scholarly journals Molecular mimicry between Spike and human thrombopoietin may induce thrombocytopenia in COVID-19

2021 ◽  
Author(s):  
Janelle Nunez-Castilla ◽  
Vitalii Stebliankin ◽  
Prabin Baral ◽  
Christian A Balbin ◽  
Masrur Sobhan ◽  
...  
Keyword(s):  
Platelet Count ◽  
Molecular Mimicry ◽  
Cross Reactivity ◽  
Spike Protein ◽  
Sequence Motif ◽  
Computational Investigation ◽  
Binding Properties ◽  
Platelet Production ◽  
Additional Support ◽  
Common Sequence

Thrombocytopenia, characterized by reduced platelet count, increases mortality in COVID-19 patients. We performed a computational investigation of antibody-induced cross-reactivity due to molecular mimicry between SARS-CoV-2 Spike protein and human thrombopoietin, the regulator of platelet production, as a mechanism for thrombocytopenia in COVID-19 infections. The presence of a common sequence motif with similar structure and antibody-binding properties for these proteins strongly indicate shared molecular mimicry. Recent reports of antibodies in COVID-19 patients and pre-pandemic samples against epitopes containing the motif offer additional support for the cross-reactivity. Altogether, this suggests cross-reactivity between an antibody with affinity for Spike protein and a human protein. Consideration of cross-reactivity for SARS-CoV-2 is important for therapeutic intervention and when designing the next generation of COVID-19 vaccines to avoid potential autoimmune interference.

scholarly journals Anti-SARS-CoV-2 Spike Protein and Anti-Platelet Factor 4 Antibody Responses Induced by COVID-19 Disease and ChAdOx1 nCov-19 vaccination

2021 ◽  
Author(s):  
Andreas Greinacher ◽  
Kathleen Selleng ◽  
Julia Mayerle ◽  
Raghavendra Palankar ◽  
Jan Wesche ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Molecular Mimicry ◽  
Cross Reactivity ◽  
Platelet Factor 4 ◽  
Antibody Responses ◽  
Spike Protein ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Activation Assay ◽  
Heparin Complexes

Abstract Background: Some recipients of ChAdOx1 nCoV-19 COVID-19 Vaccine AstraZeneca develop antibody-mediated vaccine-induced thrombotic thrombocytopenia (VITT), associated with cerebral venous and other unusual thrombosis resembling autoimmune heparin-induced thrombocytopenia. A prothrombotic predisposition is also observed in Covid-19. We explored whether antibodies against the SARS-CoV-2 spike protein induced by Covid-19 cross-react with platelet factor 4 (PF4/CXLC4), the protein targeted in both VITT and autoimmune heparin-induced thrombocytopenia.Methods: Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared via prediction tools and 3D modelling software (IMED, SIM, MacMYPOL). Sera from 222 PCR-confirmed Covid-19 patients from five European centers were tested by PF4/heparin ELISA, heparin-dependent and PF4-dependent platelet activation assays. Immunogenic reactivity of purified anti-PF4 and anti-PF4/heparin antibodies from patients with VITT were tested against recombinant SARS-CoV-2 spike protein. Results: Three motifs within the spike protein sequence share a potential immunogenic epitope with PF4. Nineteen of 222 (8.6%) Covid-19 patient sera tested positive in the IgG-specific PF4/heparin ELISA, none of which showed platelet activation in the heparin-dependent activation assay, including 10 (4.5%) of the 222 Covid-19 patients who developed thromboembolic complications. Purified anti-PF4 and anti-PF4/heparin antibodies from two VITT patients did not show cross-reactivity to recombinant SARS-CoV-2 spike protein. Conclusions: The antibody responses to PF4 in SARS-CoV-2 infection and after vaccination with COVID-19 Vaccine AstraZeneca differ. Antibodies against SARS-CoV-2 spike protein do not cross-react with PF4 or PF4/heparin complexes through molecular mimicry. These findings make it very unlikely that the intended vaccine-induced immune response against SARS-CoV-2 spike protein would itself induce VITT.

scholarly journals Thrombotic Thrombocytopenia after COVID-19 Vaccination: In Search of the Underlying Mechanism

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 559
Author(s):  
Piotr Rzymski ◽  
Bartłomiej Perek ◽  
Robert Flisiak
Keyword(s):  
Direct Interaction ◽  
Underlying Mechanism ◽  
The United States ◽  
Cross Reactivity ◽  
Spike Protein ◽  
Vaccine Hesitancy ◽  
Future Research ◽  
Platelet Factor ◽  
Precautionary Measures ◽  
Adenoviral Proteins

The rollout of COVID-19 vaccines brings hope for successful pandemic mitigation and getting the transmission of SARS-CoV-2 under control. The vaccines authorized in Europe displayed a good safety profile in the clinical trials. However, during their post-authorization use, unusual thrombotic events associated with thrombocytopenia have rarely been reported for vector vaccines. This led to the temporary suspension of the AZD1222 vaccine (Oxford/AstraZeneca) in various European countries and the Ad26.COV2 vaccine (Janssen/Johnson&Johnson) in the United States, with regulatory bodies launching investigations into potential causal associations. The thromboembolic reactions were also rarely reported after mRNA vaccines. The exact cause of these adverse effects remains to be elucidated. The present paper outlines the hypotheses on the mechanisms behind the very rare thrombotic thrombocytopenia reported after the COVID-19 vaccination, along with currently existing evidence and future research prospects. The following are discussed: (i) the role of antibodies against platelet factor 4 (PF4), (ii) the direct interaction between adenoviral vector and platelets, (iii) the cross-reactivity of antibodies against SARS-CoV-2 spike protein with PF4, (iv) cross-reactivity of anti-adenovirus antibodies and PF4, (v) interaction between spike protein and platelets, (vi) the platelet expression of spike protein and subsequent immune response, and (vii) the platelet expression of other adenoviral proteins and subsequent reactions. It is also plausible that thrombotic thrombocytopenia after the COVID-19 vaccine is multifactorial. The elucidation of the causes of these adverse events is pivotal in taking precautionary measures and managing vaccine hesitancy. It needs to be stressed, however, that the reported cases are currently sporadic and that the benefits of COVID-19 vaccines vastly outweigh their potential risks.

scholarly journals Automated Western immunoblotting detection of anti-SARS-CoV-2 serum antibodies

2021 ◽  
Author(s):  
Sophie Edouard ◽  
Rita Jaafar ◽  
Nicolas Orain ◽  
Philippe Parola ◽  
Philippe Colson ◽  
...  
Keyword(s):  
Negative Control ◽  
Cross Reactivity ◽  
Spike Protein ◽  
Rt Pcr ◽  
Substantial Agreement ◽  
Western Immunoblotting ◽  
Elisa Kit ◽  
Line Test ◽  
Serologic Assay ◽  
Control Samples

AbstractELISA and chemiluminescence serological assays for COVID-19 are currently incorporating only one or two SARS-CoV-2 antigens. We developed an automated Western immunoblotting as a complementary serologic assay for COVID-19. The JessTM Simple Western system, an automated capillary-based assay, was used, incorporating an inactivated SARS-CoV-2 lineage 20a strain as the source of antigen, and total immunoglobulins (IgG, IgM, IgA) detection. In total, 602 sera were tested including 223 from RT-PCR-confirmed COVID-19 patients, 76 from patients diagnosed with seasonal HCoVs and 303 from coronavirus-negative control sera. We also compared this assay with the EUROIMMUN® SARS-CoV-2 IgG ELISA kit. Among 223 sera obtained from RT-PCR-confirmed COVID-19 patients, 180/223 (81%) exhibited reactivity against the nucleocapsid and 70/223 (31%) against the spike protein. Nucleocapsid reactivity was further detected in 9/76 (14%) samples collected from patients diagnosed with seasonal HCoVs and in 15/303 (5%) coronavirus-negative control samples. In the subset of sera collected more than 2 weeks after the onset of symptoms, the sensitivity was 94% and the specificity 93%, the latter value probably reflecting cross-reactivity of SARS-CoV-2 with other coronaviruses. The automated Western immunoblotting presented a substantial agreement (90%) with the compared ELISA (Cohen’s Kappa=0.64). Automated Western immunoblotting may be used as a second line test to monitor exposure of people to HCoVs including SARS-CoV-2.

scholarly journals Molecular Characterization of HOXA2 and HOXA3 Binding Properties

2021 ◽  
Vol 9 (4) ◽  
pp. 55
Author(s):  
Joshua Mallen ◽  
Manisha Kalsan ◽  
Peyman Zarrineh ◽  
Laure Bridoux ◽  
Shandar Ahmad ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Molecular Characterization ◽  
Sequence Motif ◽  
Body Parts ◽  
Binding Affinities ◽  
Binding Properties ◽  
Functional Consequences

The highly conserved HOX homeodomain (HD) transcription factors (TFs) establish the identity of different body parts along the antero–posterior axis of bilaterian animals. Segment diversification and the morphogenesis of different structures is achieved by generating precise patterns of HOX expression along the antero–posterior axis and by the ability of different HOX TFs to instruct unique and specific transcriptional programs. However, HOX binding properties in vitro, characterised by the recognition of similar AT-rich binding sequences, do not account for the ability of different HOX to instruct segment-specific transcriptional programs. To address this problem, we previously compared HOXA2 and HOXA3 binding in vivo. Here, we explore if sequence motif enrichments observed in vivo are explained by binding affinities in vitro. Unexpectedly, we found that the highest enriched motif in HOXA2 peaks was not recognised by HOXA2 in vitro, highlighting the importance of investigating HOX binding in its physiological context. We also report the ability of HOXA2 and HOXA3 to heterodimerise, which may have functional consequences for the HOX patterning function in vivo.

scholarly journals Autoantibodies Against Ubiquitous and Confined Antigens in Patients With Ocular, Neuro-Ophthalmic and Congenital Cerebral Toxoplasmosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Monica Goldberg-Murow ◽  
Carlos Cedillo-Peláez ◽  
Luz Elena Concha-del-Río ◽  
Rashel Cheja-Kalb ◽  
María José Salgar-Henao ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mimicry ◽  
Clinical Manifestations ◽  
Protective Role ◽  
Cross Reactivity ◽  
Ocular Toxoplasmosis ◽  
Cerebral Toxoplasmosis ◽  
Blood Retinal Barrier ◽  
The Central Nervous System

Toxoplasma gondii infection can trigger autoreactivity by different mechanisms. In the case of ocular toxoplasmosis, disruption of the blood-retinal barrier may cause exposure of confined retinal antigens such as recoverin. Besides, cross-reactivity can be induced by molecular mimicry of parasite antigens like HSP70, which shares 76% identity with the human ortholog. Autoreactivity can be a determining factor of clinical manifestations in the eye and in the central nervous system. We performed a prospective observational study to determine the presence of autoantibodies against recoverin and HSP70 by indirect ELISA in the serum of 65 patients with ocular, neuro-ophthalmic and congenital cerebral toxoplasmosis. We found systemic autoantibodies against recoverin and HSP70 in 33.8% and 15.6% of individuals, respectively. The presence of autoantibodies in cases of OT may be related to the severity of clinical manifestations, while in cases with CNS involvement they may have a protective role. Unexpectedly, anti-recoverin antibodies were found in patients with cerebral involvement, without ocular toxoplasmosis; therefore, we analyzed and proved cross-reactivity between recoverin and a brain antigen, hippocalcin, so the immunological phenomenon occurring in one immune-privileged organ (e.g. the central nervous system) could affect the environment of another (egg. the eye).

scholarly journals The Y14-p53 Regulatory Circuit in Megakaryocyte Differentiation and Thrombocytopenia

2020 ◽  
Author(s):  
Chun-Hao Su ◽  
Wei-Ju Liao ◽  
Wei-Chi Ke ◽  
Ruey-Bing Yang ◽  
Woan-Yuh Tarn
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Ex Vivo ◽  
Critical Role ◽  
Platelet Production ◽  
Noncoding Regions ◽  
Regulatory Circuit ◽  
Hel Cells ◽  
Absent Radius ◽  
Megakaryocyte Differentiation

SUMMARYThrombocytopenia-absent radius syndrome is caused by a deletion in chromosome 1q21.1 in trans with RBM8A mutations in the noncoding regions. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, indicating a disorder of platelet production. Rbm8aKOMK mice accumulated immature megakaryocytes in the bone marrow and spleen. Depletion of Y14/RBM8A in human erythroleukemia (HEL) cells inhibited phorbol ester-induced polyploidy and downregulated the signaling pathways associated with megakaryocyte maturation. Accordingly, Rbm8aKOMK mice had reduced expression of surface glycoproteins on platelets and impaired coagulation. Moreover, p53 level was increased in Y14-depleted HEL cells and Rbm8aKOMK megakaryocytes. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKOMK megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Knockout of Trp53 in part restored the platelet count of Rbm8aKOMK mice. These results indicate that the Y14-p53 circuit plays a critical role in megakaryocyte differentiation and platelet production.

Thrombocytosis

2010 ◽  
pp. 4280-4287
Author(s):  
Stefan O. Ciurea ◽  
Ronald Hoffman
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Iron Deficiency ◽  
Blood Loss ◽  
Haematopoietic Stem Cell ◽  
Polycythaemia Vera ◽  
Essential Thrombocythaemia ◽  
Platelet Production ◽  
The Many ◽  
Different Levels

Thrombocytosis describes a platelet count elevated above 450 × 109/litre, which can be (1) primary—including essential thrombocythaemia, chronic myeloid leukaemia, polycythaemia vera and myelodysplastic syndromes; or (2) secondary—including iron deficiency, infection, blood loss, malignancy. Platelets are released from megakaryocytes, whose development is principally regulated by thrombopoietin. This is chiefly produced in the liver and binds to its receptor (c-Mpl) to cause activation via the JAK-STAT signalling pathway at different levels of the platelet production pathway, ranging from the proliferation and survival of haematopoietic stem cell/progenitor cells to megakaryocyte maturation. Thrombopoietin production is increased by a wide variety of stimuli, which explains the many causes of secondary thrombocytosis....

Platelet Survival and Platelet Production in Systemic Lupus Erythematosus (SLE)

1975 ◽  
Author(s):  
A.-L. Bergström ◽  
J. Kutti
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Platelet Count ◽  
Life Span ◽  
Lupus Erythematosus ◽  
Control Group ◽  
Healthy Male ◽  
Systemic Lupus ◽  
Platelet Production ◽  
Platelet Survival ◽  
The Mean

In 16 patients (3 males and 13 females) with SLE platelet survival and platelet production were determined. At the time of study 3 patients received no therapy, 10 were treated with corticosteroids, and the remaining 3 received corticosteroids and azathioprin. The control group consists of 21 healthy male volunteers. In all experiments autologous platelets labelled with 51Cr were employed.The mean peripheral platelet count for the SLE patients was 222,000/μl, range 122,000-347,000/μl. In this group the mean for platelet mean life span (MLS) was 6.8±0,3 (S. E.), range 5.5-9.7 days, and did not differ from the mean for the controls (6.9±0.3 days). In the SLE group the mean platelet turnover was 49,000 ±8,000/μl/day. The corresponding value for the controls was 43,000 ± 3,000/μl/day. The values for platelet MLS and platelet turnover in SLE patients were not related to given therapy.Previously it has been suggested that a state of compensated thrombocytolysis is present i SLE. Our results could, however, not confirm this.

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