Neutrophils are the primary cells of the innate immune system. They destroy pathogenic microorganisms carrying out the oxidative stress mechanism through phagocytosis and extracellular traps (NETs). The aim of the present work is the study of the influence of the viral infection on functional activity (respiratory burst reaction intensity) of peripheral blood neutrophils. The study was conducted on the whole human blood using the flow cytometry technique. The changes in respiratory burst reaction intensity during ARVI development and in case of bacterial complications appearance were analyzed. The blood plasma component priming neutrophils in viral infections was determined (acute phase protein fibrinogen). It was shown that healthy donors’ neutrophils react differently to vaccination with inactivated and “alive” influenza vaccines. The fact that neutrophils' capacity to generate reactive oxygen species correlates with the titer of IgA and IgG antibodies to SARS-CoV-2 in patients with asymptomatic or mild Covid-19 was revealed. The obtained data confirm the influence of viral infections on the neutrophils’ functional activity. Also, the protein that might be responsible for this influence was suggested.
neutrophils, oxidative stress, respiratory viral infection, flow cytometry
1. Schonrich G., Raftery M.J. Neutrophil Extracellular Traps Go Viral. Front. Immunol., 2016, vol. 7, p. 366.
2. Nordenfelt P., Tapper H. Phagosome dynamics during phagocytosis by neutrophils. J. Leukoc. Biol., 2011, vol. 90, pp. 271-284.
3. Soehnlein O. Direct and alternative antimicrobial mechanisms of neutrophil-derived granule proteins. J. Mol. Med., 2009, vol. 87, pp. 1157-1164.
4. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol., 2006, vol. 6, pp. 173-182.
5. Mantovani A., Cassatella M.A., Costantini C., Jaillon S. Neutrophils in activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol., 2011, vol. 11, pp. 519-531.
6. Essin K.M., Gollasch M., Rolle S., Weissgerber P., Sausbier M., Bohn E. et al. BK channels in innate immune functions of neutrophils and macrophages. Blood, 2009, vol. 113, pp. 1326-1331.
7. Yipp B.G., Petri B., Salina D., Jenne C.N., Scott B.N.V., Zbytnuik L.D. et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat. Med., 2012, vol. 18, pp. 1386-1393.
8. Tillack K., Breiden P., Martin R., Sospedra M. T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses. J. Immunol., 2012, vol. 188, pp. 3150-3159.
9. Jenne C.N., Wong CH.Y., Zemp F.J., McDonald B., Rahman M.M., Forsyth P.A., et al. Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe, 2013, vol. 13, pp. 169-180.
10. Hiroki C.H., Toller J.E., Fumagalli M.J., Colon D.F., Figueireo L.T.M., Fonseca B. Neutrophil Extracellular Traps effectively control acute Chikungunya virus infection. Front. Immunol., 2020, vol. 10, p. 3108.
11. Muraro S.P., De Souza G.F., Gallo S.W., De Silva B.K. Respiratory Syncytial Virus induces the classical ROS-dependent NETosis through PAD-4 and necroptosis pathways activation. Sci. Rep., 2018, vol. 8, p. 14166.
12. Mozzini C., Girelli D. The role of neutrophil extracellular traps in Covid-19: only a hypothesis or a potential new field of research? Thromb Res., 2020, vol. 191, pp. 26-27.
13. White M.R., Crouch E., Vesona J., Tacken P.J., Batenburg J.J., Leth-Larsen R. et al. Respiratory innate immune proteins differentially modulate the neutrophil respiratory burst response to influenza A virus. Am J Physiol Lung Cell Mol Physiol., 2005, vol. 289, pp. L606-L616.
14. Zhang Z., Rong L., Li Y.P. Flaviviridae Viruses and Oxidative Stress: Implications for Viral Pathogenesis. Oxid Med Cell Longev, 2019.
15. Ivanov A.V., Valuev-Elliston V.T., Ivanova O.N., Kotchetkov S.N., Starodubova E.S. et al. Oxidative Stress during HIV Infection: Mechanisms and Consequences. Oxid Med Cell Longev., 2016.
16. Ntyonga-Pono M.-P. COVID-19 infection and oxidative stress: an under-explored approach for prevention and treatment? Pan Afr Med J., 2020, vol. 35, p. 12.
17. Khomich O.A., Kochetkov S.N., Bartosch B. Redox biology of respiratory viral infections. Viruses, 2018.
18. Imai Y., Kuba K., Neely G.G. Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury. Cell, 2008, vol. 133, pp. 235-249.
19. Jorch S.K., Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat. Med., 2017, vol. 23, pp. 279-287.
20. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol., 2018, vol. 18, pp. 134-147.
21. Hong C.W. Current understanding in neutrophil differentiation and heterogeneity. Immune Netw., 2017, vol. 17, pp. 298-306.
22. Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types? Front. Physiol., 2018, vol. 9, p. 113.
23. Klemke M., Wabnitz G.H., Funke F., Funk B., Kirchgessner H., Samstag Y. Oxidation of cofilin mediates T cell hyporesponsiveness under oxidative stress conditions. Immunity, 2008, vol. 29, pp. 404-413.
24. Hock B.D., Taylor K.G., Cross N.B., Kettle A.J., Hampton M.B., McKenzie J.L. Effect of activated human polymorphonuclear leucocytes on T lymphocyte proliferation and viability. Immunology, 2012, vol. 137, pp. 249-258.
25. Filatov M., Varfolomeeva E., Ivanov E. Flow cytofluorometric detection of inflammatory processes by measuring respiratory burst reaction of peripheral blood neutrophils. Biochem. Mol. Med., 1995, vol. 55, pp. 116-121.
26. Thomas G., Rogues B. Proton magnetic resonance studies of ethidium bromide and its sodium borohydride reduced derivative. FEBS Lett., 1972, vol. 26, pp. 169-175.
27. Himmelfarb J., Hakim R.M., Holbrook D.G., Leeber D.A., Ault K.A. Detection of granulocyte reactive oxygen species formation in whole blood using flow cytometry. Cytometry, 1992, vol. 13, pp. 83-89.
28. Varfolomeeva E.Yu., Ivanov E.I., Drobchenko E.A., Semenova E.V., Filatov M.V. Detection of inflammatory processes during various diseases by the method of flow cytofluorometry. Bull Exp Biol Med., 2010, vol. 149, pp. 485-489.
29. Varfolomeeva E.Y., Semenova E.V., Sokolov A.V., Aplin K.D., Timofeeva K.E. et al. Ceruloplasmin decreases respiratory burst reaction during pregnancy. Free Radic Res., 2016, vol. 50, pp. 909-919.
30. Delgado-Roche L., Mesta F. Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection. Arch Med Res., 2020, vol. 51, pp. 384-387.
31. Barnes B.J., Adrover J.M., Baxter-Stoltzfus A., Borczuk A., Cools-Lartigue J., Crawford J.M. et al. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J. Exp. Med., 2020.
32. Bonow R.O., Fonarow G.C., O’Gara P.T., Yancy C.W. Association of Coronavirus Disease 2019 (COVID-19) With Myocardial Injury and Mortality. JAMA Cardiol, 2020.
33. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y. et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet, 2020, vol. 395, pp. 507-513.
34. Hartshorn K.L., Sastry K., Brown D., White M.R., Okarma T.B. et al. Conglutinin acts as an opsonin for influenza A viruses. J Immunol., 1993a, vol. 151, pp. 1-9.
35. Jaaskelainen A.J., Kekalainen E., Kallio-Kokko H., Mannonen L, Kortela E., Vapalahti O. et al. Evaluation of commercial and automated SARS-CoV-2 IgG and IgA ELISAs using coronavirus disease (COVID-19) patient samples. Euro Surveill, 2020.
36. Padoan A., Sciacovelli L., Basso D., Negrini D., Zuin S., Cosma C. et al. IgA-Ab response to spike glycoprotein of SARS-CoV-2 in patients with COVID-19: A longitudinal study. Clin Chim Acta., 2020, vol. 507, pp. 164-166.
37. Haveri A., Smura T., Kuivanen S., Osterlund P., Hepojoki J., Ikonen N. et al. Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020. Euro Surveill, 2020.
38. Connors J.M., Levy J.H. COVID-19 and its implications for thrombosis and anticoagulation. Blood, 2020, vol. 135, pp. 2033-2040.
39. Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost., 2020, vol. 18, pp. 844-847.