Single-cell meta-analysis of T lymphocytes functional differences in various organs after SARS-CoV-2 infection_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

TONG Xia ^1,2 ^# , ZHANG Hua ³ ^# , PENG Ling ^1,2 ,  ZHANG Xin ^2,4 ,  ZHANG Lanlan ¹

1. Department of Respiratory and Critical Care Medicine, West China Hospital, Chengdu, Sichuan 610041, P. R. China;
2. West China (Airport) Hospital of Sichuan University (The First People’s Hospital of Shuangliu District, Chengdu), Chengdu, Sichuan 610200, P. R. China;
3. West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
4. Division of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

ZHANG Xin, Email: llzhang@scu.edu.cn; ZHANG Lanlan, Email: xinzhang201618@gmail.com

Keywords：

Computational biology; bioinformatics; SARS-CoV-2; COVID-19; T lymphocytes; metabolism; interferon

DOI：

10.7507/1671-6205.202201042

Video：

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Objective To explore the functional heterogeneity of T lymphocytes in various organs after SARS-CoV-2 infection. Methods Using the public database GEO data (GSE171668, GSE159812, GSE159556, GSE167747) and the analysis method of single-cell technology, the functional differences of T lymphocytes in various organs of patients after infection with SARS-CoV-2 were analyzed. Results Through single-cell data extraction of 16 livers, 19 hearts,2 spleens, 6 brains, 58 lungs, 21 kidneys and 5 pancreases from SARS-CoV-2 infected patients, invasion genes were relatively highly expressed in T lymphocytes of the lung and pancreas. The lung had a special ability to express the interferon signaling pathway, while the expression of other organs was relatively low; at the same time, the T lymphocytes of the lung also highly expressed fatty acid binding sites. Conclusion After SARS-CoV-2 infection, compared with other organs, the lung has a special interferon-activated signaling pathway and fatty acid binding site.

Citation： TONG Xia, ZHANG Hua, PENG Ling, ZHANG Xin, ZHANG Lanlan. Single-cell meta-analysis of T lymphocytes functional differences in various organs after SARS-CoV-2 infection. Chinese Journal of Respiratory and Critical Care Medicine, 2022, 21(5): 330-339. doi: 10.7507/1671-6205.202201042 Copy

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3.	Gong F, Dai YP, Zheng T, et al. Peripheral CD4⁺ T cell subsets and antibody response in COVID-19 convalescent individuals. J Clin Invest, 2020, 130(12): 6588-6599.
4.	Lucas C, Wong P, Klein J, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature, 2020, 584(7821): 463-469.
5.	Xu G, Qi F, Li H, et al. The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing. Cell Discov, 2020, 6: 73.
6.	Hoang TN, Pino M, Boddapati AK, et al. Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell, 2021, 184(2): 460-475.e21.
7.	Minervina AA, Komech EA, Titov A, et al. Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T-cell memory formation after mild COVID-19 infection. Elife, 2021, 10: e63502.
8.	Bacher P, Rosati E, Esser D, et al. Low-avidity CD4⁺ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19. Immunity, 2020, 53(6): 1258-1271.e5.
9.	Le Bert N, Tan AT, Kunasegaran K, et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature, 2020, 584(7821): 457-462.
10.	Meckiff BJ, Ramírez-Suástegui C, Fajardo V, et al. Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4⁺ T cells in COVID-19. Cell, 2020, 183(5): 1340-1353. e16.
11.	Peng YC, Mentzer AJ, Liu GH, et al. Broad and strong memory CD4⁺ and CD8⁺ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19. Nat Immunol, 2020, 21(11): 1336-1345.
12.	Sahin U, Muik A, Derhovanessian E, et al. COVID-19 vaccine BNT162b1 elicits human antibody and T_H1 T cell responses. Nature, 2020, 586(7830): 594-599.
13.	Sadoff J, Le Gars M, Shukarev G, et al. Interim results of a phase 1-2a trial of Ad26.COV2. S Covid-19 vaccine. N Engl J Med, 2021, 384(19): 1824-1835.
14.	Zhou F, Yu T, Du RH, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet, 2020, 395(10229): 1054-1062.
15.	Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med, 2020, 383(2): 120-128.
16.	Weiskopf D, Schmitz KS, Raadsen MP, et al. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci Immunol, 2020, 5(48): eabd2071.
17.	Ronit A, Berg RMG, Bay JT, et al. Compartmental immunophenotyping in COVID-19 ARDS: a case series. J Allergy Clin Immunol, 2021, 147(1): 81-91.
18.	Shen CG, Wang ZQ, ZHAO F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA, 2020, 323(16): 1582-1589.
19.	Hamming I, Timens W, Bulthuis ML, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol, 2004, 203(2): 631-637.
20.	Zou X, Chen K, ZOU JW, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med, 2020, 14(2): 185-192.
21.	Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020, 579(7798): 270-273.
22.	Gu J, Gong EC, Zhang B, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med, 2005, 202(3): 415-424.
23.	Delorey TM, Ziegler CGK, Heimberg G, et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature, 2021, 595(7865): 107-113.
24.	Yang AC, Kern F, Losada PM, et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature, 2021, 595(7868): 565-571. Erratum in: Nature, 2021, 598(7882): E4.
25.	Tang XM, Uhl S, Zhang T, et al. SARS-CoV-2 infection induces beta cell transdifferentiation. Cell Metab, 2021, 33(8): 1577-1591.e7.
26.	Jansen J, Reimer KC, Nagai JS, et al. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell, 2022, 29(2): 217-231.e8.
27.	Satija R, Farrell JA, Gennert D, et al. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol, 2015, 33(5): 495-502.
28.	Qi FR, Qian S, Zhang SY, et al. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun, 2020, 526(1): 135-140.
29.	Stuart T, Butler A, Hoffman P, et al. Comprehensive integration of single-cell data. Cell, 2019, 177(7): 1888-1902. e21.
30.	Korsunsky I, Millard N, Fan J, et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods, 2019, 16(4): 1-8.
31.	Travaglini KJ, Nabhan AN, Penland L, et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature, 2020, 587(7835): 619-625.
32.	Peng R, Wu LA, Wang Q, et al. Cell entry by SARS-CoV-2. Trends Biochem Sci, 2021, 46(10): 848-860.
33.	Kvietys PR, Fakhoury HMA, Kadan S, et al. COVID-19: lung-centric immunothrombosis. Front Cell Infect Microbiol, 2021, 11: 679878.
34.	Huang LL, Shi Y, Gong B, et al. Dynamic blood single-cell immune responses in patients with COVID-19. Signal Transduct Target Ther, 2021, 6(1): 110.
35.	Yu GC, Wang LG, Han YY, et al. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5): 284-287.
36.	Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell, 2020, 181(7): 1489-1501.e15.
37.	Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science, 2021, 371(6529): eabf4063.
38.	Sekine T, Perez-Potti A, Rivera-Ballesteros O, et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell, 2020, 183(1): 158-68.e14.
39.	Corbett KS, Flynn B, Foulds KE, et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N Engl J Med, 2020, 383(16): 1544-1555.
40.	Wilk AJ, Rustagi A, Zhao NQ, et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med, 2020, 26(7): 1070-1076.
41.	Zhang NN, Li XF, Deng YQ, et al. A thermostable mRNA vaccine against COVID-19. Cell, 2020, 182(5): 1271-1283.e16.
42.	Ewer KJ, Barrett J, Belij-Rammerstorfer S, et al. T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial. Nat Med, 2021, 27(2): 270-278.
43.	Kared H, Redd AD, Bloch EM, et al. SARS-CoV-2-specific CD8⁺ T cell responses in convalescent COVID-19 individuals. J Clin Invest, 2021, 131(5): e145476.
44.	Graham BS. Rapid COVID-19 vaccine development. Science, 2020, 368(6494): 945-946.
45.	Smith TRF, Patel A, Ramos S, et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun, 2020, 11(1): 2601.
46.	Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet, 2020, 395(10240): 1845-1854.
47.	Jarjour NN, Masopust D, Jameson SC. T cell memory: understanding COVID-19. Immunity, 2021, 54(1): 14-18.
48.	Ke ZL, Oton J, Qu K, et al. Structures and distributions of SARS-CoV-2 spike proteins on intact virions. Nature, 2020, 588(7838): 498-502.
49.	Bost P, Giladi A, Liu Y, et al. Host-viral infection maps reveal signatures of severe COVID-19 patients. Cell, 2020, 181(7): 1475-1488.e12.
50.	Kumar A, Kumar S, Narayan RK, et al. Expression of SARS-CoV-2 host cell entry factors in immune system components of healthy individuals and its relevance for COVID-19 immunopathology. Viral Immunol, 2021, 34(5): 352-357.
51.	Yao C, Bora SA, Parimon T, et al. Cell-type-specific immune dysregulation in severely ill COVID-19 patients. Cell Rep, 2021, 34(1): 108590.
52.	Teijeira A, Garasa S, Etxeberria I, et al. Metabolic consequences of T-cell costimulation in anticancer immunity. Cancer Immunol Res, 2019, 7(10): 1564-1569.
53.	Siska PJ, Decking SM, Babl N, et al. Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone. J Clin Invest, 2021, 131(22): e148225.

1. Chen YM, Zheng Y, Yu Y, et al. Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage. EMBO J, 2020, 39(24): e105896.
2. Consiglio CR, Cotugno N, Sardh F, et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell, 2020, 183(4): 968-981.e7.
3. Gong F, Dai YP, Zheng T, et al. Peripheral CD4⁺ T cell subsets and antibody response in COVID-19 convalescent individuals. J Clin Invest, 2020, 130(12): 6588-6599.
4. Lucas C, Wong P, Klein J, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature, 2020, 584(7821): 463-469.
5. Xu G, Qi F, Li H, et al. The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing. Cell Discov, 2020, 6: 73.
6. Hoang TN, Pino M, Boddapati AK, et al. Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell, 2021, 184(2): 460-475.e21.
7. Minervina AA, Komech EA, Titov A, et al. Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T-cell memory formation after mild COVID-19 infection. Elife, 2021, 10: e63502.
8. Bacher P, Rosati E, Esser D, et al. Low-avidity CD4⁺ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19. Immunity, 2020, 53(6): 1258-1271.e5.
9. Le Bert N, Tan AT, Kunasegaran K, et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature, 2020, 584(7821): 457-462.
10. Meckiff BJ, Ramírez-Suástegui C, Fajardo V, et al. Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4⁺ T cells in COVID-19. Cell, 2020, 183(5): 1340-1353. e16.
11. Peng YC, Mentzer AJ, Liu GH, et al. Broad and strong memory CD4⁺ and CD8⁺ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19. Nat Immunol, 2020, 21(11): 1336-1345.
12. Sahin U, Muik A, Derhovanessian E, et al. COVID-19 vaccine BNT162b1 elicits human antibody and T_H1 T cell responses. Nature, 2020, 586(7830): 594-599.
13. Sadoff J, Le Gars M, Shukarev G, et al. Interim results of a phase 1-2a trial of Ad26.COV2. S Covid-19 vaccine. N Engl J Med, 2021, 384(19): 1824-1835.
14. Zhou F, Yu T, Du RH, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet, 2020, 395(10229): 1054-1062.
15. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med, 2020, 383(2): 120-128.
16. Weiskopf D, Schmitz KS, Raadsen MP, et al. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci Immunol, 2020, 5(48): eabd2071.
17. Ronit A, Berg RMG, Bay JT, et al. Compartmental immunophenotyping in COVID-19 ARDS: a case series. J Allergy Clin Immunol, 2021, 147(1): 81-91.
18. Shen CG, Wang ZQ, ZHAO F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA, 2020, 323(16): 1582-1589.
19. Hamming I, Timens W, Bulthuis ML, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol, 2004, 203(2): 631-637.
20. Zou X, Chen K, ZOU JW, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med, 2020, 14(2): 185-192.
21. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020, 579(7798): 270-273.
22. Gu J, Gong EC, Zhang B, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med, 2005, 202(3): 415-424.
23. Delorey TM, Ziegler CGK, Heimberg G, et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature, 2021, 595(7865): 107-113.
24. Yang AC, Kern F, Losada PM, et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature, 2021, 595(7868): 565-571. Erratum in: Nature, 2021, 598(7882): E4.
25. Tang XM, Uhl S, Zhang T, et al. SARS-CoV-2 infection induces beta cell transdifferentiation. Cell Metab, 2021, 33(8): 1577-1591.e7.
26. Jansen J, Reimer KC, Nagai JS, et al. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell, 2022, 29(2): 217-231.e8.
27. Satija R, Farrell JA, Gennert D, et al. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol, 2015, 33(5): 495-502.
28. Qi FR, Qian S, Zhang SY, et al. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun, 2020, 526(1): 135-140.
29. Stuart T, Butler A, Hoffman P, et al. Comprehensive integration of single-cell data. Cell, 2019, 177(7): 1888-1902. e21.
30. Korsunsky I, Millard N, Fan J, et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods, 2019, 16(4): 1-8.
31. Travaglini KJ, Nabhan AN, Penland L, et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature, 2020, 587(7835): 619-625.
32. Peng R, Wu LA, Wang Q, et al. Cell entry by SARS-CoV-2. Trends Biochem Sci, 2021, 46(10): 848-860.
33. Kvietys PR, Fakhoury HMA, Kadan S, et al. COVID-19: lung-centric immunothrombosis. Front Cell Infect Microbiol, 2021, 11: 679878.
34. Huang LL, Shi Y, Gong B, et al. Dynamic blood single-cell immune responses in patients with COVID-19. Signal Transduct Target Ther, 2021, 6(1): 110.
35. Yu GC, Wang LG, Han YY, et al. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5): 284-287.
36. Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell, 2020, 181(7): 1489-1501.e15.
37. Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science, 2021, 371(6529): eabf4063.
38. Sekine T, Perez-Potti A, Rivera-Ballesteros O, et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell, 2020, 183(1): 158-68.e14.
39. Corbett KS, Flynn B, Foulds KE, et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N Engl J Med, 2020, 383(16): 1544-1555.
40. Wilk AJ, Rustagi A, Zhao NQ, et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med, 2020, 26(7): 1070-1076.
41. Zhang NN, Li XF, Deng YQ, et al. A thermostable mRNA vaccine against COVID-19. Cell, 2020, 182(5): 1271-1283.e16.
42. Ewer KJ, Barrett J, Belij-Rammerstorfer S, et al. T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial. Nat Med, 2021, 27(2): 270-278.
43. Kared H, Redd AD, Bloch EM, et al. SARS-CoV-2-specific CD8⁺ T cell responses in convalescent COVID-19 individuals. J Clin Invest, 2021, 131(5): e145476.
44. Graham BS. Rapid COVID-19 vaccine development. Science, 2020, 368(6494): 945-946.
45. Smith TRF, Patel A, Ramos S, et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun, 2020, 11(1): 2601.
46. Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet, 2020, 395(10240): 1845-1854.
47. Jarjour NN, Masopust D, Jameson SC. T cell memory: understanding COVID-19. Immunity, 2021, 54(1): 14-18.
48. Ke ZL, Oton J, Qu K, et al. Structures and distributions of SARS-CoV-2 spike proteins on intact virions. Nature, 2020, 588(7838): 498-502.
49. Bost P, Giladi A, Liu Y, et al. Host-viral infection maps reveal signatures of severe COVID-19 patients. Cell, 2020, 181(7): 1475-1488.e12.
50. Kumar A, Kumar S, Narayan RK, et al. Expression of SARS-CoV-2 host cell entry factors in immune system components of healthy individuals and its relevance for COVID-19 immunopathology. Viral Immunol, 2021, 34(5): 352-357.
51. Yao C, Bora SA, Parimon T, et al. Cell-type-specific immune dysregulation in severely ill COVID-19 patients. Cell Rep, 2021, 34(1): 108590.
52. Teijeira A, Garasa S, Etxeberria I, et al. Metabolic consequences of T-cell costimulation in anticancer immunity. Cancer Immunol Res, 2019, 7(10): 1564-1569.
53. Siska PJ, Decking SM, Babl N, et al. Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone. J Clin Invest, 2021, 131(22): e148225.

Chinese Journal of Respiratory and Critical Care Medicine

Single-cell meta-analysis of T lymphocytes functional differences in various organs after SARS-CoV-2 infection

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