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image of TLR2 Activation as a Marker of Severe COVID-19 and a Potential Therapeutic Target

Abstract

SARS-CoV-2-induced COVID-19 has been a serious public health problem, resulting in millions of lives lost over the previous three years. Although the direct infection caused by virus invasion is important for the pathobiology of COVID-19, the hyperinflammatory response and tissue injury are major contributors in critically ill patients. As a host sensor, toll-like receptor 2 (TLR2) recognizes multiple pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), producing various inflammatory cytokines and inflammatory cell death signals, which are central to the inflammatory pathology observed in COVID-19. The objectives of this narrative review are to summarize the role of TLR2 activation during SARS-CoV-2 infection and emphasize the importance of SARS-CoV-2 viral proteins in TLR2 activation. Additionally, we presented some compounds related to TLR2 regulation clinically or experimentally, which may provide new insights into targets for pharmaceutical discovery and development.

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2024-10-31
2024-11-26
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References

  1. Tay M.Z. Poh C.M. Rénia L. MacAry P.A. Ng L.F.P. The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 2020 20 6 363 374 10.1038/s41577‑020‑0311‑8 32346093
    [Google Scholar]
  2. Clinical Spectrum. Available from:https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/(accessed on 2-10-2024)
  3. Kevadiya B.D. Machhi J. Herskovitz J. Oleynikov M.D. Blomberg W.R. Bajwa N. Soni D. Das S. Hasan M. Patel M. Senan A.M. Gorantla S. McMillan J. Edagwa B. Eisenberg R. Gurumurthy C.B. Reid S.P.M. Punyadeera C. Chang L. Gendelman H.E. Diagnostics for SARS-CoV-2 infections. Nat. Mater. 2021 20 5 593 605 10.1038/s41563‑020‑00906‑z 33589798
    [Google Scholar]
  4. Lee S. Channappanavar R. Kanneganti T.D. Coronaviruses: Innate immunity, inflammasome activation, inflammatory cell death, and cytokines. Trends Immunol. 2020 41 12 1083 1099 10.1016/j.it.2020.10.005 33153908
    [Google Scholar]
  5. Bader S.M. Cooney J.P. Pellegrini M. Doerflinger M. Programmed cell death: the pathways to severe COVID-19? Biochem. J. 2022 479 5 609 628 10.1042/BCJ20210602 35244141
    [Google Scholar]
  6. Morais da Silva M. Lira de Lucena A.S. Paiva Júnior S.S.L. Florêncio De Carvalho V.M. Santana de Oliveira P.S. da Rosa M.M. Barreto de Melo Rego M.J. Pitta M.G.R. Pereira M.C. Cell death mechanisms involved in cell injury caused by SARS-CoV-2. Rev. Med. Virol. 2022 32 3 e2292 10.1002/rmv.2292 34590761
    [Google Scholar]
  7. Merad M. Martin J.C. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat. Rev. Immunol. 2020 20 6 355 362 10.1038/s41577‑020‑0331‑4 32376901
    [Google Scholar]
  8. Jafarzadeh A. Chauhan P. Saha B. Jafarzadeh S. Nemati M. Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions. Life Sci. 2020 257 118102 10.1016/j.lfs.2020.118102 32687918
    [Google Scholar]
  9. Zhou R. To K.K.W. Wong Y.C. Liu L. Zhou B. Li X. Huang H. Mo Y. Luk T.Y. Lau T.T.K. Yeung P. Chan W.M. Wu A.K.L. Lung K.C. Tsang O.T.Y. Leung W.S. Hung I.F.N. Yuen K.Y. Chen Z. Acute SARS-CoV-2 infection impairs dendritic cell and t cell responses. Immunity 2020 53 4 864 877.e5 10.1016/j.immuni.2020.07.026 32791036
    [Google Scholar]
  10. Ye C.H. Hsu W.L. Peng G.R. Yu W.C. Lin W.C. Hu S. Yu S.H. Role of the immune microenvironment in sars-cov-2 infection. Cell Transplant. 2021 30 10632 10.1177/09636897211010632 33949207
    [Google Scholar]
  11. Ragab D. Salah Eldin H. Taeimah M. Khattab R. Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Front. Immunol. 2020 11 1446 10.3389/fimmu.2020.01446 32612617
    [Google Scholar]
  12. Jamilloux Y. Henry T. Belot A. Viel S. Fauter M. El Jammal T. Walzer T. François B. Sève P. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun. Rev. 2020 19 7 102567 10.1016/j.autrev.2020.102567 32376392
    [Google Scholar]
  13. Lucas C. Wong P. Klein J. Castro T.B.R. Silva J. Sundaram M. Ellingson M.K. Mao T. Oh J.E. Israelow B. Takahashi T. Tokuyama M. Lu P. Venkataraman A. Park A. Mohanty S. Wang H. Wyllie A.L. Vogels C.B.F. Earnest R. Lapidus S. Ott I.M. Moore A.J. Muenker M.C. Fournier J.B. Campbell M. Odio C.D. Casanovas-Massana A. Obaid A. Lu-Culligan A. Nelson A. Brito A. Nunez A. Martin A. Watkins A. Geng B. Kalinich C. Harden C. Todeasa C. Jensen C. Kim D. McDonald D. Shepard D. Courchaine E. White E.B. Song E. Silva E. Kudo E. DeIuliis G. Rahming H. Park H-J. Matos I. Nouws J. Valdez J. Fauver J. Lim J. Rose K-A. Anastasio K. Brower K. Glick L. Sharma L. Sewanan L. Knaggs L. Minasyan M. Batsu M. Petrone M. Kuang M. Nakahata M. Campbell M. Linehan M. Askenase M.H. Simonov M. Smolgovsky M. Sonnert N. Naushad N. Vijayakumar P. Martinello R. Datta R. Handoko R. Bermejo S. Prophet S. Bickerton S. Velazquez S. Alpert T. Rice T. Khoury-Hanold W. Peng X. Yang Y. Cao Y. Strong Y. Herbst R. Shaw A.C. Medzhitov R. Schulz W.L. Grubaugh N.D. Dela Cruz C. Farhadian S. Ko A.I. Omer S.B. Iwasaki A. Yale IMPACT Team Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 2020 584 7821 463 469 10.1038/s41586‑020‑2588‑y 32717743
    [Google Scholar]
  14. Akira S. Uematsu S. Takeuchi O. Pathogen recognition and innate immunity. Cell 2006 124 4 783 801 10.1016/j.cell.2006.02.015 16497588
    [Google Scholar]
  15. Cao X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 2016 16 1 35 50 10.1038/nri.2015.8 26711677
    [Google Scholar]
  16. Choudhury A. Mukherjee S. In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs. J. Med. Virol. 2020 92 10 2105 2113 10.1002/jmv.25987 32383269
    [Google Scholar]
  17. Yu L. Wang L. Chen S. Endogenous toll-like receptor ligands and their biological significance. J. Cell. Mol. Med. 2010 14 11 2592 2603 10.1111/j.1582‑4934.2010.01127.x 20629986
    [Google Scholar]
  18. Wada J. Makino H. Innate immunity in diabetes and diabetic nephropathy. Nat. Rev. Nephrol. 2016 12 1 13 26 10.1038/nrneph.2015.175 26568190
    [Google Scholar]
  19. Sang W. Zhong Z. Linghu K. Xiong W. Tse A.K.W. Cheang W.S. Yu H. Wang Y. Siegesbeckia pubescens Makino inhibits Pam3CSK4-induced inflammation in RAW 264.7 macrophages through suppressing TLR1/TLR2-mediated NF-κB activation. Chin. Med. 2018 13 1 37 10.1186/s13020‑018‑0193‑x 30002726
    [Google Scholar]
  20. Lan F. Yue X. Ren G. Li H. Ping L. Wang Y. Xia T. miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-κB signaling pathway. Int. J. Radiat. Oncol. Biol. Phys. 2015 91 1 73 81 10.1016/j.ijrobp.2014.09.021 25442346
    [Google Scholar]
  21. Śmiałek-Bartyzel J. Bzowska M. Mężyk-Kopeć R. Kwissa M. Mak P. BacSp222 bacteriocin as a novel ligand for TLR2/TLR6 heterodimer. Inflamm. Res. 2023 72 5 915 928 10.1007/s00011‑023‑01721‑3 36964784
    [Google Scholar]
  22. Luo X. Bao X. Weng X. Bai X. Feng Y. Huang J. Liu S. Jia H. Yu B. The protective effect of quercetin on macrophage pyroptosis via TLR2/Myd88/NF-κB and ROS/AMPK pathway. Life Sci. 2022 291 120064 10.1016/j.lfs.2021.120064 34688696
    [Google Scholar]
  23. Wang H. Bi C. Wang Y. Sun J. Meng X. Li J. Selenium ameliorates Staphylococcus aureus-induced inflammation in bovine mammary epithelial cells by inhibiting activation of TLR2, NF-κB and MAPK signaling pathways. BMC Vet. Res. 2018 14 1 197 10.1186/s12917‑018‑1508‑y 29925372
    [Google Scholar]
  24. Fang L. Shen Q. Wu H. He F. Ding P. Xu K. Yan X. Wang M. Li S. Liu R. TLR2 favors OVA-induced allergic airway inflammation in mice through JNK signaling pathway with activation of autophagy. Life Sci. 2020 256 117896 10.1016/j.lfs.2020.117896 32504758
    [Google Scholar]
  25. Wilson A.S. Randall K.L. Pettitt J.A. Ellyard J.I. Blumenthal A. Enders A. Quah B.J. Bopp T. Parish C.R. Brüstle A. Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2. Nat. Commun. 2022 13 1 528 10.1038/s41467‑022‑28172‑4 35082281
    [Google Scholar]
  26. Sung P.S. Yang S.P. Peng Y.C. Sun C.P. Tao M.H. Hsieh S.L. CLEC5A and TLR2 are critical in SARS-CoV-2-induced NET formation and lung inflammation. J. Biomed. Sci. 2022 29 1 52 10.1186/s12929‑022‑00832‑z 35820906
    [Google Scholar]
  27. Antoni A.C. Pylaeva E. Budeus B. Jablonska J. Klein-Hitpaß L. Dudda M. Flohé S.B. TLR2-induced CD8+ T-cell deactivation shapes dendritic cell differentiation in the bone marrow during sepsis. Front. Immunol. 2022 13 945409 10.3389/fimmu.2022.945409 36148245
    [Google Scholar]
  28. Chen Y. Zhou Y. Wang Q. Chen J. Chen H. Xie H. Li L. Conciliatory Anti-Allergic Decoction Attenuates Pyroptosis in RSV-Infected Asthmatic Mice and Lipopolysaccharide (LPS)-Induced 16HBE Cells by Inhibiting TLR3/NLRP3/NF-κB/IRF3 Signaling Pathway. J. Immunol. Res. 2022 2022 1 16 10.1155/2022/1800401 36213326
    [Google Scholar]
  29. Hu X. Chen L. Li T. Zhao M. TLR3 is involved in paraquat-induced acute renal injury. Life Sci. 2019 223 102 109 10.1016/j.lfs.2019.03.029 30876938
    [Google Scholar]
  30. Yu Q. Nie S.P. Wang J.Q. Yin P.F. Huang D.F. Li W.J. Xie M.Y. Toll-like receptor 4-mediated ROS signaling pathway involved in Ganoderma atrum polysaccharide-induced tumor necrosis factor-α secretion during macrophage activation. Food Chem. Toxicol. 2014 66 14 22 10.1016/j.fct.2014.01.018 24447977
    [Google Scholar]
  31. Wu L. Du L. Ju Q. Chen Z. Ma Y. Bai T. Ji G. Wu Y. Liu Z. Shao Y. Peng X. Silencing TLR4/MyD88/NF-κB Signaling Pathway Alleviated Inflammation of Corneal Epithelial Cells Infected by ISE. Inflammation 2021 44 2 633 644 10.1007/s10753‑020‑01363‑1 33174138
    [Google Scholar]
  32. Zhu K. Zhu X. Sun S. Yang W. Liu S. Tang Z. Zhang R. Li J. Shen T. Hei M. Inhibition of TLR4 prevents hippocampal hypoxic-ischemic injury by regulating ferroptosis in neonatal rats. Exp. Neurol. 2021 345 113828 10.1016/j.expneurol.2021.113828 34343528
    [Google Scholar]
  33. Yan J. Shen S. He Y. Li Z. TLR5 silencing reduced hyperammonaemia-induced liver injury by inhibiting oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals. Chem. Biol. Interact. 2019 299 102 110 10.1016/j.cbi.2018.11.026 30508503
    [Google Scholar]
  34. Sharma N. Akhade A.S. Qadri A. Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells. J. Leukoc. Biol. 2013 93 4 521 528 10.1189/jlb.0712328 23345392
    [Google Scholar]
  35. Ifuku M. Hinkelmann L. Kuhrt L.D. Efe I.E. Kumbol V. Buonfiglioli A. Krüger C. Jordan P. Fulde M. Noda M. Kettenmann H. Lehnardt S. Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury. Acta Neuropathol. Commun. 2020 8 1 159 10.1186/s40478‑020‑01031‑3 32912327
    [Google Scholar]
  36. Into T. Kiura K. Yasuda M. Kataoka H. Inoue N. Hasebe A. Takeda K. Akira S. Shibata K. Stimulation of human Toll-like receptor (TLR) 2 and TLR6 with membrane lipoproteins of Mycoplasma fermentans induces apoptotic cell death after NF-κB activation. Cell. Microbiol. 2004 6 2 187 199 10.1046/j.1462‑5822.2003.00356.x 14706104
    [Google Scholar]
  37. Lu Z. Chang L. Du Q. Huang Y. Zhang X. Wu X. Zhang J. Li R. Zhang Z. Zhang W. Zhao X. Tong D. Arctigenin Induces an Activation Response in Porcine Alveolar Macrophage Through TLR6-NOX2-MAPKs Signaling Pathway. Front. Pharmacol. 2018 9 475 10.3389/fphar.2018.00475 29867481
    [Google Scholar]
  38. de Marcken M. Dhaliwal K. Danielsen A.C. Gautron A.S. Dominguez-Villar M. TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection. Sci. Signal. 2019 12 605 eaaw1347 10.1126/scisignal.aaw1347 31662487
    [Google Scholar]
  39. Li L. Liu X. Sanders K.L. Edwards J.L. Ye J. Si F. Gao A. Huang L. Hsueh E.C. Ford D.A. Hoft D.F. Peng G. TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy. Cell Metab. 2019 29 1 103 123.e5 10.1016/j.cmet.2018.09.020 30344014
    [Google Scholar]
  40. Lai J.H. Wang M.Y. Huang C.Y. Wu C.H. Hung L.F. Yang C.Y. Ke P.Y. Luo S.F. Liu S.J. Ho L.J. Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells. EMBO Rep. 2018 19 8 e46182 10.15252/embr.201846182 29880709
    [Google Scholar]
  41. De Nardo D. De Nardo C.M. Nguyen T. Hamilton J.A. Scholz G.M. Signaling crosstalk during sequential TLR4 and TLR9 activation amplifies the inflammatory response of mouse macrophages. J. Immunol. 2009 183 12 8110 8118 10.4049/jimmunol.0901031 19923461
    [Google Scholar]
  42. Leadbetter E.A. Rifkin I.R. Hohlbaum A.M. Beaudette B.C. Shlomchik M.J. Marshak-Rothstein A. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002 416 6881 603 607 10.1038/416603a 11948342
    [Google Scholar]
  43. Henrick B.M. Yao X.D. Zahoor M.A. Abimiku A. Osawe S. Rosenthal K.L. TLR10 Senses HIV-1 Proteins and Significantly Enhances HIV-1 Infection. Front. Immunol. 2019 10 482 10.3389/fimmu.2019.00482 30930906
    [Google Scholar]
  44. Kirschning C.J. Schumann R.R. TLR2: cellular sensor for microbial and endogenous molecular patterns. Curr. Top. Microbiol. Immunol. 2002 270 121 144 10.1007/978‑3‑642‑59430‑4_8 12467248
    [Google Scholar]
  45. Brennan J.J. Gilmore T.D. Evolutionary Origins of Toll-like Receptor Signaling. Mol. Biol. Evol. 2018 35 7 1576 1587 10.1093/molbev/msy050 29590394
    [Google Scholar]
  46. Narayanan K.B. Park H.H. Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways. Apoptosis 2015 20 2 196 209 10.1007/s10495‑014‑1073‑1 25563856
    [Google Scholar]
  47. Kang J.Y. Nan X. Jin M.S. Youn S.J. Ryu Y.H. Mah S. Han S.H. Lee H. Paik S.G. Lee J.O. Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer. Immunity 2009 31 6 873 884 10.1016/j.immuni.2009.09.018 19931471
    [Google Scholar]
  48. Gong Y. Zou L. Feng Y. Li D. Cai J. Chen D. Chao W. Importance of Toll-like receptor 2 in mitochondrial dysfunction during polymicrobial sepsis. Anesthesiology 2014 121 6 1236 1247 10.1097/ALN.0000000000000470 25272245
    [Google Scholar]
  49. Kumar S. Duan Q. Wu R. Harris E.N. Su Q. Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis. Adv. Drug Deliv. Rev. 2021 176 113869 10.1016/j.addr.2021.113869 34280515
    [Google Scholar]
  50. Sims G.P. Rowe D.C. Rietdijk S.T. Herbst R. Coyle A.J. HMGB1 and RAGE in inflammation and cancer. Annu. Rev. Immunol. 2010 28 1 367 388 10.1146/annurev.immunol.021908.132603 20192808
    [Google Scholar]
  51. Kaufmann A. Musset B. Limberg S.H. Renigunta V. Sus R. Dalpke A.H. Heeg K.M. Robaye B. Hanley P.J. “Host tissue damage” signal ATP promotes non-directional migration and negatively regulates toll-like receptor signaling in human monocytes. J. Biol. Chem. 2005 280 37 32459 32467 10.1074/jbc.M505301200 16030017
    [Google Scholar]
  52. Takeda K. Akira S. TLR signaling pathways. Semin. Immunol. 2004 16 1 3 9 10.1016/j.smim.2003.10.003 14751757
    [Google Scholar]
  53. Kawai T. Akira S. TLR signaling. Semin. Immunol. 2007 19 1 24 32 10.1016/j.smim.2006.12.004 17275323
    [Google Scholar]
  54. Lim K.H. Staudt L.M. Toll-like receptor signaling. Cold Spring Harb. Perspect. Biol. 2013 5 1 a011247 10.1101/cshperspect.a011247 23284045
    [Google Scholar]
  55. Wang H. Huang X. Xu P. Liu X. Zhou Z. Wang F. Li J. Wang Y. Xian X. Liu G. Huang W. Apolipoprotein C3 aggravates diabetic nephropathy in type 1 diabetes by activating the renal TLR2/NF-κB pathway. Metabolism 2021 119 154740 10.1016/j.metabol.2021.154740 33639183
    [Google Scholar]
  56. Huang R. Hu Z. Chen X. Cao Y. Li H. Zhang H. Li Y. Liang L. Feng Y. Wang Y. Su W. Kong Z. Melgiri N.D. Jiang L. Li X. Du J. Chen Y. The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis. Adv. Sci. (Weinh.) 2021 8 19 2004162 10.1002/advs.202004162 34378353
    [Google Scholar]
  57. Song Z. Chen J. Ji Y. Yang Q. Chen Y. Wang F. Wu Z. Amuc attenuates high-fat diet-induced metabolic disorders linked to the regulation of fatty acid metabolism, bile acid metabolism, and the gut microbiota in mice. Int. J. Biol. Macromol. 2023 242 Pt 2 124650 10.1016/j.ijbiomac.2023.124650 37119914
    [Google Scholar]
  58. Morrissey S.M. Zhang F. Ding C. Montoya-Durango D.E. Hu X. Yang C. Wang Z. Yuan F. Fox M. Zhang H. Guo H. Tieri D. Kong M. Watson C.T. Mitchell R.A. Zhang X. McMasters K.M. Huang J. Yan J. Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming. Cell Metab. 2021 33 10 2040 2058.e10 10.1016/j.cmet.2021.09.002 34559989
    [Google Scholar]
  59. Feng H. Guo Z. Chen X. Liu K. Li H. Jia W. Wang C. Luo F. Ji X. Zhang T. Zhao R. Cheng X. Excessive HSP70/TLR2 activation leads to remodeling of the tumor immune microenvironment to resist chemotherapy sensitivity of mFOLFOX in colorectal cancer. Clin. Immunol. 2022 245 109157 10.1016/j.clim.2022.109157 36244673
    [Google Scholar]
  60. He Y. Lawlor N.T. Newburg D.S. Human Milk Components Modulate Toll-Like Receptor–Mediated Inflammation. Adv. Nutr. 2016 7 1 102 111 10.3945/an.115.010090 26773018
    [Google Scholar]
  61. Diehl G.E. Yue H.H. Hsieh K. Kuang A.A. Ho M. Morici L.A. Lenz L.L. Cado D. Riley L.W. Winoto A. TRAIL-R as a negative regulator of innate immune cell responses. Immunity 2004 21 6 877 889 10.1016/j.immuni.2004.11.008 15589175
    [Google Scholar]
  62. Zhang G. Ghosh S. Negative regulation of toll-like receptor-mediated signaling by Tollip. J. Biol. Chem. 2002 277 9 7059 7065 10.1074/jbc.M109537200 11751856
    [Google Scholar]
  63. Wu H.M. Zhao C.C. Xie Q.M. Xu J. Fei G.H. TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation. Front. Immunol. 2020 11 172 10.3389/fimmu.2020.00172 32117301
    [Google Scholar]
  64. Carreto-Binaghi L.E. Herrera M.T. Guzmán-Beltrán S. Juárez E. Sarabia C. Salgado-Cantú M.G. Juarez-Carmona D. Guadarrama-Pérez C. González Y. Reduced IL-8 Secretion by NOD-like and Toll-like Receptors in Blood Cells from COVID-19 Patients. Biomedicines 2023 11 4 1078 10.3390/biomedicines11041078 37189696
    [Google Scholar]
  65. Alhabibi A.M. Hassan A.S. Abd Elbaky N.M. Eid H.A. III Khalifa M.A.A.A. Wahab M.A. Althoqapy A.A. Abdou A.E. Zakaria D.M. Nassef E.M. Kasim S.A. Saleh O.I. Elsheikh A.A. Lotfy M. Sayed A. Impact of Toll-Like Receptor 2 and 9 Gene Polymorphisms on COVID-19: Susceptibility, Severity, and Thrombosis. J. Inflamm. Res. 2023 16 665 675 10.2147/JIR.S394927 36825132
    [Google Scholar]
  66. Salamaikina S. Karnaushkina M. Korchagin V. Litvinova M. Mironov K. Akimkin V. TLRs Gene Polymorphisms Associated with Pneumonia before and during COVID-19 Pandemic. Diagnostics (Basel) 2022 13 1 121 10.3390/diagnostics13010121 36611413
    [Google Scholar]
  67. Fortmann S.D. Patton M.J. Frey B.F. Tipper J.L. Reddy S.B. Vieira C.P. Hanumanthu V.S. Sterrett S. Floyd J.L. Prasad R. Zucker J.D. Crouse A.B. Huls F. Chkheidze R. Li P. Erdmann N.B. Harrod K.S. Gaggar A. Goepfert P.A. Grant M.B. Might M. Circulating SARS-CoV-2+ megakaryocytes are associated with severe viral infection in COVID-19. Blood Adv. 2023 7 15 4200 4214 10.1182/bloodadvances.2022009022 36920790
    [Google Scholar]
  68. Bagheri-Hosseinabadi Z. Mohammadizadeh Ranjbar F. Nassiri M. Amiri A. Abbasifard M. Nasopharyngeal epithelial cells from patients with coronavirus disease 2019 express abnormal levels of Toll-like receptors. Pathog. Glob. Health 2023 117 4 401 408 10.1080/20477724.2023.2166378 36651678
    [Google Scholar]
  69. Milara J. Martínez-Expósito F. Montero P. Roger I. Bayarri M.A. Ribera P. Oishi-Konari M.N. Alba-García J.R. Zapater E. Cortijo J. N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro. Int. J. Mol. Sci. 2022 23 23 14518 10.3390/ijms232314518 36498845
    [Google Scholar]
  70. Beltrán-Camacho L. Eslava-Alcón S. Rojas-Torres M. Sánchez-Morillo D. Martinez-Nicolás M.P. Martín-Bermejo V. de la Torre I.G. Berrocoso E. Moreno J.A. Moreno-Luna R. Durán-Ruiz M.C. The serum of COVID-19 asymptomatic patients up-regulates proteins related to endothelial dysfunction and viral response in circulating angiogenic cells ex-vivo. Mol. Med. 2022 28 1 40 10.1186/s10020‑022‑00465‑w 35397534
    [Google Scholar]
  71. Sultan R.H. Elesawy B.H. Ali T.M. Abdallah M. Assal H.H. Ahmed A.E. Ahmed O.M. Correlations between Kidney and Heart Function Bioindicators and the Expressions of Toll-Like, ACE2, and NRP-1 Receptors in COVID-19. Vaccines (Basel) 2022 10 7 1106 10.3390/vaccines10071106 35891270
    [Google Scholar]
  72. Dotan A. Muller S. Kanduc D. David P. Halpert G. Shoenfeld Y. The SARS-CoV-2 as an instrumental trigger of autoimmunity. Autoimmun. Rev. 2021 20 4 102792 10.1016/j.autrev.2021.102792 33610751
    [Google Scholar]
  73. Cambier S. Metzemaekers M. de Carvalho A.C. Nooyens A. Jacobs C. Vanderbeke L. Malengier-Devlies B. Gouwy M. Heylen E. Meersseman P. Hermans G. Wauters E. Wilmer A. Schols D. Matthys P. Opdenakker G. Marques R.E. Wauters J. Vandooren J. Proost P. CONTAGIOUS Consortium Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza. JCI Insight 2022 7 1 e155055 10.1172/jci.insight.155055 34793331
    [Google Scholar]
  74. Marchand L. Pecquet M. Luyton C. Type 1 diabetes onset triggered by COVID-19. Acta Diabetol. 2020 57 10 1265 1266 10.1007/s00592‑020‑01570‑0 32653960
    [Google Scholar]
  75. Root-Bernstein R. From Co-Infections to Autoimmune Disease via Hyperactivated Innate Immunity: COVID-19 Autoimmune Coagulopathies, Autoimmune Myocarditis and Multisystem Inflammatory Syndrome in Children. Int. J. Mol. Sci. 2023 24 3 3001 10.3390/ijms24033001 36769320
    [Google Scholar]
  76. Al-kuraishy H.M. Al-Gareeb A.I. Alkazmi L. Habotta O.A. Batiha G.E.S. High-mobility group box 1 (HMGB1) in COVID-19: extrapolation of dangerous liaisons. Inflammopharmacology 2022 30 3 811 820 10.1007/s10787‑022‑00988‑y 35471628
    [Google Scholar]
  77. Sung P.S. Huang T.F. Hsieh S.L. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nat. Commun. 2019 10 1 2402 10.1038/s41467‑019‑10360‑4 31160588
    [Google Scholar]
  78. Sung P.S. Hsieh S.L. C-type lectins and extracellular vesicles in virus-induced NETosis. J. Biomed. Sci. 2021 28 1 46 10.1186/s12929‑021‑00741‑7 34116654
    [Google Scholar]
  79. Salehi-Vaziri M. Fazlalipour M. Seyed Khorrami S.M. Azadmanesh K. Pouriayevali M.H. Jalali T. Shoja Z. Maleki A. The ins and outs of SARS-CoV-2 variants of concern (VOCs). Arch. Virol. 2022 167 2 327 344 10.1007/s00705‑022‑05365‑2 35089389
    [Google Scholar]
  80. Kayesh M.E.H. Kohara M. Tsukiyama-Kohara K. An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants. Viruses 2021 13 11 2302 10.3390/v13112302 34835108
    [Google Scholar]
  81. Priyangi Kuruppuarachchi K.A.P. Jang Y. Seo S.H. Comparison of the Pathogenicity of SARS-CoV-2 Delta and Omicron Variants by Analyzing the Expression Patterns of Immune Response Genes in K18-hACE2 Transgenic Mice. Frontiers in Bioscience-Landmark 2022 27 11 316 10.31083/j.fbl2711316 36472114
    [Google Scholar]
  82. Kircheis R. Planz O. Could a Lower Toll-like Receptor (TLR) and NF-κB Activation Due to a Changed Charge Distribution in the Spike Protein Be the Reason for the Lower Pathogenicity of Omicron? Int. J. Mol. Sci. 2022 23 11 5966 10.3390/ijms23115966 35682644
    [Google Scholar]
  83. Kircheis R. In Silico Analyses Indicate a Lower Potency for Dimerization of TLR4/MD-2 as the Reason for the Lower Pathogenicity of Omicron Compared to Wild-Type Virus and Earlier SARS-CoV-2 Variants. Int. J. Mol. Sci. 2024 25 10 5451 10.3390/ijms25105451 38791489
    [Google Scholar]
  84. Li D. Wu M. Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther. 2021 6 1 291 10.1038/s41392‑021‑00687‑0 34344870
    [Google Scholar]
  85. Yadav R. Chaudhary J.K. Jain N. Chaudhary P.K. Khanra S. Dhamija P. Sharma A. Kumar A. Handu S. Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19. Cells 2021 10 4 821 10.3390/cells10040821 33917481
    [Google Scholar]
  86. Zheng M. Karki R. Williams E.P. Yang D. Fitzpatrick E. Vogel P. Jonsson C.B. Kanneganti T.D. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nat. Immunol. 2021 22 7 829 838 10.1038/s41590‑021‑00937‑x 33963333
    [Google Scholar]
  87. Huang H. Li X. Zha D. Lin H. Yang L. Wang Y. Xu L. Wang L. Lei T. Zhou Z. Xiao Y.F. Xin H.B. Fu M. Qian Y. SARS-CoV-2 E protein-induced THP-1 pyroptosis is reversed by Ruscogenin. Biochem. Cell Biol. 2023 101 4 303 312 10.1139/bcb‑2022‑0359 36927169
    [Google Scholar]
  88. van der Sluis R.M. Cham L.B. Gris-Oliver A. Gammelgaard K.R. Pedersen J.G. Idorn M. Ahmadov U. Hernandez S.S. Cémalovic E. Godsk S.H. Thyrsted J. Gunst J.D. Nielsen S.D. Jørgensen J.J. Bjerg T.W. Laustsen A. Reinert L.S. Olagnier D. Bak R.O. Kjolby M. Holm C.K. Tolstrup M. Paludan S.R. Kristensen L.S. Søgaard O.S. Jakobsen M.R. TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection. EMBO J. 2022 41 10 e109622 10.15252/embj.2021109622 35178710
    [Google Scholar]
  89. Giannakopoulos S. Strange D.P. Jiyarom B. Abdelaal O. Bradshaw A.W. Nerurkar V.R. Ward M.A. Bakse J. Yap J. Vanapruks S. Boisvert W.A. Tallquist M.D. Shikuma C. Sadri-Ardekani H. Clapp P. Murphy S.V. Verma S. In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury. PLoS Pathog. 2023 19 5 e1011409 10.1371/journal.ppat.1011409 37200377
    [Google Scholar]
  90. Menden H.L. Mabry S.M. Venkatraman A. Xia S. DeFranco D.B. Yu W. Sampath V. The SARS-CoV-2 E protein induces Toll-like receptor 2-mediated neonatal lung injury in a model of COVID-19 viremia that is rescued by the glucocorticoid ciclesonide. Am. J. Physiol. Lung Cell. Mol. Physiol. 2023 324 5 L722 L736 10.1152/ajplung.00410.2022 36976925
    [Google Scholar]
  91. Su W. Ju J. Gu M. Wang X. Liu S. Yu J. Mu D. SARS-CoV-2 envelope protein triggers depression-like behaviors and dysosmia via TLR2-mediated neuroinflammation in mice. J. Neuroinflammation 2023 20 1 110 10.1186/s12974‑023‑02786‑x 37158916
    [Google Scholar]
  92. Planès R. Bert J.B. Tairi S. BenMohamed L. Bahraoui E. SARS-CoV-2 Envelope (E) Protein Binds and Activates TLR2 Pathway: A Novel Molecular Target for COVID-19 Interventions. Viruses 2022 14 5 999 10.3390/v14050999 35632741
    [Google Scholar]
  93. Khan S. Shafiei M.S. Longoria C. Schoggins J.W. Savani R.C. Zaki H. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway. eLife 2021 10 e68563 10.7554/eLife.68563 34866574
    [Google Scholar]
  94. Umar S. Palasiewicz K. Meyer A. Kumar P. Prabhakar B.S. Volin M.V. Rahat R. Al-Awqati M. Chang H.J. Zomorrodi R.K. Rehman J. Shahrara S. Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming. Cell. Mol. Life Sci. 2022 79 6 301 10.1007/s00018‑022‑04329‑8 35588018
    [Google Scholar]
  95. Al-Qahtani A.A. Pantazi I. Alhamlan F.S. Alothaid H. Matou-Nasri S. Sourvinos G. Vergadi E. Tsatsanis C. SARS-CoV-2 modulates inflammatory responses of alveolar epithelial type II cells via PI3K/AKT pathway. Front. Immunol. 2022 13 1020624 10.3389/fimmu.2022.1020624 36389723
    [Google Scholar]
  96. Rahman M. Irmler M. Keshavan S. Introna M. Beckers J. Palmberg L. Johanson G. Ganguly K. Upadhyay S. Differential Effect of SARS-CoV-2 Spike Glycoprotein 1 on Human Bronchial and Alveolar Lung Mucosa Models: Implications for Pathogenicity. Viruses 2021 13 12 2537 10.3390/v13122537 34960806
    [Google Scholar]
  97. Tyrkalska S.D. Martínez-López A. Pedoto A. Candel S. Cayuela M.L. Mulero V. The Spike protein of SARS-CoV-2 signals via Tlr2 in zebrafish. Dev. Comp. Immunol. 2023 140 104626 10.1016/j.dci.2022.104626 36587712
    [Google Scholar]
  98. Frank M.G. Nguyen K.H. Ball J.B. Hopkins S. Kelley T. Baratta M.V. Fleshner M. Maier S.F. SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties. Brain Behav. Immun. 2022 100 267 277 10.1016/j.bbi.2021.12.007 34915155
    [Google Scholar]
  99. Qian Y. Lei T. Patel P.S. Lee C.H. Monaghan-Nichols P. Xin H.B. Qiu J. Fu M. Direct Activation of Endothelial Cells by SARS-CoV-2 Nucleocapsid Protein Is Blocked by Simvastatin. J. Virol. 2021 95 23 e01396-21 10.1128/JVI.01396‑21 34549987
    [Google Scholar]
  100. Boodhoo N. Matsuyama-kato A. Shojadoost B. Behboudi S. Sharif S. The severe acute respiratory syndrome coronavirus 2 non-structural proteins 1 and 15 proteins mediate antiviral immune evasion. Current Research in Virological Science 2022 3 100021 10.1016/j.crviro.2022.100021 35187506
    [Google Scholar]
  101. Cao Y. Yang R. Lee I. Zhang W. Sun J. Wang W. Meng X. Characterization of the SARS-CoV -2 E Protein: Sequence, Structure, Viroporin, and Inhibitors. Protein Sci. 2021 30 6 1114 1130 10.1002/pro.4075 33813796
    [Google Scholar]
  102. Cubuk J. Alston J.J. Incicco J.J. Singh S. Stuchell-Brereton M.D. Ward M.D. Zimmerman M.I. Vithani N. Griffith D. Wagoner J.A. Bowman G.R. Hall K.B. Soranno A. Holehouse A.S. The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA. Nat. Commun. 2021 12 1 1936 10.1038/s41467‑021‑21953‑3 33782395
    [Google Scholar]
  103. Shuaib M. Adroub S. Mourier T. Mfarrej S. Zhang H. Esau L. Alsomali A. Alofi F.S. Ahmad A.N. Shamsan A. Khogeer A. Hashem A.M. Almontashiri N.A.M. Hala S. Pain A. Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity. Genome Med. 2023 15 1 54 10.1186/s13073‑023‑01208‑0 37475040
    [Google Scholar]
  104. Xia J. Wang J. Ying L. Huang R. Zhang K. Zhang R. Tang W. Xu Q. Lai D. Zhang Y. Hu Y. Zhang X. Zang R. Fan J. Shu Q. Xu J. RAGE Is a Receptor for SARS-CoV-2 N Protein and Mediates N Protein–induced Acute Lung Injury. Am. J. Respir. Cell Mol. Biol. 2023 69 5 508 520 10.1165/rcmb.2022‑0351OC 37478333
    [Google Scholar]
  105. Lai D. Zhu K. Li S. Xiao Y. Xu Q. Sun Y. Yao P. Ma D. Shu Q. SARS-CoV-2 N Protein Triggers Acute Lung Injury via Modulating Macrophage Activation and Infiltration in in vitro and in vivo. J. Inflamm. Res. 2023 16 1867 1877 10.2147/JIR.S405722 37143821
    [Google Scholar]
  106. Gao T. Zhu L. Liu H. Zhang X. Wang T. Fu Y. Li H. Dong Q. Hu Y. Zhang Z. Jin J. Liu Z. Yang W. Liu Y. Jin Y. Li K. Xiao Y. Liu J. Zhao H. Liu Y. Li P. Song J. Zhang L. Gao Y. Kang S. Chen S. Ma Q. Bian X. Chen W. Liu X. Mao Q. Cao C. Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation. Signal Transduct. Target. Ther. 2022 7 1 318 10.1038/s41392‑022‑01133‑5 36100602
    [Google Scholar]
  107. Blanco-Melo D. Nilsson-Payant B.E. Liu W.C. Uhl S. Hoagland D. Møller R. Jordan T.X. Oishi K. Panis M. Sachs D. Wang T.T. Schwartz R.E. Lim J.K. Albrecht R.A. tenOever B.R. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell 2020 181 5 1036 1045.e9 10.1016/j.cell.2020.04.026 32416070
    [Google Scholar]
  108. Zhou S.H. Zhang R.Y. Zhang H.W. Liu Y.L. Wen Y. Wang J. Li Y.T. You Z.W. Yin X.G. Qiu H. Gong R. Yang G.F. Guo J. RBD conjugate vaccine with a built-in TLR1/2 agonist is highly immunogenic against SARS-CoV-2 and variants of concern. Chem. Commun. (Camb.) 2022 58 13 2120 2123 10.1039/D1CC06520C 35040862
    [Google Scholar]
  109. Qiao Y. Zhan Y. Zhang Y. Deng J. Chen A. Liu B. Zhang Y. Pan T. Zhang W. Zhang H. He X. Pam2CSK4-adjuvanted SARS-CoV-2 RBD nanoparticle vaccine induces robust humoral and cellular immune responses. Front. Immunol. 2022 13 992062 10.3389/fimmu.2022.992062 36569949
    [Google Scholar]
  110. Diallo B.K. Ní Chasaide C. Wong T.Y. Schmitt P. Lee K.S. Weaver K. Miller O. Cooper M. Jazayeri S.D. Damron F.H. Mills K.H.G. Intranasal COVID-19 vaccine induces respiratory memory T cells and protects K18-hACE mice against SARS-CoV-2 infection. NPJ Vaccines 2023 8 1 68 10.1038/s41541‑023‑00665‑3 37179389
    [Google Scholar]
  111. Ashhurst A.S. Johansen M.D. Maxwell J.W.C. Stockdale S. Ashley C.L. Aggarwal A. Siddiquee R. Miemczyk S. Nguyen D.H. Mackay J.P. Counoupas C. Byrne S.N. Turville S. Steain M. Triccas J.A. Hansbro P.M. Payne R.J. Britton W.J. Mucosal TLR2-activating protein-based vaccination induces potent pulmonary immunity and protection against SARS-CoV-2 in mice. Nat. Commun. 2022 13 1 6972 10.1038/s41467‑022‑34297‑3 36379950
    [Google Scholar]
  112. Deliyannis G. Gherardin N.A. Wong C.Y. Grimley S.L. Cooney J.P. Redmond S.J. Ellenberg P. Davidson K.C. Mordant F.L. Smith T. Gillard M. Lopez E. McAuley J. Tan C.W. Wang J.J. Zeng W. Littlejohn M. Zhou R. Fuk-Woo Chan J. Chen Z. Hartwig A.E. Bowen R. Mackenzie J.M. Vincan E. Torresi J. Kedzierska K. Pouton C.W. Gordon T.P. Wang L. Kent S.J. Wheatley A.K. Lewin S.R. Subbarao K. Chung A.W. Pellegrini M. Munro T. Nolan T. Rockman S. Jackson D.C. Purcell D.F.J. Godfrey D.I. Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine. EBioMedicine 2023 92 104574 10.1016/j.ebiom.2023.104574 37148585
    [Google Scholar]
  113. Mao L. Liu C. Liu J.Y. Jin Z.L. Jin Z. Xue R.Y. Feng R. Li G.C. Deng Y. Cheng H. Zou Q.M. Li H.B. Novel Synthetic Lipopeptides as Potential Mucosal Adjuvants Enhanced SARS-CoV-2 rRBD-Induced Immune Response. Front. Immunol. 2022 13 833418 10.3389/fimmu.2022.833418 35356002
    [Google Scholar]
  114. Khan K. Khan S.A. Jalal K. Ul-Haq Z. Uddin R. Immunoinformatic approach for the construction of multi-epitopes vaccine against omicron COVID-19 variant. Virology 2022 572 28 43 10.1016/j.virol.2022.05.001 35576833
    [Google Scholar]
  115. Jiang F. Liu Y. Xue Y. Cheng P. Wang J. Lian J. Gong W. Developing a multiepitope vaccine for the prevention of SARS-CoV-2 and monkeypox virus co-infection: A reverse vaccinology analysis. Int. Immunopharmacol. 2023 115 109728 10.1016/j.intimp.2023.109728 36652758
    [Google Scholar]
  116. Izquierdo J.L. Soriano J.B. González Y. Lumbreras S. Ancochea J. Echeverry C. Rodríguez J.M. Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19. Sci. Prog. 2022 105 1 10.1177/00368504221074574 35084258
    [Google Scholar]
  117. de Alencar J.C.G. Moreira C.L. Müller A.D. Chaves C.E. Fukuhara M.A. da Silva E.A. Miyamoto M.F.S. Pinto V.B. Bueno C.G. Lazar Neto F. Gomez Gomez L.M. Menezes M.C.S. Marchini J.F.M. Marino L.O. Brandão Neto R.A. Souza H.P. Valente F.S. Rahhal H. Pereira J.B.R. Padrão E.M.H. Wanderley A.P.B. Marques B. Gomez L.M.G. D’Souza E.A. Bellintani A.P. Miléo R.C. Toccoli R.W. Silva F.M.F. Baptista J.M. Silva M.O. Costa G.B. Luna R.B. dos Santos H.T. De Calasans M.M.G.C. Sanches M.P. Takamune D.J. Boscolo L. Simões P.A.A. Pandolfi M.C.A. Fantinatti B.L. Travessini G. de Faria M.F.L. Lima L.T. Nicolao B.R. Escudeiro G.P.M. Nascimento J.P.A. Caldeira B.T. Campos L.G. Medeiros V.M.B. Monsalvarga T.C. Omori I.H. Guidotte D.V. Bortolotto A.L. Abreu R.S. Martins N.A.B. Juck C.E.U. Utiyama L.O. Bortoleto F.M. Tinel R.D. Andreola G.M. Cardoso N.P. Claure O.S. Lopes J.V.Z. da Costa Ribeiro S.C. COVID Register Group Double-blind, Randomized, Placebo-controlled Trial With N-acetylcysteine for Treatment of Severe Acute Respiratory Syndrome Caused by Coronavirus Disease 2019 (COVID-19). Clin. Infect. Dis. 2021 72 11 e736 e741 10.1093/cid/ciaa1443 32964918
    [Google Scholar]
  118. Alamdari D.H. Moghaddam A.B. Amini S. Keramati M.R. Zarmehri A.M. Alamdari A.H. Damsaz M. Banpour H. Yarahmadi A. Koliakos G. Application of methylene blue -vitamin C –N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial. Eur. J. Pharmacol. 2020 885 173494 10.1016/j.ejphar.2020.173494 32828741
    [Google Scholar]
  119. Dushianthan A. Clark H. Madsen J. Mogg R. Matthews L. Berry L. de la Serna J.B. Batchelor J. Brealey D. Hussell T. Porter J. Djukanovic R. Feelisch M. Postle A. Grocott M.P.W. Nebulised surfactant for the treatment of severe COVID-19 in adults (COV-Surf): A structured summary of a study protocol for a randomized controlled trial. Trials 2020 21 1 1014 10.1186/s13063‑020‑04944‑5 33302976
    [Google Scholar]
  120. Ong E.Z. Yee J.X. Ooi J.S.G. Syenina A. de Alwis R. Chen S. Sim J.X.Y. Kalimuddin S. Leong Y.S. Chan Y.F.Z. Sekulovich R. Sullivan B.M. Lindert K. Sullivan S.B. Chivukula P. Hughes S.G. Low J.G. Ooi E.E. Chan K.R. Immune gene expression analysis indicates the potential of a self-amplifying Covid-19 mRNA vaccine. NPJ Vaccines 2022 7 1 154 10.1038/s41541‑022‑00573‑y 36443317
    [Google Scholar]
  121. Proud P.C. Tsitoura D. Watson R.J. Chua B.Y. Aram M.J. Bewley K.R. Cavell B.E. Cobb R. Dowall S. Fotheringham S.A. Ho C.M.K. Lucas V. Ngabo D. Rayner E. Ryan K.A. Slack G.S. Thomas S. Wand N.I. Yeates P. Demaison C. Zeng W. Holmes I. Jackson D.C. Bartlett N.W. Mercuri F. Carroll M.W. Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model. EBioMedicine 2021 63 103153 10.1016/j.ebiom.2020.103153 33279857
    [Google Scholar]
  122. Magana M. Pushpanathan M. Santos A.L. Leanse L. Fernandez M. Ioannidis A. Giulianotti M.A. Apidianakis Y. Bradfute S. Ferguson A.L. Cherkasov A. Seleem M.N. Pinilla C. de la Fuente-Nunez C. Lazaridis T. Dai T. Houghten R.A. Hancock R.E.W. Tegos G.P. The value of antimicrobial peptides in the age of resistance. Lancet Infect. Dis. 2020 20 9 e216 e230 10.1016/S1473‑3099(20)30327‑3 32653070
    [Google Scholar]
  123. Cortés-Ciriano I. Gulhan D.C. Lee J.J.K. Melloni G.E.M. Park P.J. Computational analysis of cancer genome sequencing data. Nat. Rev. Genet. 2022 23 5 298 314 10.1038/s41576‑021‑00431‑y 34880424
    [Google Scholar]
  124. Naz A. Shahid F. Butt T.T. Awan F.M. Ali A. Malik A. Designing Multi-Epitope Vaccines to Combat Emerging Coronavirus Disease 2019 (COVID-19) by Employing Immuno-Informatics Approach. Front. Immunol. 2020 11 1663 10.3389/fimmu.2020.01663 32754160
    [Google Scholar]
  125. Yaseen A.R. Suleman M. Qadri A.S. Asghar A. Arshad I. Khan D.M. Development of conserved multi-epitopes based hybrid vaccine against SARS-CoV-2 variants: an immunoinformatic approach. In Silico Pharmacol. 2023 11 1 18 10.1007/s40203‑023‑00156‑2 37519944
    [Google Scholar]
  126. Farhani I. Yamchi A. Madanchi H. Khazaei V. Behrouzikhah M. Abbasi H. Salehi M. Moradi N. Sanami S. Designing a multi-epitope vaccine against the sars-cov-2 variant based on an immunoinformatics approach. Curr Comput Aided Drug Des. 2023 20 3 274 290 10.2174/1573409919666230612125440
    [Google Scholar]
  127. Sahu L.K. Singh K. Cross-variant proof predictive vaccine design based on SARS-CoV-2 spike protein using immunoinformatics approach. Beni. Suef Univ. J. Basic Appl. Sci. 2023 12 1 5 10.1186/s43088‑023‑00341‑4 36644779
    [Google Scholar]
  128. Ezzemani W. Kettani A. Sappati S. Kondaka K. El Ossmani H. Tsukiyama-Kohara K. Altawalah H. Saile R. Kohara M. Benjelloun S. Ezzikouri S. Reverse vaccinology-based prediction of a multi-epitope SARS-CoV-2 vaccine and its tailoring to new coronavirus variants. J. Biomol. Struct. Dyn. 2022 41 11 1 22 10.1080/07391102.2022.2075468 35549819
    [Google Scholar]
  129. Rafi M.O. Al-Khafaji K. Sarker M.T. Taskin-Tok T. Rana A.S. Rahman M.S. Design of a multi-epitope vaccine against SARS-CoV-2: immunoinformatic and computational methods. RSC Advances 2022 12 7 4288 4310 10.1039/D1RA06532G 35425433
    [Google Scholar]
  130. Saba A.A. Adiba M. Saha P. Hosen M.I. Chakraborty S. Nabi A.H.M.N. An in-depth in silico and immunoinformatics approach for designing a potential multi-epitope construct for the effective development of vaccine to combat against SARS-CoV-2 encompassing variants of concern and interest. Comput. Biol. Med. 2021 136 104703 10.1016/j.compbiomed.2021.104703 34352457
    [Google Scholar]
  131. Akpınar S. Oran M. Doğan M. Çelikkol A. Erdem I. Turgut B. The role of oxidized phospholipids in COVID-19-associated hypercoagulopathy. Eur. Rev. Med. Pharmacol. Sci. 2021 25 16 5304 5309 10.26355/eurrev_202108_26551 34486706
    [Google Scholar]
  132. Ma Z. Li J. Yang L. Mu Y. Xie W. Pitt B. Li S. Inhibition of LPS- and CpG DNA-induced TNF-α response by oxidized phospholipids. Am. J. Physiol. Lung Cell. Mol. Physiol. 2004 286 4 L808 L816 10.1152/ajplung.00220.2003 14644758
    [Google Scholar]
  133. Nonas S. Miller I. Kawkitinarong K. Chatchavalvanich S. Gorshkova I. Bochkov V.N. Leitinger N. Natarajan V. Garcia J.G.N. Birukov K.G. Oxidized phospholipids reduce vascular leak and inflammation in rat model of acute lung injury. Am. J. Respir. Crit. Care Med. 2006 173 10 1130 1138 10.1164/rccm.200511‑1737OC 16514111
    [Google Scholar]
  134. Mokhtari V. Afsharian P. Shahhoseini M. Kalantar S.M. Moini A. A Review on Various Uses of N-Acetyl Cysteine. Cell J. 2017 19 1 11 17 28367412
    [Google Scholar]
  135. Islam A.B.M.M.K. Khan M.A.A.K. Lung transcriptome of a COVID-19 patient and systems biology predictions suggest impaired surfactant production which may be druggable by surfactant therapy. Sci. Rep. 2020 10 1 19395 10.1038/s41598‑020‑76404‑8 33173052
    [Google Scholar]
  136. Ji J. Sun L. Luo Z. Zhang Y. Xianzheng W. Liao Y. Tong X. Shan J. Potential Therapeutic Applications of Pulmonary Surfactant Lipids in the Host Defence Against Respiratory Viral Infections. Front. Immunol. 2021 12 730022 10.3389/fimmu.2021.730022 34646269
    [Google Scholar]
  137. Bollag W.B. Gonzales J.N. Phosphatidylglycerol and surfactant: A potential treatment for COVID-19? Med. Hypotheses 2020 144 110277 10.1016/j.mehy.2020.110277 33254581
    [Google Scholar]
  138. Numata M. Voelker D.R. Anti-inflammatory and anti-viral actions of anionic pulmonary surfactant phospholipids. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2022 1867 6 159139 10.1016/j.bbalip.2022.159139 35240310
    [Google Scholar]
  139. Numata M. Chu H.W. Dakhama A. Voelker D.R. Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection. Proc. Natl. Acad. Sci. USA 2010 107 1 320 325 10.1073/pnas.0909361107 20080799
    [Google Scholar]
  140. Sato M. Sano H. Iwaki D. Kudo K. Konishi M. Takahashi H. Takahashi T. Imaizumi H. Asai Y. Kuroki Y. Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A. J. Immunol. 2003 171 1 417 425 10.4049/jimmunol.171.1.417 12817025
    [Google Scholar]
  141. Fajgenbaum D.C. June C.H. Cytokine Storm. N. Engl. J. Med. 2020 383 23 2255 2273 10.1056/NEJMra2026131 33264547
    [Google Scholar]
  142. Numata M. Kandasamy P. Voelker D.R. The anti-inflammatory and antiviral properties of anionic pulmonary surfactant phospholipids. Immunol. Rev. 2023 317 1 166 186 10.1111/imr.13207 37144896
    [Google Scholar]
  143. Takano H. Pulmonary surfactant itself must be a strong defender against SARS-CoV-2. Med. Hypotheses 2020 144 110020 10.1016/j.mehy.2020.110020 32590326
    [Google Scholar]
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  • Article Type:
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Keywords: inflammatory response ; COVID-19 ; therapeutic target ; SARS-CoV-2 ; TLR2 ; viral proteins
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