Sci Rep. 2021 Dec 09;11(1):23713. doi: 10.1038/s41598-021-03273-0.

The potential of COVID-19 patients' sera to cause antibody-dependent enhancement of infection and IL-6 production.

Scientific reports

Jun Shimizu, Tadahiro Sasaki, Atsushi Yamanaka, Yoko Ichihara, Ritsuko Koketsu, Yoshihiro Samune, Pedro Cruz, Kei Sato, Naomi Tanga, Yuka Yoshimura, Ami Murakami, Misuzu Yamada, Kiyoe Itoi, Emi E Nakayama, Kazuo Miyazaki, Tatsuo Shioda

PMID: 34887501 DOI: 10.1038/s41598-021-03273-0

Abstract

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many vaccine trials have been initiated. An important goal of vaccination is the development of neutralizing antibody (Ab) against SARS-CoV-2. However, the possible induction of antibody-dependent enhancement (ADE) of infection, which is known for other coronaviruses and dengue virus infections, is a particular concern in vaccine development. Here, we demonstrated that human iPS cell-derived, immortalized, and ACE2- and TMPRSS2-expressing myeloid cell lines are useful as host cells for SARS-CoV-2 infection. The established cell lines were cloned and screened based on their function in terms of susceptibility to SARS-CoV-2-infection or IL-6 productivity. Using the resulting K-ML2 (AT) clone 35 for SARS-CoV-2-infection or its subclone 35-40 for IL-6 productivity, it was possible to evaluate the potential of sera from severe COVID-19 patients to cause ADE and to stimulate IL-6 production upon infection with SARS-CoV-2.

© 2021. The Author(s).

References

1. Moi, M. L., Lim, C. K., Kotaki, A., Takasaki, T. & Kurane, I. Development of an antibody-dependent enhancement assay for dengue virus using stable BHK-21 cell lines expressing Fc gammaRIIA. J. Virol. Methods 163, 205–209. https://doi.org/10.1016/j.jviromet.2009.09.018 (2010). - PubMed
2. Yamanaka, A., Miyazaki, K., Shimizu, J. & Senju, S. Dengue virus susceptibility in novel immortalized myeloid cells. Heliyon 6, e05407. https://doi.org/10.1016/j.heliyon.2020.e05407 (2020). - PubMed
3. Sariol, C. A., Nogueira, M. L. & Vasilakis, N. A tale of two viruses: Does heterologous flavivirus immunity enhance Zika disease? Trends Microbiol. 26, 186–190. https://doi.org/10.1016/j.tim.2017.10.004 (2018). - PubMed
4. Yip, M. S. et al. Antibody-dependent infection of human macrophages by severe acute respiratory syndrome coronavirus. Virol. J. 11, 82. https://doi.org/10.1186/1743-422x-11-82 (2014). - PubMed
5. Wan, Y. et al. Molecular mechanism for antibody-dependent enhancement of coronavirus entry. J. Virol. https://doi.org/10.1128/jvi.02015-19 (2020). - PubMed
6. Robinson, W. E. Jr., Montefiori, D. C. & Mitchell, W. M. Antibody-dependent enhancement of human immunodeficiency virus type 1 infection. Lancet 1, 790–794. https://doi.org/10.1016/s0140-6736(88)91657-1 (1988). - PubMed
7. Takada, A., Watanabe, S., Okazaki, K., Kida, H. & Kawaoka, Y. Infectivity-enhancing antibodies to Ebola virus glycoprotein. J. Virol. 75, 2324–2330. https://doi.org/10.1128/jvi.75.5.2324-2330.2001 (2001). - PubMed
8. Huisman, W., Martina, B. E., Rimmelzwaan, G. F., Gruters, R. A. & Osterhaus, A. D. Vaccine-induced enhancement of viral infections. Vaccine 27, 505–512. https://doi.org/10.1016/j.vaccine.2008.10.087 (2009). - PubMed
9. Hadinegoro, S. R. et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N. Engl. J. Med. 373, 1195–1206. https://doi.org/10.1056/NEJMoa1506223 (2015). - PubMed
10. Dans, A. L., Dans, L. F., Lansang, M. A. D., Silvestre, M. A. A. & Guyatt, G. H. Controversy and debate on dengue vaccine series-paper 1: Review of a licensed dengue vaccine: Inappropriate subgroup analyses and selective reporting may cause harm in mass vaccination programs. J. Clin. Epidemiol. 95, 137–139. https://doi.org/10.1016/j.jclinepi.2017.11.019 (2018). - PubMed
11. Lee, W. S., Wheatley, A. K., Kent, S. J. & DeKosky, B. J. Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nat. Microbiol. 5, 1185–1191. https://doi.org/10.1038/s41564-020-00789-5 (2020). - PubMed
12. Arvin, A. M. et al. A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature 584, 353–363. https://doi.org/10.1038/s41586-020-2538-8 (2020). - PubMed
13. Bournazos, S., Gupta, A. & Ravetch, J. V. The role of IgG Fc receptors in antibody-dependent enhancement. Nat. Rev. Immunol. 20, 633–643. https://doi.org/10.1038/s41577-020-00410-0 (2020). - PubMed
14. Grant, R. A. et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature 590, 635–641. https://doi.org/10.1038/s41586-020-03148-w (2021). - PubMed
15. Hui, K. P. Y. et al. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: An analysis in ex-vivo and in-vitro cultures. Lancet Respir. Med. 8, 687–695. https://doi.org/10.1016/s2213-2600(20)30193-4 (2020). - PubMed
16. Chu, H. et al. Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: An observational study. The Lancet Microbe 1, e14–e23. https://doi.org/10.1016/s2666-5247(20)30004-5 (2020). - PubMed
17. Cloutier, M. et al. ADE and hyperinflammation in SARS-CoV2 infection-comparison with dengue hemorrhagic fever and feline infectious peritonitis. Cytokine 136, 155256. https://doi.org/10.1016/j.cyto.2020.155256 (2020). - PubMed
18. Haruta, M. et al. TAP-deficient human iPS cell-derived myeloid cell lines as unlimited cell source for dendritic cell-like antigen-presenting cells. Gene Ther. 20, 504–513. https://doi.org/10.1038/gt.2012.59 (2013). - PubMed
19. Haruta, M. et al. Generation of a large number of functional dendritic cells from human monocytes expanded by forced expression of cMYC plus BMI1. Hum. Immunol. 74, 1400–1408. https://doi.org/10.1016/j.humimm.2013.05.017 (2013). - PubMed
20. Imamura, Y. et al. Generation of large numbers of antigen-expressing human dendritic cells using CD14-ML technology. PLoS ONE 11, e0152384. https://doi.org/10.1371/journal.pone.0152384 (2016). - PubMed
21. Chen, X. et al. Detectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically ill patients with coronavirus disease 2019. Clin. Infect. Dis. 71, 1937–1942. https://doi.org/10.1093/cid/ciaa449 (2020). - PubMed
22. Giamarellos-Bourboulis, E. J. et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 27, 992–1000. https://doi.org/10.1016/j.chom.2020.04.009 (2020). - PubMed
23. Geijtenbeek, T. B. et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575–585. https://doi.org/10.1016/s0092-8674(00)80693-5 (2000). - PubMed
24. Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280. https://doi.org/10.1016/j.cell.2020.02.052 (2020). - PubMed
25. Manh, D. H. et al. iPS cell serves as a source of dendritic cells for in vitro dengue virus infection model. J. Gen. Virol. 99, 1239–1247. https://doi.org/10.1099/jgv.0.001119 (2018). - PubMed
26. Littaua, R., Kurane, I. & Ennis, F. A. Human IgG Fc receptor II mediates antibody-dependent enhancement of dengue virus infection. J. Immunol. 144, 3183–3186 (1990). - PubMed
27. Taylor, A. et al. Fc receptors in antibody-dependent enhancement of viral infections. Immunol. Rev. 268, 340–364. https://doi.org/10.1111/imr.12367 (2015). - PubMed
28. Tirado, S. M. & Yoon, K. J. Antibody-dependent enhancement of virus infection and disease. Viral Immunol. 16, 69–86. https://doi.org/10.1089/088282403763635465 (2003). - PubMed
29. Hadjadj, J. et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369, 718–724. https://doi.org/10.1126/science.abc6027 (2020). - PubMed
30. Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 395, 497–506. https://doi.org/10.1016/s0140-6736(20)30183-5 (2020). - PubMed
31. Wang, J., Jiang, M., Chen, X. & Montaner, L. J. Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts. J. Leukoc. Biol. 108, 17–41. https://doi.org/10.1002/JLB.3COVR0520-272R (2020). - PubMed
32. Moore, J. B. & June, C. H. Cytokine release syndrome in severe COVID-19. Science 368, 473–474. https://doi.org/10.1126/science.abb8925 (2020). - PubMed
33. Ragab, D., Salah Eldin, H., Taeimah, M., Khattab, R. & Salem, R. The COVID-19 cytokine storm; What we know so far. Front. Immunol. 11, 1446. https://doi.org/10.3389/fimmu.2020.01446 (2020). - PubMed
34. Hojyo, S. et al. How COVID-19 induces cytokine storm with high mortality. Inflamm. Regen. 40, 37. https://doi.org/10.1186/s41232-020-00146-3 (2020). - PubMed
35. Wilson, J. G. et al. Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI Insight. https://doi.org/10.1172/jci.insight.140289 (2020). - PubMed
36. Jiang, Y. et al. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am. J. Respir. Crit. Care Med. 171, 850–857. https://doi.org/10.1164/rccm.200407-857OC (2005). - PubMed
37. Leisman, D. E. et al. Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir. Med. 8, 1233–1244. https://doi.org/10.1016/s2213-2600(20)30404-5 (2020). - PubMed
38. Karwaciak, I., Sałkowska, A., Karaś, K., Dastych, J. & Ratajewski, M. Nucleocapsid and spike proteins of the coronavirus SARS-CoV-2 induce IL6 in monocytes and macrophages-potential implications for cytokine storm syndrome. Vaccines (Basel). https://doi.org/10.3390/vaccines9010054 (2021). - PubMed
39. Coomes, E. A. & Haghbayan, H. Interleukin-6 in Covid-19: A systematic review and meta-analysis. Rev. Med. Virol. 30, 1–9. https://doi.org/10.1002/rmv.2141 (2020). - PubMed
40. Rutkowska-Zapala, M. et al. Human monocyte subsets exhibit divergent angiotensin I-converting activity. Clin. Exp. Immunol. 181, 126–132. https://doi.org/10.1111/cei.12612 (2015). - PubMed
41. Ziegler, C. G. K. et al. SARS-CoV-2 Receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 181, 1016–1035. https://doi.org/10.1016/j.cell.2020.04.035 (2020). - PubMed
42. Wang, S. et al. Characterization of neutralizing antibody with prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus monkeys. Nat. Commun. 11, 5752. https://doi.org/10.1038/s41467-020-19568-1 (2020). - PubMed
43. Mannar, D., Leopold, K. & Subramaniam, S. Glycan reactive anti-HIV-1 antibodies bind the SARS-CoV-2 spike protein but do not block viral entry. BioRxiv. https://doi.org/10.1101/2021.01.03.425141 (2021). - PubMed
44. Wu, F. et al. Antibody-dependent enhancement (ADE) of SARS-CoV-2 infection in recovered COVID-19 patients: Studies based on cellular and structural biology analysis. MedRxiv. https://doi.org/10.1101/2020.10.08.20209114 (2020). - PubMed
45. Li, D. et al. In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies. Cell 184, 4203–4219. https://doi.org/10.1016/j.cell.2021.06.021 (2021). - PubMed
46. Liu, Y. et al. An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies. Cell. https://doi.org/10.1016/j.cell.2021.05.032 (2021). - PubMed
47. Zhou, Y. et al. Enhancement versus neutralization by SARS-CoV-2 antibodies from a convalescent donor associates with distinct epitopes on the RBD. Cell Rep. 34, 108699. https://doi.org/10.1016/j.celrep.2021.108699 (2021). - PubMed
48. Sabino, E. C. et al. Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. The Lancet 397, 452–455. https://doi.org/10.1016/s0140-6736(21)00183-5 (2021). - PubMed
49. Bölke, E., Matuschek, C. & Fischer, J. C. Loss of anti-Sars-Cov-2 antibodies in mild covid-19. N. Engl. J. Med. 383, 1694–1695. https://doi.org/10.1056/NEJMc2028468 (2020). - PubMed
50. Kutsuna, S., Asai, Y. & Matsunaga, A. Loss of anti-Sars-Cov-2 antibodies in mild covid-19. N. Engl. J. Med. 383, 1695–1696. https://doi.org/10.1056/NEJMc2028468 (2020). - PubMed
51. Terpos, E., Mentis, A. & Dimopoulos, M. A. Loss of anti-Sars-Cov-2 antibodies in mild covid-19. N. Engl. J. Med. 383, 1695. https://doi.org/10.1056/NEJMc2028468 (2020). - PubMed
52. Kaneko, N. et al. Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19. Cell 183, 143–157. https://doi.org/10.1016/j.cell.2020.08.025 (2020). - PubMed
53. Yamayoshi, S. et al. Antibody titers against SARS-CoV-2 decline, but do not disappear for several months. EClinicalMedicine 32, 100734. https://doi.org/10.1016/j.eclinm.2021.100734 (2021). - PubMed
54. Leung, K., Shum, M. H., Leung, G. M., Lam, T. T. & Wu, J. T. Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, October to November 2020. Euro Surveill. https://doi.org/10.2807/1560-7917.ES.2020.26.1.2002106 (2021). - PubMed
55. Tegally, H. et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. MedRxiv. https://doi.org/10.1101/2020.12.21.20248640 (2020). - PubMed
56. Fujino, T. et al. Novel SARS-CoV-2 variant identified in travelers from Brazil to Japan. Emerg. Infect. Dis. J. https://doi.org/10.3201/eid2704.210138 (2021). - PubMed

Publication Types

• Journal Article
• Research Support, Non-U.S. Gov't

Grant support

• JP20he0822004/the Japan Agency for Medical Research and Development (AMED)