Immunological features of acute cytomegalovirus infection in immunocompetent patients

Objective. To identify and evaluate immunological features in immunocompetent patients with acute cytomegalovirus infection (CMVI).
Materials and methods. Thirty-three immunocompetent adult patients with acute cytomegalovirus infection were included in the study; 4 of them had thrombotic complications. The control group consisted of 10 healthy donors. All 33 blood samples were tested by flow cytometry. The content of antigen-specific cells was checked in all patients. Results. All patients had positive cytomegalovirus DNA PCR tests. The content of activated T cells in patients with acute CMV infection and thrombotic complications is 7.7 times higher (p < 0.001) than in conditionally healthy patients (median values: 36.02% (31.01; 47.92) and 4.68% (3.39; 5.25), respectively). The content of granulocytic myeloid suppressor cells (G-MLSC) in patients with acute CMV infection and thrombosis exceeds the same indicator in the group of healthy volunteers by 8.3 times (p < 0.001) (median values were 0.38% (0.24; 0.54) and 0.05% (0.03; 0.07) respectively). The number of regulatory T cells in patients with acute CMV infection and thrombosis was reduced by 3.1 times (p < 0.001) compared to the same indicator in the group of healthy volunteers (median indicators: 0.79% (0.57; 1.09) and 2.45% (2.01; 3.86), respectively). Immunophenotyping of CD3+ cells showed a tendency to increase the proportion of more mature cells, namely effector memory cells (TEM) and terminally differentiated memory cells (TEM RA) with a decrease in the percentage of “naive” cells.
Conclusion. A high level of antigen-specific T-cell response and a low content of T-regulatory cells may indicate insufficient control of the proliferation of T-cytotoxic lymphocytes, which may contribute to the long-term persistence of the virus and the development of chronic inflammation of the vessel wall, which requires further study. Thus, in patients with acute CMV infection, an additional risk factor for thrombosis appears, which must be taken into account when carrying out therapeutic and diagnostic measures.

1. Dioverti MV, Razonable RR. Cytomegalovirus. Microbiology Spectrum. 2016 Aug;4(4). DOI: https://doi.org/10.1128/microbiolspec.DMIH2-0022-2015

2. Fowler K, Mucha J, Neumann M, Lewandowski W, Kaczanowska M, Grys M, et al. A systematic literature review of the global seroprevalence of cytomegalovirus: possible implications for treatment, screening, and vaccine development. BMC Public Health. 2022 Sep 1;22(1):1659. DOI: https://doi.org/10.1186/s12889-022-13971-7

3. Lachmann R, Loenenbach A, Waterboer T, Brenner N, Pawlita M, Michel A, et al. Cytomegalovirus (CMV) seroprevalence in the adult population of Germany. PLoS One. 2018 Jul 25;13(7):e0200267. DOI: https://doi.org/10.1371/journal.pone.0200267

4. Shnayder M, Nachshon A, Krishna B, Poole E, Boshkov A, Binyamin A, et al. Defining the transcriptional landscape during cytomegalovirus latency with single-cell RNA sequencing. mBio. 2018 Mar 13;9(2):e00013-18. DOI: https://doi.org/10.1128/mbio.00013-18

5. DiNardo AR, Netea MG, Musher DM. Postinfectious epigenetic immune modifications a double-edged sword. N Engl J Med. 2021 Jan 21;384(3):261-270. DOI: https://doi.org/10.1056/ NEJMra2028358

6. Ishii T, Sasaki Y, Maeda T, Komatsu F, Suzuki T, Urita Y. Clinical differentiation of infectious mononucleosis that is caused by epstein-barr virus or cytomegalovirus: a single-center case-control study in Japan. J Infect Chemother. 2019 Jun;25(6):431-436. DOI: https://doi: 10.1016/j.jiac.2019.01.012

7. Yamada N, Kaneko M, Yang L, Matsuzawa S, Minematsu T, Kodama Y. Cell-mediated and humoral immune responses to human cytomegalovirus in pregnant women with vertically transmitted infection following primary infection: A case report. J Infect Chemother. 2023 Nov;29(11):1071-1074. DOI: https://doi.org/10.1016/j.jiac.2023.07.004

8. Forte E, Zhang Z, Thorp EB, Hummel M. Cytomegalovirus latency and reactivation: an intricate interplay with the host immune response. Front Cell Infect Microbiol. 2020 Mar 31;10:130. DOI: https://doi.org/10.3389/fcimb.2020.00130

9. Lam VC, Lanier LL. NK cells in host responses to viral infections. Curr Opin Immunol. 2017 Feb;44:43-51. DOI: https://doi.org/10.1016/j.coi.2016.11.003

10. Patel M, Vlahava VM, Forbes SK, Fielding CA, Stanton RJ, Wang ECY. HCMV-encoded NK modulators: lessons from in vitro and in vivo genetic variation. Front Immunol. 2018 Oct 1;9:2214. DOI: https://doi.org/10.3389/fimmu.2018.02214

11. Jenks JA, Goodwin ML, Permar SR. The roles of host and viral antibody Fc receptors in herpes simplex virus (HSV) and human cytomegalovirus (HCMV) infections and immunity. Front Immunol. 2019 Sep 6;10:2110. DOI: https://doi.org/10.3389/fimmu.2019.02110

12. Basinger J, Kapp ME. Cytomegalovirus pneumonia presenting as pulmonary nodules. Autops Case Rep. 2021 Oct 21;12:e2021362. DOI: http://dx.doi.org/10.4322/acr.2021.362

13. Lefeuvre L, Schibler M, Lalive PH. Elsberg syndrome secondary to cytomegalovirus infection in an immunocompetent patient: a case report. Neurol Neuroimmunol Neuroinflamm. 2022 Dec 23;10(2):e200079. DOI: https://doi.org/10.1212/NXI.0000000000200079

14. Gugliesi F, Pasquero S, Griffante G, Scutera S, Albano C, Pacheco SFC, et al. Human cytomegalovirus and autoimmune diseases: where are we? Viruses. 2021 Feb 8;13(2):260. DOI: https://doi.org/10.3390/v13020260

15. Paran Y, Shalev V, Steinvil A, Justo D, Zimmerman O, Finn T, et al. Thrombosis following acute cytomegalovirus infection: a community prospective study. Ann Hematol. 2013 Jul;92(7):969-974. DOI: https://doi.org/10.1007/s00277-013-1715-3

16. Walter G, Richert Q, Ponnampalam A, Sharma A. Acute superior mesenteric vein thrombosis in the setting of cytomegalovirus mononucleosis: a case report and review of the literature. Lancet Infect Dis. 2021 Jul;21(7):e202-e207. DOI: https://doi.org/10.1016/S1473-3099(20)30782-9

17. Sherman S, Eytan O, Justo D. Thrombosis associated with acute cytomegalovirus infection: a narrative review. Arch Med Sci. 2014 Dec 22;10(6):1186-90. DOI: https://doi.org/10.5114/aoms.2014.47828

18. Forghani P, Petersen CT, Waller EK. Activation of VIP signaling enhances immunosuppressive effect of MDSCs on CMV-induced adaptive immunity. Oncotarget. 2017 Sep 7;8(47):81873-81879. DOI: https://doi.org/10.18632/oncotarget.20704

19. Manandhar T, Hò GT, Pump WC, Blasczyk R, BadeDoeding C. Battle between host immune cellular responses and HCMV immune evasion. Int J Mol Sci. 2019 Jul 24;20(15):3626. DOI: https://doi.org/10.3390/ijms20153626

20. Van de Berg PJ, Yong SL, Remmerswaal EB, van Lier RA, ten Berge IJ. Cytomegalovirus-induced effector T cells cause endothelial cell damage. Clin Vaccine Immunol. 2012 May;19(5):772-729. DOI: https://doi.org/10.1128/CVI.00011-12

21. Bayard C, Lepetitcorps H, Roux A, Larsen M, Fastenackels S, Salle V, et al. Coordinated expansion of both memory T cells and NK cells in response to CMV infection in humans. Eur J Immunol. 2016 May;46(5):1168-1179. DOI: https://doi.org/10.1002/eji.201546179

22. Vieira Braga FA, Hertoghs KM, van Lier RA, van Gisbergen KP. Molecular characterization of HCMV-specific immune responses: Parallels between CD8(+) T cells, CD4(+) T cells, and NK cells. Eur J Immunol. 2015 Sep;45(9):2433-2445. DOI: https://doi.org/10.1002/eji.201545495

23. Klenerman P, Oxenius A. T cell responses to cytomegalovirus. Nat Rev Immunol. 2016 Jun;16(6):367-377. DOI: https://doi.org/10.1038/nri.2016.38

24. Lozada JR, Zhang B, Miller JS, Cichocki F. NK Cells from Human Cytomegalovirus-Seropositive Individuals Have a Distinct Metabolic Profile That Correlates with Elevated mTOR Signaling. J Immunol. 2023 Aug 15;211(4):539-550. DOI: https://doi.org/10.4049/jimmunol.2200851