The Role of TLR-2 in Lethal COVID-19 Disease Involving Medullary and Resident Lung Megakaryocyte Up-Regulation in the Microthrombosis Mechanism

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2024 May 24

PMID 38786077

Authors

Giuseppe Pannone

Maria Carmela Pedicillo

Ilenia Sara De Stefano

Francesco Angelillis

Raffaele Barile

Chiara Pannone

Giuliana Villani

Francesco Miele

Maurizio Municino

Andrea Ronchi

Gaetano Serviddio

Federica Zito Marino

Renato Franco

Tommaso Colangelo

Rosanna Zamparese

Affiliations

Soon will be listed here.

Abstract

Methods: The aim of this study was to study the expression of platelet glycoprotein IIIa (CD61), playing a critical role in platelet aggregation, together with TRL-2 as a marker of innate immune activation.

Results: A total of 25 patients were investigated, with the majority (24/25, 96%) having co-morbidities and dying from a fatal form of SARS-CoV-2(+) infection (COVID-19+), with 13 men and 12 females ranging in age from 45 to 80 years. When compared to a control group of SARS-CoV-2 (-) negative lungs (COVID-19-), TLR-2 expression was up-regulated in a subset of patients with deadly COVID-19 fatal lung illness. The proportion of Spike-1 (+) patients found by PCR and ISH correlates to the proportion of Spike-S1-positive cases as detected by digital pathology examination. Furthermore, CD61 expression was considerably higher in the lungs of deceased patients. In conclusion, we demonstrate that innate immune prolonged hyperactivation is related to platelet/megakaryocyte over-expression in the lung.

Conclusions: Microthrombosis in deadly COVID-19+ lung disease is associated with an increase in the number of CD61+ platelets and megakaryocytes in the pulmonary interstitium, as well as their functional activation; this phenomenon is associated with increased expression of innate immunity TLR2+ cells, which binds the SARS-CoV-2 E protein, and significantly with the persistence of the Spike-S1 viral sequence.

References

Gordon M, Hoffman R . Growth factors affecting human thrombocytopoiesis: potential agents for the treatment of thrombocytopenia. Blood. 1992; 80(2):302-7. View

Zaid Y, Guessous F . The ongoing enigma of SARS-CoV-2 and platelet interaction. Res Pract Thromb Haemost. 2022; 6(1):e12642. PMC: 8787413. DOI: 10.1002/rth2.12642. View

Lippi G, Plebani M, Henry B . Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020; 506:145-148. PMC: 7102663. DOI: 10.1016/j.cca.2020.03.022. View

Pang L, Weiss M, Poncz M . Megakaryocyte biology and related disorders. J Clin Invest. 2005; 115(12):3332-8. PMC: 1297258. DOI: 10.1172/JCI26720. View

BURSTEIN S . Effects of interleukin 6 on megakaryocytes and on canine platelet function. Stem Cells. 1994; 12(4):386-93. DOI: 10.1002/stem.5530120405. View

Menter D, Kopetz S, Hawk E, Sood A, Loree J, Gresele P . Platelet "first responders" in wound response, cancer, and metastasis. Cancer Metastasis Rev. 2017; 36(2):199-213. PMC: 5709140. DOI: 10.1007/s10555-017-9682-0. View

Carestia A, Kaufman T, Rivadeneyra L, Landoni V, Pozner R, Negrotto S . Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets. J Leukoc Biol. 2015; 99(1):153-62. DOI: 10.1189/jlb.3A0415-161R. View

Yang X, Yang Q, Wang Y, Wu Y, Xu J, Yu Y . Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost. 2020; 18(6):1469-1472. PMC: 9906135. DOI: 10.1111/jth.14848. View

D Atri L, Schattner M . Platelet toll-like receptors in thromboinflammation. Front Biosci (Landmark Ed). 2017; 22(11):1867-1883. DOI: 10.2741/4576. View

10.

Gray-Rodriguez S, Jensen M, Otero-Jimenez M, Hanley B, Swann O, Ward P . Multisystem screening reveals SARS-CoV-2 in neurons of the myenteric plexus and in megakaryocytes. J Pathol. 2022; 257(2):198-217. PMC: 9325073. DOI: 10.1002/path.5878. View

11.

Yin S, Huang M, Li D, Tang N . Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. 2020; 51(4):1107-1110. PMC: 7124128. DOI: 10.1007/s11239-020-02105-8. View

12.

Noetzli L, French S, Machlus K . New Insights Into the Differentiation of Megakaryocytes From Hematopoietic Progenitors. Arterioscler Thromb Vasc Biol. 2019; 39(7):1288-1300. PMC: 6594866. DOI: 10.1161/ATVBAHA.119.312129. View

13.

Basso C, Calabrese F, Sbaraglia M, Del Vecchio C, Carretta G, Saieva A . Feasibility of postmortem examination in the era of COVID-19 pandemic: the experience of a Northeast Italy University Hospital. Virchows Arch. 2020; 477(3):341-347. PMC: 7282199. DOI: 10.1007/s00428-020-02861-1. View

14.

Semeraro F, Ammollo C, Morrissey J, Dale G, Friese P, Esmon N . Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011; 118(7):1952-61. PMC: 3158722. DOI: 10.1182/blood-2011-03-343061. View

15.

Roden A, Vrana J, Koepplin J, Hudson A, Norgan A, Jenkinson G . Comparison of In Situ Hybridization, Immunohistochemistry, and Reverse Transcription-Droplet Digital Polymerase Chain Reaction for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Testing in Tissue. Arch Pathol Lab Med. 2021; 145(7):785-796. DOI: 10.5858/arpa.2021-0008-SA. View

16.

Viksne V, Strumfa I, Sperga M, Ziemelis J, Abolins J . Pathological Changes in the Lungs of Patients with a Lethal COVID-19 Clinical Course. Diagnostics (Basel). 2022; 12(11). PMC: 9689224. DOI: 10.3390/diagnostics12112808. View

17.

Takeuchi O, Akira S . Pattern recognition receptors and inflammation. Cell. 2010; 140(6):805-20. DOI: 10.1016/j.cell.2010.01.022. View

18.

Hamzeh-Cognasse H, Berthelot P, Tardy B, Pozzetto B, Bourlet T, Laradi S . Platelet toll-like receptors are crucial sensors of infectious danger moieties. Platelets. 2018; 29(6):533-540. DOI: 10.1080/09537104.2018.1445842. View

19.

Lefrancais E, Ortiz-Munoz G, Caudrillier A, Mallavia B, Liu F, Sayah D . The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017; 544(7648):105-109. PMC: 5663284. DOI: 10.1038/nature21706. View

20.

Hooper J, Padera R, Dolhnikoff M, Ferraz da Silva L, Duarte-Neto A, Kapp M . A Postmortem Portrait of the Coronavirus Disease 2019 (COVID-19) Pandemic: A Large Multi-institutional Autopsy Survey Study. Arch Pathol Lab Med. 2021; 145(5):529-535. DOI: 10.5858/arpa.2020-0786-SA. View