Pathogenic priming likely contributes to serious and critical illness and mortality in COVID-19 via autoimmunity

 2020; 3: 100051.
Published online 2020 Apr 9. doi: 10.1016/j.jtauto.2020.100051
PMCID: PMC7142689
PMID: 32292901


Homology between human and viral proteins is an established factor in viral- or vaccine-induced autoimmunity. Failure of SARS and MERS vaccines in animal trials involved pathogenesis consistent with an immunological priming that could involve autoimmunity in lung tissues due to previous exposure to the SARS and MERS spike protein. Exposure pathogenesis to SARS-CoV-2 in COVID-19 likely will lead to similar outcomes. Immunogenic peptides in viruses or bacteria that match human proteins are good candidates for pathogenic priming peptides (similar to the more diffuse idea of “immune enhancement”). Here I provide an assessment of potential for human pathogenesis via autoimmunity via exposure, via infection or injection. SAR-CoV-2 spike proteins, and all other SARS-CoV-2 proteins, immunogenic epitopes in each SARS-CoV-2 protein were compared to human proteins in search of high local homologous matching. Only one immunogenic epitope in a SARS-CoV-2 had no homology to human proteins. If all of the parts of the epitopes that are homologous to human proteins are excluded from consideration due to risk of pathogenic priming, the remaining immunogenic parts of the epitopes may be still immunogenic and remain as potentially viable candidates for vaccine development. Mapping of the genes encoding human protein matches to pathways point to targets that could explain the observed presentation of symptoms in COVID-19 disease. It also strongly points to a large number of opportunities for expected disturbances in the immune system itself, targeting elements of MHC Class I and Class II antigen presentation, PD-1 signaling, cross-presentation of soluble exogenous antigens and the ER-Phagosome pathway. Translational consequences of these findings are explored.

Keywords: SARS-CoV-2, COVID-19, Autoimmunity, Pathogenic priming, Immune Enhancement

1. Introduction

Autopsies of Chinese citizens who have died from COVID-19 following SARS-CoV-19 infection show evidence of interstitial changes, suggesting the development of pulmonary fibrosis []. This suggests, at least partly, an autoimmunology basis of the pathogenesis of COVID-19. A number of causal bases of autoimmunity from exposure to viral epitopes is well established, whether the route of administration be by exposure via infection or vaccination. Systemic respiratory viral infections can have numerous serious health effects, including dyspnea, hypoxemia, dysuria, meningitis, low blood pressure, shock and death. Sequalae of viral infections can include various short-term and sometimes permanent effects on the central nervous system, via direct injury to CNS tissue due to viral replication (viral neuropathology) or due to the host immune system learning to attack CNS tissue (viral neuroimmunopathology). The public health consequences from some viruses can include impaired immunity, encephalitis, and long-term neurological diseases such as demyelinating disorders and relapsing events such as those seen in multiple sclerosis (MS).

Both genetic and environmental factors are thought to contribute both to the severity of viral infections, and in determining who will develop autoimmune conditions. Various specific mechanisms (etiologies) of autoimmunity are recognized as plausible in viral induction of autoimmunity, including epitope spreading, molecular mimicry, cryptic antigen, and bystander activation, each a plausible etiological mechanism responsible for activating self-reactive (SR) immune cells.

Mortality in SARS-CoV-2 infection from COVID-19 is highly age-dependent, with older patient having the highest probability of death. The etiology of the age-specific mortality seen in COVID-19 is largely unknown. SARS-CoV and SARS-CoV-2 coronaviruses targets the epithelial cells of the respiratory tract, resulting in diffuse alveolar damage. Other tissues are obviously also potential targets for viral immunopathology, including mucosal cells of the intestine, epithelial cells of the kidneys, brain cells (neurons), and cellular components of the immune system. In severe cases of SARS, and likely in SARS-CoV-2, this viral targeting leads acutely to pneumonia. Exposure to other viral and ambient antigens are known causal factors in chronic autoimmune diseases of the airways including asthma. The role of autoimmunity in enhancing the severity of secondary exposures following prior infection or vaccinations has been given little consideration.

Among coronaviruses, the spike surface glycoprotein is known to play a role in neuroimmunopathology. However, the SARS-CoV-2 virus has numerous other proteins and polyproteins, each which may serve as an antigen source during infection leading to autoimmunity. the immune system presents those proteins, like all human proteins, as “normal”. T-cells are trained to recognize a normal protein shape in the thymus. Biomimicry between or among proteins from pathogens (infection or injection) can conflate the signaling by creating a population of memory B-cells, especially if the reaction switches from a Th-1 toward a Th-2 response.

In SARS, a type of “priming” of the immune system was observed during animal studies of SARS spike protein-based vaccines leading to increased morbidity and mortality in vaccinated animals who were subsequently exposed to wild SARS virus. The problem, highlighted in two studies, became obvious following post-vaccination challenge with the SARS virus []. found that recombinant SARS spike-protein-based vaccines not only failed to provide protection from SARS-CoV infection, but also that the mice experienced increased immunopathology with eosinophilic infiltrates in their lungs. Similarly [], found that ferrets previously vaccinated against SARS-CoV also developed a strong inflammatory response in liver tissue (hepatitis). Both studies suspected a “cellular immune response”.

These types of unfortunate outcomes are sometimes referred to as “immune enhancement”; however, this nearly euphemistic phrase fails to convey the increased risk of illness and death due to prior exposure to the SARS spike protein. For this reason, I refer to the concept as “pathogen priming”; the peptides with pathogenic potential therefore are referred to as “putative pathogenic priming peptides”.

In this study, I present the likely human epitopic targets of biomimicry-induced autoimmunological components of morbidity and mortality caused by SARS-CoV-2 infection. This is achieved via bioinformatics analysis of the homology between highly immunogenic SARS-CoV-2 epitopes and human proteins to promote comprehension of the etiologies of pathogenesis of SARS-CoV-2 in COVID-19. Thirty-seven identified proteins in SARS-CoV-2 were evaluated.

2. Methods

The investigative data analysis procedure included the following steps. First, for each ORF (open reading frame) reported as a canonical CDS (coding sequence) for the SARS-CoV-2 virus, flagged (significant) immunogenetic SARS-CoV-2 epitopes were found using SVMTriP (; []. These immunogenetic epitopes were then compared to human proteins using p-Blast (settings optimized for short sequences) against the Homo sapiens entries in the Protein Databank ( A list of human peptides with high local homology was compiled and their roles in the pathogenesis of COVID-19 from SARS-CoV-2 infection noted. The protein entries were mapped to nucleotide accession number, which were used to map as a gene set to pathways via Reactome ( Tissue distribution of the targeted proteins was explored using the Protein Atlas (

3. Results

Thirty-seven SARS-CoV-2 proteins were downloaded from the NCBI SARS-CoV-2 NCBI resource. Of these, 8 proteins had no recognizably immunogenic peptides. The remaining proteins had between one and six immunogenic peptides (Table 1). The proteins with the largest number of immunogenic peptides were the Spike, or S protein (N ​= ​6 in total), and the non-structural protein NS3 (also N ​= ​6; Table 1). All of the proteins had at least one match to human proteins except one, specifically nucleocapsid phosphoprotein (epitope ‘QQQQGQTVTKKSAAEASKKP’), however even nucleocapsid phosphoprotein has one other epitope (‘RRGPEQTQGNFGDQELIRQG’) which has a localized match to the immunoglobulin heavy chain junction region (MOO20493; GNFGDQ).

Table 1

Protein Accession SARS-CoV-2 Protein Name Immunogenetic epitope(s) Accession Human Protein Name Putative pathogenic priming peptide (self-antigen) Tissue RNA/Protein Expression
1 QHN73821 ORF1ab polyprotein RARTVAGVSICSTMTNRQFH CCO13833 alternative protein TJP1 TVICDTMLCPKVYFFTNRQF nearly ubiquitous
(partial) CSTMTSR MCD32611 IHCJ CSTMTSR B-cells, plasma cells
2 QHN73794 ORF1ab protein VATLQAENVTGLFKDCSKVI NP_001339255 la-related protein 4 (LARP4) EEVKGLFKSENCPKVI ubiquitous
3 QIA98594 ORF1ab polyprotein DRRATCFSTASDTYACWHHS AIT38911 IGJHCVR DTYACW B-cells, plasma cells
DRRATCFSTASDTYACWHHS NP_001712 cytoplasmic tyrosine-protein kinase BMX isoform 1 ASDTYACWH epididymous
4 QIA98597 ORF3a protein YQIGGYTEKWESGVKDCVVL AAH82244 PH domain and leucine rich repeat protein phosphatase 1(PHLPP1) GYTEASGVKNKLCV brain, lung, kidney
5 QIA98604 ORF7a protein GVKHVYQLRARSVSPKLFIR XP_016871107 sortilin related VPS10 domain containing receptor 1(SORCS1) GIKHVYQ brain, gastrointestinal tract, kidney
6 QIA98601 ORF8 protein FYSKWYIRVGARKSAPLIEL EAX03800 ankyrin repeat and sterile alpha motif domain containing 1A (ANKS1A) RVGVRKSAVPL eye, lung, gastrointestinal tract, liver
7 YP_009725310 endoRNAse LIGEAVKTQFNYYKKVDGVV 3SWR_A DNA methyltransferase 1 VGEAVKTDGKKSYYKKV brain, lung, gastrointestinal tract
8 YP_009725308 helicase ATNYDLSVVNARLRAKHYVY MOQ41699 IHCJ SVVAARLRPSHFDY B-cells, plasma cells
9 YP_009725297 leader protein LPQLEQPYVFIKRSDARTAP 5SZF_L Chain L, 2A10 antibody FAB fragment light chain PYVFGGGTKLEIKRADAAP
LPQLEQPYVFIKRSDARTAP 3QXM_A glutamate ionotropic receptor kainate type subunit 2 (GRIK2) LEEPYVLFKKSD brain, kidney
10 QHO62114 matrix protein FIASFRLFARTRSMWSFNPE MCD74337 IHCJ ARERSGWSFDP B-cells, plasma cells
11 QIA98599 membrane glycoprotein FIASFRLFARTRSMWSFNPE MCD74337 IHCJ ARERSGWSFDP B-cells, plasma cells
12 QIH45026 M protein FIASFRLFARTRSMWSFNPE MCD74337 IHCJ ARERSGWSFDP B-cells, plasma cells
FIASFRLFARTRSMWSFNPE AAH80580 pentatricopeptide repeat domain 1(PTCD1) RLFARARPM ubiquitous
13 YP_009725298 nonstructural protein NS2 DGISQYSLRLIDAMMFTSDL NP_001165883 VANGL planar cell polarity protein 1(VANGL1) GIVQYAVSLVDALLF ubiquitous
14 YP_009725298 nonstructural protein NS2 VEKKKLDGFMGRIRSVYPVA EAW65335 adaptor protein containing pH domain, PTB domain and leucine zipper motif 1, isoform CRA_a LVDAMMF
15 YP_009725299 nonstructural protein NS3 LGYVTHGLNLEEAARYMRSL AAC64695 supervillin (SVIL) VTHRLLEEDTPRYMR ubiquious except eye, blood
EEVGHTDLMAAYVDNSSLTI XP_016864345 Rap guanine nucleotide exchange factor 2 (RAPGEF2) MASYVDNS brain, bone marrow (RNA)
EEVGHTDLMAAYVDNSSLTI XP_016864345 Rap guanine nucleotide exchange factor 2 (RAPGEF2) ESSSLT brain, bone marrow (RNA)
QTTLKGVEAVMYMGTLSYEQ ANO56871 T-cell receptor beta chain variable region MYLCASSLSYEQ lung, bone marrow, blood
QTTLKGVEAVMYMGTLSYEQ NP_001292017 N-acetyltransferase 9 isoform GTEAVLAM–LSYE spleen
QVESDDYIATNGPLKVGGSC CAA56042 protein-tyrosine-phosphatase DYIATQGPLK ubiquitous
16 YP_009725300 nonstructural protein NS4 VHVMSKHTDFSSEIIGYKAI AIT39025 IGJHCVR THFNSEIIGY B-cells, plasma cells
VHVMSKHTDFSSEIIGYKAI 2W3C_AL General vesicular transport factor P115 IHVLQTDRSDSEIIGY skeletal muscle, others
17 YP_009725303 nonstructural protein NS7 GAVDINKLCEEMLDNRATLQ 5VHJ_D Proteasome 26S subunit, ATPase 4(PSMC4) GADINSICQESGMLAVRENR ubiquitous
18 YP_009725304 nonstructural protein NS8 AVANGDSEVVLKKLKKSLNV AAI11491 Bromodomain and WD repeat domain containing 3(BRWD3) VANGDGEVV ubiquitous
19 YP_009725305 nonstructural protein NS9 AKVTSAMQTMLFTMLRKLDN 1A4P_A S100 calcium binding protein A10(S100A10) AMETMMFT lung, blood
20 YP_009725306 nonstructural protein NS10 TLKNTVCTVCGMWKGYGCSC EAW66814 hCG1795641 KGYGCSC
TLKNTVCTVCGMWKGYGCSC EAW84736 Cartilage oligomeric matrix protein LKNTVMECDACGM adipose tissue, muscle
21 YP_009725307 RNA-dependent RNA polymerase QYIRKLHDELTGHMLDMYSV NP_001271153 Elongator acetyltransferase complex subunit 3 (ELP3) FIRNLHDALSGH nearly ubiquitous
MPNMLRIMASLVLARKHTTC XP_011508049 Hedgehog acyltransferase (HHAT) MATLLARKH nearly ubiquitous
DVNLHSSRLSFKELLVYAAD XP_006713353 Semaphorin 3F(SEMA3F) RLSFKEL nearly ubiquitous
TLVKQLSSNFGAISSVLNDI XP_016871528 Attractin-like protein 1 FGAISSVLNDI brain
TLVKQLSSNFGAISSVLNDI XP_016871528 Attractin-like protein 1 AIASALIDI brain
QQLIRAAEIRASANLAATKM XP_011528323 tetratricopeptide repeat protein 28 QQLGIAEDLKDRAAEGRASSN ubiquitous
KEELDKYFKNHTSPDVDLGD XP_024309095 follistatin-related protein EILDKYFKN placenta, most others
VMVTIMLCCMTSCCSCLKGC AAO32957 Metallothionein 1E (MT1E) CKTSCCSC liver, most others
23 QIA98596 Spike protein LNEVAKNLNESLIDLQELGK XP_011535432 Coiled-coil domain-containing protein 175 isoform X8 KNMEEGLITLQEL brain, pituitary gland, testis
QQLIRAAEIRASANLAATKM XP_011528323 Tetratricopeptide repeat protein 28 isoform X8 QQLGIAEDLKDRAAEGRASSNL ubiquitous
KEELDKYFKNHTSPDVDLGD XP_024309095 Follistatin-related protein 1 isoform X1 EILDKYFKN placenta, most others
VMVTIMLCCMTSCCSCLKGC NP_149050 Keratin associated protein 4-7(KRTAP4-7) CCMSSCC skin
24 YP_009725301 3C-like proteinase AENVTGLFKDCSKVITGLHP AAH22377 La ribonucleoprotein domain family member 4 (LARP4) EEVKGLFKSENCPKVI ubiquitous
HLSVDTKFKTEGLCVDIPGI XP_024308868 Titin DTKFKTTGLDEGL heart muscle, skeletal muscle
25 QIA98602 nucleocapsid phosphoprotein RRGPEQTQGNFGDQELIRQG MOO20493 IHCJ GNFGDQ B-cells, plasma cells
26 QHR63265 nonstructural protein NS7a GVKHVYQLRARSVSPKLFIR XP_016871107 VPS10 domain-containing receptor SorCS1 GIKHVYQ thyroid gland, many others
27 QHR63267 nonstructural protein NS8 FYSKWYIRVGARKSAPLIEL AAH31934 Ankyrin repeat and sterile alpha motif domain containing 1A RVGVRKSAVPL ubiquitous
28 QIA98602 nucleocapsid phosphoprotein QQQQGQTVTKKSAAEASKKP n/a n/a n/a
30 QHR63254 nonstructural protein NS6 n/a n/a n/a n/a
31 QHR63276 nonstructural protein NS7b n/a n/a n/a n/a
32 QHW06053 orf6 protein n/a n/a n/a n/a
33 QIA20050 ORF7b protein n/a n/a n/a n/a
34 YP_009725312 nsp11 n/a n/a n/a n/a
35 YP_009725311 2′-O-ribose methyltransferase n/a n/a n/a n/a
36 YP_009725309 3′-to-5′ exonuclease n/a n/a n/a n/a
37 QIH45025 E protein n/a n/a n/a n/a
immunoglobulin heavy chain junction region

Remarkably, over 1/3 (11/27) of the immunogenic proteins in SARS-CoV-2 have potentially problematic homology to proteins that are key to the human adaptive immune system (emboldened in Table 1). Mapping of the overall gene list to Pathways via revealed that many functions of the human adaptive immune system might be impacted via autoimmunity against these proteins and their interactors, including MCH Class I and Class II antigen presentation, PD-1 signaling, cross-presentation of soluble exogenous antigens and the ER-Phagosome pathway.

4. Discussion

These results could explain in part the high rates of serious illness associated with SARS-CoV-2. They could also explain the lengthy asymptomatic period prior to presentation of symptoms characteristic of COVID-19. SARS-CoV-2 could impair the immune response, at first, and then, over time, the immune system could begin to mount an attack on the myriad of proteins. Most of the identified human target proteins had low overall homology but high local homology over short segments of their epitopes. The Protein Atlas results indicated that numerous proteins are expressed in a variety of tissues as noted in Table 1.

Unintended consequences of pathogenesis from vaccines are not new, nor are they unexpected. They are unanticipated only if those who develop them do not include available knowledge in their formulation plan. For example, the H1N1 influenza vaccine used in Europe led to narcolepsy in some patients, resulting from homology between the human hypocretin (aka, orexin) receptor 2 molecule and proteins present in the vaccine. This was established via the detection of cross-reactive antibodies in the serum of patients who develop narcolepsy following H1N1 vaccination in Europe [].

The fact that pathogenic priming may be occurring involving autoimmunity against multiple proteins following CoV vaccination is consistent with other observations observed during autoimmunity, including the release of proinflammatory cytokines and cytokine storm. Similar to the SARS-CoV animal studies [], found that mice vaccinated against MERS-CoV (Middle East Respiratory Syndrome) development exaggerated pulmonary immunopathology when challenged with the MERS virus following vaccination. They reported that lung mononuclear infiltrates were observed in all groups after virus challenge, and that increased infiltrates that contained eosinophils and the eosinophil promoting IL-5 and IL-13 cytokines were observed only in the vaccinated animals.

Pathogenic priming may be more or less severe in vaccine or infection induced immune responses to some proteins than for others due to original antigenic sin; the immunologic reaction against self-antigens may be made less severe as fast-evolving viruses evolve away from the original vaccine type. Thus, the screening of immunogenic epitopes for pathogenic priming potential via homology may be augmented by studies of autoantibodies that cross-react with epitopes included in vaccines.

SARS-CoV-2 has some unexplained pathogenic features that might be related to the table of putative pathogenic priming peptides. Exposure to these specific peptides – via either infection or vaccination – might prime patients for increased risk of enhanced pathogenicity during future exposure due either to future pandemic or outbreaks or via universal vaccination programs. While the mechanisms pathogenesis of COVID-19 are still poorly understood, the morbidity and mortality of SARS has been extensively studied. Thus, the involvement of pathogenic priming in re-infection by COVID-19 is a theoretical possibility; of course no vaccine against SARS-CoV-2 has yet been tested in animals and therefore we do not yet know if pathogenic priming is in fact expected. Such studies should be undertaken before use of any vaccine against SARS-CoV-2 is used in humans.

Declaration of competing interest

Dr. Lyons-Weiler has, in the past, served as expert witness in the National Vaccine Injury Compensation Program.


This research was funded by private donations from the pubic to The Institute for Pure and Applied Knowledge.


Appendix ASupplementary data to this article can be found online at

Statement of interests

The author has served as an expert witness in the US National Vaccine Injury Compensation Program.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1:

Click here to view.(26K, xlsx)Multimedia component 1


1. Shi H. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 doi: 10.1016/S1473-3099(20)30086-4. [PMC free article] [PubMed] [CrossRef[]
2. Deming D., Sheahan T., Heise M. Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Med. 2006;3(12):e525. 2006 Dec. [PMC free article] [PubMed[]
3. Weingartl H., Czub M., Czub S. Immunization with modified vaccinia virus Ankara-based recombinant vaccine against severe acute respiratory syndrome is associated with enhanced hepatitis in ferrets. J. Virol. 2004 Nov;78(22):12672–12676. [PMC free article] [PubMed[]
4. Yao B., Zhang L., Liang S., SVMTriP C. Zhang. A method to predict antigenic epitopes using support vector machine to integrate tri-peptide similarity and propensity. PloS One. 2012;7(9) [PMC free article] [PubMed[]
5. Ahmed S.S., Volkmuth W., Duca J. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci. Transl. Med. 2015 Jul 1;7(294) doi: 10.1126/scitranslmed.aab2354. 294ra105. [PubMed] [CrossRef[]
6. Agrawal A.S., Tao X., Algaissi A. Immunization with inactivated Middle East Respiratory Syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus. Hum. Vaccines Immunother. 2016 Sep;12(9):2351–2356. doi: 10.1080/21645515.2016.1177688. Epub 2016 Jun 7. [PMC free article] [PubMed] [CrossRef[]

Articles from Journal of Translational Autoimmunity are provided here courtesy of Elsevier

Be the first to comment

Leave a Reply