein heptamer Species Homologous protein heptamer Localization in the human body
A2S mAdsngt1-7 No homological heptamers in commensal or opportunistic bacteria mSdsngt1-7 No homological heptamers in commensal or opportunistic bacteria
Adsngti2-8 Lachnospira-ceae bacterium 7_1_58FAA Uncharacterized protein252-258 gut Sdsngti2-8
F28L lvigflF22-28 Enterococcus faecalis R508 Putative ferrichrome transport system permease protein FhuG203-206 gut lvigflL22-28 Eubacterium ventriosum ATCC 27560 Putative K(+)-stimulated pyrophosphate-energized sodium pump573.579 gut
Enterococcus caccae ATCC BAA-1240 Uncharacterized protein 104-110 gut
Faecalibacterium sp. CAG:74 Binding-protein-dependent transport systems inner membrane compo- nent86-92 gut
Prevotella histicola F0411 Uncharacterized protein 15-21 gut
Lachnospiraceae bacterium 2_1_58FAA Uncharacterized protein65-71 gut
Escherichia coli ISC11 Putative cell envelope opacity-associated protein A42.48 gut
VIGFLFL23-29 Enterococcus flavescens ATCC 49996 Uncharacterized prateini28-i34 gut VIGFLLL23-29 Prevotella sp. oral taxon 472 str. F0295 Uncharacterized protein 178-184 gut
Lachnospiraceae bacterium COE1 MATE efflux family protein112-118 gut Lactobacillus brevis ATCC 14869 = DSM 20054 Potassium uptake protein, TrkH family239-245 gut
Lactobacillus antri DSM 16041 Transporter, major facilitator family protein422.428 gut
Enterobacter cloacae subsp. cloacae (strain ATCC 13047 / DSM 30054 / NBRC 13535 / NCDC 279-56) Putative multidrug resistance protein MdtD183.189 gut
Lachnospiraceae bacterium 28-4 Uncharacterized pro- tein18-24 gut
IGFLFLT24-30 Lachnospira-ceae bacterium CAG215 Transporter468-474 gut[9 IGFLLLT24-30 Lactobacillus paraca-seisubsp. paracasei Lpp126 Oligopeptide transport system permease protein oppB9.15 oral cavity
Eubacterium nodatum ATCC 33099 TIGR02185 family protein43-49 oral cavity
Bacteroides uniformis dnLKV2 Uncharacterized protein737_743 gut
Escherichia coli 2845650 Uncharacterized protein^ gut
Prevotella sp. CAG:1320 Putative thiol:disulfide interchange protein DsbD8.14 gut
Enterococcus faecalis 06-MB-DW-09 Putative transmembrane permease MsmF16-22 gut
gflFltw^, No homological heptamers in commensal or opportunistic bacteria gflLltw^, No homological heptamers in commensal or opportunistic bacteria
Endind of the table б
Wuhan-Hu Delta
Mutation M protein heptamer Species Homologous protein heptamer Loca lization in the human body M protein heptamer Species Homologous protein heptamer Localization in the human body
flFltwi26.32 No homological heptamers in commensal or opportunistic bacteria flLltwi2,32 No homological heptamers in commensal or opportunistic bacteria
LFLTWIC27.33 No homological heptamers in commensal or opportunistic bacteria LLLTWIC27.33 Peptoniphilus sp. oral taxon 375 str. F0436 Na+/H+ antiporter family Pr0teini05-111 gut
FLTWICL28.34 No homological heptamers in commensal or opportunistic bacteria LLTWICL28.34 No homological heptamers in commensal or opportunistic bacteria
V70L cfvlaaV64_70 Enterobacter sp. Ag1 Formate dehydro-genase-O subunit gamma24-30 gut cfvlaaL64_70 No homological heptamers in commensal or opportunistic bacteria
fvlaaVy65_7, No homological heptamers in commensal or opportunistic bacteria fvlaaLy65.7, Bacteroides dorei CL03T12C01 HAD hydrolase, family IA344-350 gut
vlaaVyr66.72 No homological heptamers in commensal or opportunistic bacteria vlaaLyr66.72 Bifidobacterium longum subsp. infantis (strain ATCC 15697 / DSM 20088 / JCM 1222 / NCTC 11817 / S12) Putative ABC transporter permease component110-116 gut
Haemophilus parainflu-enzae ATCC 33392 ABC transporter, permease protein121-127 upper respiratory tract, lung
laaVyri67_73 Lachnospira-ceae bacterium 3_1_57FAA_CT1 Uncharacterized proteinl30-136 gut laaLyri6,73 Acinetobacter sp. CIP 101966 Uncharacterized protein18-24 oral cavity
aaVyrin68.74 Lautropia mirabilis ATCC 51599 Selenide, water dikinase56-62 oral cavity, upper respiratory tract aaLyrin68.74 Prevotella melaninogenica (strain ATCC 25845 / DSM 7089 / JCM 6325 / VPI2381 / B282) GN=HMPREF0659 A647 Hydrolase, NUDIX family54-60 upper respiratory tract
Lachnospiraceae bacterium JC7 Diguanylate cyclase (GGDEF) domain-containing protein gut Lactobacillus ruminis (strain ATCC 27782 / RF3) Conserved hypothetical YitT family protein gut
(Precursor)m-,20 Bacteroides nordii CL02T12C05 Uncharacterized protein700-706 gut
aVyrinw69_75 No homological heptamers in commensal or opportunistic bacteria aLyrinw69.75 No homological heptamers in commensal or opportunistic bacteria
Vyrinwi70-76 No homological heptamers in commensal or opportunistic bacteria Lyrinwi70-76 No homological heptamers in commensal or opportunistic bacteria
I82T itggiaI 7g.82 Ruminococcus obeum ATCC 29174 Ion channel143.149 gut itggiaT76.82 Enterococcus faecalis Dephospho-CoA kinase7-13 gut
Bacteroides sp. 3_1_19 Putative uncharacterized protein158.164 gut Clostridium asparagi-forme DSM 15981 ABC transporter, permease protein268-274 gut
TGGIAIA77.83 No homological heptamers in commensal or opportunistic bacteria tggiaTa77-83 Veillonella sp. oral taxon 780 str. F0422 PrpF protein3i2.3i8 oral cavity
ggiaIam78-84 Enterobacte-riaceae bacterium 9_2_54FAA Uncharacterized protein270-276 gut ggiaTam78-84 No homological heptamers in commensal or opportunistic bacteria
Eubacterium sulci ATCC 35585 Peptidase, M20/M25/ M40 family136-142 gut
Lactobacillus brevis subsp. gravesensis ATCC 27305 Transporter, major facilitator family protein421-427 gut
giaIama79-85 Lachnospiraceae bacterium 10-1 Uncharacterized proteini48-154 gut giaTama79-85 Enterobacter aerogenes UCI48 Uncharacterized Pr0tein320-326 gut
iaIamac80.86 No homological heptamers in commensal or opportunistic bacteria iaTamac80.86 No homological heptamers in commensal or opportunistic bacteria
aIamacl81.87 No homological heptamers in commensal or opportunistic bacteria aTamacl81.87 Lactobacillus paracasei subsp. paracasei CNCM I-4649 Class II aldolase/adducin family protein101-107 oral cavity, gut
Iamaclv82-88 No homological heptamers in commensal or opportunistic bacteria Tamaclv82-88 No homological heptamers in commensal or opportunistic bacteria
Nucleocapsid protein
Two mutations are known in the Delta variant nucleocapsid (N) protein, namely R203M and D377Y [11]. N protein Delta variant 419 aa
MSDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQR RPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDD QIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYG ANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPK
gfyaegsrggsqassrsssrsrnssrnstpgssMgtsparm
AGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAA EASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQ GTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAI
klddkdpnfkdqvillnkhidayktfpptepkkdkkkkaYetqa
LPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADSTQA
The heptamers of N protein homologous with the proteins of some opportunistic bacteria and the most common cereals are listed in Table 7.
Table 7
The heptamers of N protein homologous with the proteins of some opportunistic bacteria and the most common cereals
Mutation Wuhan-Hu Delta
N protein heptamer Species Homologous protein heptamer Localization in the human body N protein heptamer Species Homologous protein heptamer Localization in the human body
R203M stpgssR197-203 Prevotella buccalis ATCC 35310 NHL repeat protein306-312 oral cavity STPGSsMi97-203 No bacterial or cereal sample
tpgssRG198-204 No bacterial or cereal sample tpgssMgI98-204 Bacteroides uniformis CAG:3 Uncharacterized protein 128-134 gut
PGSSRGT199-205 Zeamays Putative WRKY DNA-binding domain superfamily Protein78-84 gut pgssMgtI99-205 Oryza sativa subsp. indica Putative uncharacterized protein558-564 gut
Sorghum bicolor Putative unchar-acterized protein Sb07g00249027-33 gut
GSsRgTS200-206 Sorghum bicolor Putative unchar-acterized protein Sb08g014350176.182 gut GSsMGTS200-206 Fusobacterium sp. CM21 Permease family protein294-300 oral cavity
SsRgTSP201-207 Hordeum vulgare var. distichum Uncharacterized pro- tein267-273 gut ssMgtsp201-207 No bacterial or cereal sample
Oryza sativa subsp. japonica Expressed pro- tein216-222 gut
sRgTSPA202-208 No bacterial or cereal sample sMgtspa202-208 No bacterial or cereal sample
RgTSPAR203-209 Oryza sativa subsp. japonica 0s06g0523800 protein 118-124 gut MGTSPAR203.209 No bacterial or cereal sample
D377Y DKKKKAÜ37,-377 Prevotella sp. oral taxon 473 str. F0040 Pseudouridine synthase, RluA family295-30i oral cavity DKKKKAY371.377 Lachnospiraceae bacterium 3-1 0ligoendopep tidase F439-445 gut
KKKKADE372-377 Prevotella sp. oral taxon 473 str. F0040 Pseudouridine synthase, RluA family296-302 oral cavity KKKKAYE372-377 Oryza sativa subsp. indica Putative uncharacterized protein 1090-1096 gut
Enterococcus faecalis Uncharacterized pro- tein396-402 gut
KKKADET373-379 No significant sample KKKaYeT373-379 Bacillus infantis NRRL B-14911 GntR family transcriptional regu-lator2-8 ?
kkaDetq374-380 No bacterial or cereal sample KKaYetq374-380 No bacterial or cereal sample
kaDetqa375-381 Homo sapiens Myopalladin90-96 ? kaYetqa375-381 No bacterial or cereal sample
aDetqal376-382 Oryza glaberrima Uncharacterized protein (Frag- ment)474-480 gut AYETQAL376-382 Lachnospiraceae bacterium M18-1 Uncharacterized protein244-250 gut
DETQALP377-383 No bacterial or cereal sample YETQALP377-383 Lachnospiraceae bacterium M18-1 Uncharacterized protein245-251 gut
As shown above, some of the mutations that occurred in the Delta variant increased the homology of its structural proteins with those of the opportunistic and some other bacteria. These data are summarized in Table 8.
Information about the effects that mutations in SARS CoV-2 Delta variant have on the homology between its structural proteins and human opportunistic bacteria proteins are summarized in Figure 1.
DISCUSSION
In Wunan-Hu variant, the S protein molecule contains dozens of heptamers homologous to human proteins. Their total length is 169 amino acid residues, or 13.3% of the S protein molecule total length [5]. For the sake of brevity, we suggest calling homologous motifs homots. For example, a SARS CoV-2 S protein human homot means a motif common for the S protein and any human protein. The same way "in SARS CoV-2 S protein, the motif SPRRARS is a human homot" means that motif SPRRARS is present in the S protein of coronavirus as well as in some human protein. The term mimics, proposed by Damoiseaux et al. [12], is close in meaning but less specific.
We assumed that the reason for the special qualities of SARS CoV-2 Delta variant should be sought in the greater homology of its proteins with those of the human body. However, we did not find any significant differences between Wuhan-Hu variant and Delta variant in their homology to human proteins.
Table 8
Mutational changes of homology SARS CoV-2 structural proteins with proteins of opportunistic bacteria
and some other functionally significant proteins
Protein Mutation Increases homology with proteins of commensal or opportunistic bacteria, inhabitants of the oral cavity, upper respiratory tract or lung Increases homology with proteins of gut commensal or opportunistic bacteria and/or the most common cereals Increases homology with some other proteins
S (Table 2) t19r + +
G142D* + -
^156,157; R158G +++ +++ Homology with a protein of Bacillus sp. NRRL B-14911 that can provoke autoimmune damage to the heart
L452R - -
T478K* - -
P681H - -
D950N* + + Homology with a protein of Human immunodeficiency virus 1 (Table 4)
M (Table 6) a2s - -
F28L + ++
V70L ++ ++
I82T + -
N (Table 7) R203M - -
D377Y - +
*The same mutation has occurred in Omicron variant.
R203M T19R F28L D337Y G142D D950N V70L
Al56, 157 Rl58G I82T
-----N-,---------
X I 4-
HOMOLOGY WITH ( OPPORTUNISTIC ) V BACTERIA J
Bypassing the immunity?
Fig. 1. The effect of mutations in SARS CoV-2 Delta variant structural proteins S, M, and N on their homology with human opportunistic bacteria. The most important mutation, in our opinion, is highlighted in red font
Delta variant stays on the nasal mucosal surface significantly longer than Wuhan-Hu variant (14 vs. 8 days) [13].
As has been already mentioned, we considered the human proteome in general as a set of proteins synthesized by the
macroorganism itself, proteins of commensal and opportunistic bacteria, and the most common digestive proteins, therefore studying the homology of SARS CoV-2 Delta variant with all the listed types of proteins.
In S protein, mutations at the positions 19, 142, 156-158, and 950 created a number of heptamers homologous to proteins of bacteria, that are always present in the human nasopharynx, mouth, throat, upper respiratory tract, and lung (Table 2). It is possible that the presence of such homologous motifs allows Delta to bypass the innate immunity protection more successfully.
Mutations S:G142D and S:D950N are also found in Omicron variant, while the mutations S:T19R and S:A156 157,R158G are only present in Delta variant. These exclusive Delta variant mutations especially the ones at the positions 156-158 may be the reason for its specific qualities.
The L452R and T478K mutations did not affect the homology of S protein with proteins of opportunistic bacteria (Table 2).
In Delta variant, the positions where the most significant increase in homology occurred — S:A156 157;R158G — are located in the N-terminus domain (NTD14.303). So far, researchers have paid less attention to this domain than to the Receptor-binding domain (RBD317-539 ). It is logically consistent to assume that in the S protein molecule one domain is responsible for binding to the receptor and other for structural mimicry and evasion.
The delta variant differs from the other SARS COV-2 variants in 14 positions. According to our data (Fig. 1), six of these alterations involved in the increase in the homology of coronavirus proteins with those of opportunistic bacteria. None of these six alterations are common to the Delta and non-VOC variants. This suggests that the increase in homology with proteins of opportunistic infections is specific to the Delta variant.
We are not yet able to analyze homology data for SARS CoV-2 S protein and the HIV-1 C protein (Table 4).
In M protein, the F28L, V70L, and I82T mutations resulted in the emergence of heptamers homologous to proteins of numerous commensal and opportunistic upper respiratory and gut bacteria (Table 6). M protein is located on the outer side of the virion envelope [5], and these heptamers can participate in immune evasion.
In N protein (Table 7), the mutation N:R203M resulted in the motif GSSMGTS200-206 which is homologous to the Permease family protein294-300 of Fusobacterium nucleatum, an opportunistic periodontal pathogen of the oral cavity [14]. The mutation M:D377Y caused the following effects: (a) disappearance of the heptamer KADETQA375-381, homologous to the human protein Myopalladin (MYPN90-96), which is involved in communication between the sar-comere and the nucleus in cardiac and skeletal muscles [15]; and (b) emergence of KKKAYET373-379, homologous to the heptamer GntR family transcriptional regulator2-8 Bacillus infantis, which is involved in the provocation of immune myocardial disorder [16].
A recent review of the available evidence for immune mechanisms of cardiovascular damage COVID-19 has been presented [17]. N protein, located inside of the virion, should act at the later stages of the infectious process, for example, provoking an autoimmune response.
Of all the Delta variant mutations we studied, none caused an increase in the homology of the SARS CoV-2 S protein with proteins with the most common cereals (Table 3).
Natural selection fixes some substitutions in the primary structure of the protein molecules of viruses and eliminates others. One of the "aims" of selection might be immune evasion. A virus can achieve this by making the most functionally important parts of the protein molecule as similar as possible to the proteins permanently present in the host. Microorganisms, due to their genetic diversity and the huge size of their combined genome, provide more opportunities for viral mimicry than the macroorganism itself. Delta variant has increased homology of S and M proteins with proteins already familiar to human immunity, namely with opportunistic bacteria proteins.
The capacity of SARS CoV-2 for immune evasion can be considered universally acknowledged [3]. Coronavirus and human protein homology may be one of the mechanisms of immune evasion [5]. Delta variant necessarily has structural features that explain its specific qualities. Perhaps the reason is the homology of its proteins with those of commensal bacteria and opportunistic infections of the upper respiratory tract and lung. In this case, the S:A156 157;R158G mutation deserves special attention. The reason why SARS CoV-2 Delta variant has these specific qualities, most importantly increased lethality, is most likely to be found in a mutation at positions 156-158 of spike protein. It has not yet been concluded whether the homology of Delta variant proteins with gut bacteria proteins and dietary protein is of any significance.
We hope that this preliminary study will open the door to further research into the immunology and bioinformatics.
METHODS
We used our original way of presenting the text search. The data were obtained from the Uniprot open-access protein database, in which the amino acid sequences of proteins are encoded by a one-letter code. We cut the primary structures of the coro-navirus proteins into heptamers using the frameshift method and searched a separate database of 75777 molecules of human proteins [18]. This number is about three times the real number of all human proteins because of repetition and minor differences in the records. We looked for a full match of the 7-mer amino acid sequences in SARS CoV-2 proteins [19] with proteins of other organisms throughout the taxonomic range of evolution from bacteria and plants to humans. Heptamers were chosen as a criterion for homology because of the lack of matches in octamers and tens of thousands of matches in hexamers. In the case of matching heptamers, an alignment was performed on the matching site.
ДОПОЛНИТЕЛЬНАЯ ИНФОРМАЦИЯ
Вклад авторов. А.Т. Марьянович и Д.К. Кормилец написали основной текст рукописи. А.Т. Марьянович и Д.К. Кормилец подготовили анализ данных. Авторы прочли и одобрили финальную версию перед публикацией.
Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи.
Источник финансирования. Данное исследование представляет собой инициативный проект авторов, финансируемый исключительно из их личных источников.
Заявление о доступности данных. Источником базы данных по 75 777 строкам белков человека является [18]. Источник базы данных объемом ок. 33 млн нитей всех видов белков [19].
Иллюстрации. Для создания наших иллюстраций мы использовали GIMP (версия 2.10.22). Рисунок полностью оригинальный и нигде не публиковался.
ADDITIONAL INFORMATION
Author contributions. A.T. Maryanovich and D.Yu. Kormi-lets wrote the main manuscript text. A.T. Maryanovich and D.Yu. Kormilets prepared data analysis. The authors read and approved the final version before publication.
Competing interests. The authors declare that they have no competing interests.
Funding: This research is an authors' initiative project funded exclusively from their personal sources.
Funding source. This study was not supported by any external sources of funding.
Data Availability Statement: The source of database of 75777 strings of human proteins is [18]. The source of database of approx. 33 mln strings of all species proteins is [19].
Artwork. We used GIMP (Version 2.10.22) to create our artwork. The figure is completely original and have not been published anywhere.
ЛИТЕРАТУРА /REFERENCES
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