Research Article

Neutrophils, NETs, NETosis and their paradoxical roles in COVID-19

Al-Anazi KA*, Al-Anazi WK and Al-Jasser AM

Published: 05/11/2020 | Volume 4 - Issue 1 | Pages: 003-010

Abstract

The pandemic of COVID-19 has adversely affected the world in many aspects. The health and economic sectors suffer most of the repercussions of this disease. The search for a cure for this rapidly spreading virus which is causing massive life losses worldwide requires clear understanding of the immunopathogenesis of this virus so as to develop pinpointed targeted therapies rather than relying mainly on supportive care measures and drug repurposing to fight this life-threatening virus infection.

Neutrophils, neutrophil extracellular traps (NETs), and NETosis are not well studied not only in COVID-19, but also in coroviruses in general. The review will shed lights on the functions of neutrophils, NETs, and NETosis in various infectious complications as well as in sepsis and acute lung conditions in an attempt to understand their actual roles and in order to help in designing targeted therapies in the near future.

Read Full Article HTML DOI: 10.29328/journal.jsctt.1001020 Cite this Article

References

  1. Wang L, Wang Y, Ye D, Liu Q. Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence. Int J Antimicrob Agents. 2020; 105948. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32201353
  2. Contini C, Di Nuzzo M, Barp N, Bonazza A, De Giorgio R, et al. The novel zoonotic COVID-19 pandemic: An expected global health concern. J Infect Dev Ctries. 2020; 14: 254-264. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32235085
  3. Park SE. Epidemiology, virology, and clinical features of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19). Clin Exp Pediatr. 2020; 63: 119-124. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32252141
  4. Sohrabi C, Alsafi Z, O’Neill N, Khan M, Kerwan A, et al. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg. 2020; 76: 71-76. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32112977
  5. Tu H, Tu S, Gao S, Shao A, Sheng J. The epidemiological and clinical features of COVID-19 and lessons from this global infectious public health event. J Infect. 2020; S0163-4453(20)30222-X. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32315723
  6. Tay MZ, Poh CM, Rénia L, Mac Ary PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32346093
  7. Yan Y, Shin WI, Pang YX, Meng Y, Lai J, et al. The first 75 days of novel coronavirus (SARS-CoV-2) outbreak: Recent advances, prevention, and treatment. Int J Environ Res Public Health. 2020; 17: E2323. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32235575
  8. Sônego F, Castanheira FV, Ferreira RG, Kanashiro A, Leite CA, et al. Paradoxical roles of the neutrophil in sepsis: protective and deleterious. Front Immunol. 2016; 7: 155. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27199981
  9. Shiogama K, Onouchi T, Mizutani Y, Sakurai K, Inada K, et al. Visualization of neutrophil extracellular traps and fibrin meshwork in human fibrinopurulent inflammatory lesions: I. light microscopic study. Acta Histochem Cytochem. 2016; 49: 109-116. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27682014
  10. Hasler P, Giaglis S, Hahn S. Neutrophil extracellular traps in health and disease. Swiss Med Wkly. 2016; 146: w14352. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27723901
  11. Kaplan MJ, Radic M. Neutrophil extracellular traps: Double-edged swords of innate immunity. J Immunol. 2012; 189: 2689-2695. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/22956760
  12. Knight JS, Carmona-Rivera C, Kaplan MJ. Proteins derived from neutrophil extracellular traps may serve as self-antigens and mediate organ damage in autoimmune diseases. Front Immunol. 2012; 3: 380. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/23248629
  13. Bornhöfft KF, Viergutz T, Kühnle A, Galuska SP. Nanoparticles equipped with α2,8-linked sialic acid chains inhibit the release of neutrophil extracellular traps. Nanomaterials. 2019; 9: E610. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31013834
  14. Barrientos L, Marin-Esteban V, de Chaisemartin L, Le-Moal VL, Sandré C, et al. An improved strategy to recover large fragments of functional human neutrophil extracellular traps. Front Immunol. 2013; 4: 166. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/23805143
  15. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007; 176: 231-241. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/17210947
  16. Chen L, Zhao Y, Lai D, Zhang P, Yang Y, et al. Neutrophil extracellular traps promote macrophage pyroptosis in sepsis. Cell Death Dis. 2018; 9: 597. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/29789550
  17. Alasmari SZ. In vivo imaging of neutrophil extracellular traps (NETs): Visualization methods and outcomes. Biomed Res Int. 2020; 2020: 4192745. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32090090
  18. Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: Is immunity the second function of chromatin? J Cell Biol. 2012; 198: 773-783. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/22945932
  19. Palmer LJ, Cooper PR, Ling MR, Wright HJ, Huissoon A, et al.  Hypochlorous acid regulates neutrophil extracellular trap release in humans. Clin Exp Immunol. 2012; 167: 261-268. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/22236002
  20. Cox LE, Walstein K, Völlger L, Reuner F, Bick A, et al. Neutrophil extracellular trap formation and nuclease activity in septic patients. BMC Anesthesiol. 2020; 20: 15. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31931719
  21. Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J, et al. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med. 2020; 217: e20200652. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32302401
  22. Niedźwiedzka-Rystwej P, Repka W, Tokarz-Deptuła B, Deptuła W. In sickness and in health - how neutrophil extracellular trap (NET) works in infections, selected diseases and pregnancy. J Inflamm. 2019; 16: 15. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31297037
  23. Zhang F, Liu AL, Gao S, Ma S, Guo SB. Neutrophil dysfunction in sepsis. Chin Med J. 2016; 129: 2741-2744. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27824008
  24. Shen XF, Cao K, Jiang JP, Guan WX, Du JF. Neutrophil dysregulation during sepsis: an overview and update. J Cell Mol Med. 2017; 21: 1687-1697. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/28244690
  25. Mortaz E, Alipoor SD, Adcock IM, Mumby S, Koenderman L. Update on neutrophil function in severe inflammation. Front Immunol. 2018; 9: 2171. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/30356867
  26. Leliefeld PH, Wessels CM, Leenen LP, Koenderman L, Pillay J. The role of neutrophils in immune dysfunction during severe inflammation. Crit Care. 2016; 20: 73. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27005275
  27. Al-Jasser AM, Al-Anazi KA.  Donor granulocyte transfusions in patients with hematologic malignancies and in recipients of hematopoietic stem cell transplantation. J Stem Cell Biol Transplant. 2019; 3: 1.
  28. Drewniak A, Kuijpers TW. Granulocyte transfusion therapy: randomization after all? Haematologica. 2009; 94: 1644-1648. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/19996116
  29. Cui J, Wei X, Lv H, Li Y, Li P, et al. The clinical efficacy of intravenous IgM-enriched immunoglobulin (pentaglobin) in sepsis or septic shock: a meta-analysis with trial sequential analysis. Ann Intensive Care. 2019; 9: 27. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/30725235
  30. Alejandria MM, Lansang MA, Dans LF, Mantaring JB 3rd. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013; CD001090.         Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/11869591
  31. Beyrau M, Bodkin JV, Nourshargh S. Neutrophil heterogeneity in health and disease: a revitalized avenue in inflammation and immunity. Open Biol. 2012; 2: 120134. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/23226600
  32. Silvestre-Roig C, Fridlender ZG, Glogauer M, Scapini P. Neutrophil diversity in health and disease. Trends Immunol. 2019; 40: 565-583. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31160207
  33. Prame Kumar K, Nicholls AJ, Wong CHY. Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease. Cell Tissue Res. 2018; 371: 551-565. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/29387942
  34. Scapini P, Cassatella MA. Social networking of human neutrophils within the immune system. Blood. 2014; 124: 710-719. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/24923297
  35. Kumar V, Sharma A. Neutrophils: Cinderella of innate immune system. Int Immunopharmacol. 2010; 10: 1325-1334. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/20828640
  36. van Rees DJ, Szilagyi K, Kuijpers TW, Matlung HL, van den Berg TK. Immunoreceptors on neutrophils. Semin Immunol. 2016; 28: 94-108. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/26976825
  37. Camp JV, Jonsson CB. A role for neutrophils in viral respiratory disease. Front Immunol. 2017; 8: 550. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/28553293
  38. Galani IE, Andreakos E. Neutrophils in viral infections: Current concepts and caveats. J Leukoc Biol. 2015; 98: 557-564. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/26160849
  39. Jenne CN, Wong CH, Zemp FJ, McDonald B, Rahman MM, et al. Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe. 2013; 13: 169-180. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/23414757
  40. D’Elia RV, Harrison K, Oyston PC, Lukaszewski RA, Clark GC. Targeting the cytokine storm for therapeutic benefit. Clin Vaccine Immunol. 2013; 20: 319-327. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/23283640
  41. Bordon J, Aliberti S, Fernandez-Botran R, Uriarte SM, Rane MJ, et al. Understanding the roles of cytokines and neutrophil activity and neutrophil apoptosis in the protective versus deleterious inflammatory response in pneumonia. Int J Infect Dis. 2013; 17: e76-83. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/23069683
  42. McDonald B, Kubes P. Chemokines: sirens of neutrophil recruitment-but is it just one song? Immunity. 2010; 33: 148-149. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/20732637
  43. McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe. 2012; 12: 324-333. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/22980329
  44. Mozzini C, Girelli D. The role of neutrophil extracellular traps in COVID-19: Only an hypothesis or a potential new field. Thrombosis Res. 2020; 26-27. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32360977
  45. Hiroki CH, Toller-Kawahisa JE, Fumagalli MJ, Colon DF, Figueiredo LTM, et al. Neutrophil extracellular traps effectively control acute Chikungunya virus infection. Front Immunol. 2020; 10: 3108. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32082301
  46. Muraro SP, De Souza GF, Gallo SW, Da Silva BK, De Oliveira SD, et al. Respiratory syncytial virus induces the classical ROS-dependent NETosis through PAD-4 and necroptosis pathways activation. Sci Rep. 2018; 8: 14166. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/30242250
  47. Schönrich G, Raftery MJ. Neutrophil extracellular traps go viral. Front Immunol. 2016; 7: 366. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27698656
  48. Opasawatchai A, Amornsupawat P, Jiravejchakul N, Chan-In W, Spoerk NJ, et al. Neutrophil activation and early features of NET formation are associated with Dengue virus infection in human. Front Immunol. 2019; 9: 3007. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/30687301
  49. Schulz C, Gabriel G, von Köckritz-Blickwede M. Detrimental role of neutrophil extracellular traps during Dengue virus infection. Trends Immunol. 2020; 41: 3-6. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31791719
  50. Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010; 33: 657-670. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/21094463
  51. Qin C, Zhou L, Hu Z, Zhang S, Yang S, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020. ciaa248. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32161940
  52. Sun S, Cai X, Wang H, He G, Lin Y, et al. Abnormalities of peripheral blood system in patients with COVID-19 in Wenzhou, China. Clin Chim Acta. 2020. 507: 174-180. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32339487
  53. Yang AP, Liu JP, Tao WQ, Li HM. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol. 2020; 84: 106504. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32304994
  54. Liu Y, Du X, Chen J, Jin Y, Peng L, et al. Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect. 2020; S0163-4453(20)30208-5. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32283162
  55. Zheng M, Gao Y, Wang G, Song G, Liu S, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 2020; 17: 533-535. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32203188
  56. Ravindran M, Khan MA, Palaniyar N. Neutrophil extracellular trap formation: Physiology, pathology, and pharmacology. Biomolecules. 2019; 9: E365. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31416173
  57. Bystrzycka W, Moskalik A, Sieczkowska S, Manda-Handzlik A, Demkow U, et al. The effect of clindamycin and amoxicillin on neutrophil extracellular trap (NET) release. Cent Eur J Immunol. 2016; 41: 1-5. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27095915
  58. Onouchi T, Shiogama K, Mizutani Y, Takaki T, Tsutsumi Y. Visualization of neutrophil extracellular traps and fibrin meshwork in human fibrinopurulent inflammatory lesions: III. Correlative light and electron microscopic study. Acta Histochem Cytochem. 2016; 49: 141-147. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27917008
  59. Remijsen Q, Vanden Berghe T, Wirawan E, Asselbergh B, Parthoens E, et al. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res. 2011; 21: 290-304. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/21060338
  60. Neubert E, Meyer D, Kruss S, Erpenbeck L. The power from within - Understanding the driving forces of neutrophil extracellular trap formation. J Cell Sci. 2020; 133: jcs241075. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32156720
  61. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, et al. Neutrophil extracellular traps kill bacteria. Science. 2004; 303: 1532-1535. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/15001782
  62. Vong L, Lorentz RJ, Assa A, Glogauer M, Sherman PM. Probiotic Lactobacillus rhamnosus inhibits the formation of neutrophil extracellular traps. J Immunol. 2014; 192: 1870-1877. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/24465012
  63. Naffah de Souza C, Breda LCD, Khan MA, de Almeida SR, Câmara NOS, et al. Alkaline pH promotes NADPH oxidase-independent neutrophil extracellular trap formation: A matter of mitochondrial reactive oxygen species generation and citrullination and cleavage of histone. Front Immunol. 2018; 8: 1849. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/29375550
  64. Steinberg BE, Grinstein S. Unconventional roles of the NADPH oxidase: Signaling, ion homeostasis and cell death. Sci STKE. 2007; 2007: pe11. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/17392241
  65. Hemmers S, Teijaro JR, Arandjelovic S, Mowen KA. PAD4-mediated neutrophil extracellular trap formation is not required for immunity against influenza infection. PLoS One. 2011; 6: e22043. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/21779371
  66. Metzler KD, Fuchs TA, Nauseef WM, Reumaux D, Roesler J, et al. Myeloperoxidase is required for neutrophil extracellular trap formation: Implications for innate immunity. Blood. 2011; 117: 953-959. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/20974672
  67. Chow OA, von Köckritz-Blickwede M, Bright AT, Hensler ME, Zinkernagel AS, et al. Statins enhance formation of phagocyte extracellular traps. Cell Host Microbe. 2010; 8: 445-454. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/21075355
  68. Pallet N. Neutrophil extracellular traps orchestrate necroinflammation. J Am Soc Nephrol. 2017; 28: 1670-1672. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/28232618
  69. Masuda S, Nakazawa D, Shida H, Miyoshi A, Kusunoki Y, et al. NETosis markers: Quest for specific, objective, and quantitative markers. Clin Chim Acta. 2016; 459: 89-93. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27259468
  70. Schneck E, Mallek F, Schiederich J, Kramer E, Markmann M, et al. Flow cytometry-based quantification of neutrophil extracellular traps shows an association with hypercoagulation in septic shock and hypocoagulation in postsurgical systemic inflammation-A proof-of-concept study. J Clin Med. 2020; 9: E174. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31936385
  71. de Buhr N, von Köckritz-Blickwede M. How neutrophil extracellular traps become visible. J Immunol Res. 2016; 2016: 4604713. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27294157
  72. Mohanty T, Sørensen OE, Nordenfelt P. NETQUANT: Automated quantification of neutrophil extracellular traps. Front Immunol. 2018; 8: 1999. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/29379509
  73. Elsherif L, Sciaky N, Metts CA, Modasshir M, Rekleitis I, et al. Machine learning to quantitate neutrophil NETosis. Sci Rep. 2019; 9: 16891. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31729453
  74. Held P, Rumble J. Automated analysis of neutrophil NETosis activity using the Lionheart™ FX to image and analyze stimulated dHL60 cells. BioTek, Application Notes, Cellular Imaging, Live Cell Image. 2019.
  75. Boeltz S, Amini P, Anders HJ, Andrade F, Bilyy R, et al. To NET or not to NET: current opinions and state of the science regarding the formation of neutrophil extracellular traps. Cell Death Differ. 2019; 26: 395-408. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/30622307
  76. Konig MF, Andrade F. A critical reappraisal of neutrophil extracellular traps and NETosis mimics based on differential requirements for protein citrullination. Front Immunol. 2016; 7: 461. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27867381
  77. Sørensen OE, Borregaard N. Neutrophil extracellular traps - the dark side of neutrophils. J Clin Invest. 2016; 126: 1612-1620. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27135878
  78. Bonaventura A, Vecchié A, Abbate A, Montecucco F. Neutrophil extracellular traps and cardiovascular diseases: An update. Cells. 2020; 9: E231. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31963447
  79. Kenny EF, Herzig A, Krüger R, Muth A, Mondal S, et al. Diverse stimuli engage different neutrophil extracellular trap pathways. Elife. 2017; 6: e24437. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/28574339
  80. Twaddell SH, Baines KJ, Grainge C, Gibson PG. The emerging role of neutrophil extracellular traps in respiratory disease. Chest. 2019; 156: 774-782. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31265835
  81. Gan T, Yang Y, Hu F, Chen X, Zhou J, et al. TLR3 regulated poly I: C-induced neutrophil extracellular traps and acute lung injury partly through p38 MAP kinase. Front Microbiol. 2018; 9: 3174. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/30622526
  82. Zhu L, Liu L, Zhang Y, Pu L, Liu J, et al. High level of neutrophil extracellular traps correlates with poor prognosis of severe influenza A infection. J Infect Dis. 2018; 217: 428-437. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/29325098
  83. Narasaraju T, Yang E, Samy RP, Ng HH, Poh WP, et al. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol. 2011; 179: 199-210. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/21703402
  84. Hosseinzadeh A, Thompson PR, Segal BH, Urban CF. Nicotine induces neutrophil extracellular traps. J Leukoc Biol. 2016; 100: 1105-1112. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/27312847
  85. Taghizadeh F, Akbari H. The powerful immune system against powerful COVID-19: A hypothesis. Med Hypothesis. 2020.  
  86. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020: 108427. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32325252
  87. Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020. 138999. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/32329756
  88. Bendib I, de Chaisemartin L, Mekontso Dessap A, Chollet-Martin S, de Prost N. Understanding the role of neutrophil extracellular traps in patients with severe pneumonia and ARDS. Chest. 2019; 156: 1278-1280. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/31812204
  89. Geerdink RJ, Pillay J, Meyaard L, Bont L. Neutrophils in respiratory syncytial virus infection: A target for asthma prevention. J Allergy Clin Immunol. 2015; 136: 838-847. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/26277597
  90. Domingo-Gonzalez R, Martínez-Colón GJ, Smith AJ, Smith CK, Ballinger MN, et al. Inhibition of neutrophil extracellular trap formation after stem cell transplant by prostaglandin E2. Am J Respir Crit Care Med. 2016; 193: 186-197. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/26417909
  91. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, et al.  Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010; 6: e1001176. Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/21079686