Citation: Jian-Bo Cao, Shu-Tong Zhu, Xiao-Shan Huang, Xing-Yuan Wang, Meng-Li Wu, Xin Li, Feng-Liang Liu, Ling Chen, Yong-Tang Zheng, Jian-Hua Wang. Mast cell degranulation-triggered by SARS-CoV-2 induces tracheal-bronchial epithelial inflammation and injury .VIROLOGICA SINICA, 2024, 39(2) : 309-318.  http://dx.doi.org/10.1016/j.virs.2024.03.001

Mast cell degranulation-triggered by SARS-CoV-2 induces tracheal-bronchial epithelial inflammation and injury

  • SARS-CoV-2 infection-induced hyper-inflammation is a key pathogenic factor of COVID-19. Our research, along with others', has demonstrated that mast cells (MCs) play a vital role in the initiation of hyper-inflammation caused by SARS-CoV-2. In previous study, we observed that SARS-CoV-2 infection induced the accumulation of MCs in the peri-bronchus and bronchioalveolar-duct junction in humanized mice. Additionally, we found that MC degranulation triggered by the spike protein resulted in inflammation in alveolar epithelial cells and capillary endothelial cells, leading to subsequent lung injury. The trachea and bronchus are the routes for SARS-CoV-2 transmission after virus inhalation, and inflammation in these regions could promote viral spread. MCs are widely distributed throughout the respiratory tract. Thus, in this study, we investigated the role of MCs and their degranulation in the development of inflammation in tracheal-bronchial epithelium. Histological analyses showed the accumulation and degranulation of MCs in the peri-trachea of humanized mice infected with SARS-CoV-2. MC degranulation caused lesions in trachea, and the formation of papillary hyperplasia was observed. Through transcriptome analysis in bronchial epithelial cells, we found that MC degranulation significantly altered multiple cellular signaling, particularly, leading to upregulated immune responses and inflammation. The administration of ebastine or loratadine effectively suppressed the induction of inflammatory factors in bronchial epithelial cells and alleviated tracheal injury in mice. Taken together, our findings confirm the essential role of MC degranulation in SARS-CoV-2-induced hyper-inflammation and the subsequent tissue lesions. Furthermore, our results support the use of ebastine or loratadine to inhibit SARS-CoV-2-triggered degranulation, thereby preventing tissue damage caused by hyper-inflammation.

  • 加载中
  • 10.1016j.virs.2024.03.001-ESM.docx
    1. Abraham, S.N., St John, A.L., 2010. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol, 10, 440-452.

    2. Ahn, J.H., Kim, J., Hong, S.P., Choi, S.Y., Yang, M.J., Ju, Y.S., Kim, Y.T., Kim, H.M., Rahman, M.D.T., Chung, M.K., Hong, S.D., Bae, H., Lee, C.S., Koh, G.Y., 2021. Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19. J Clin Invest, 131, e148517.

    3. Altmann, D.M., Whettlock, E.M., Liu, S., Arachchillage, D.J., Boyton, R.J., 2023. The immunology of long COVID. Nat Rev Immunol 23,618-634.

    4. Baker, S.A., Kwok, S., Berry, G.J., Montine, T.J., 2021. Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation. PLoS One, 16, e0247060.

    5. Barral, M., Sirol, M., El Hajjam, M., Zhang, N., Petit, A., Cornelis, F.H., 2020. Bronchial Artery Embolization Performed in COVID-19 Patients:Tolerance and Outcomes. Cardiovasc Intervent Radiol, 43, 1949-1951.

    6. Bodmer, J.L., Weinman, J., Veress, L.A., Galambos, C., 2023. Obstructive Bronchial Fibrin Cast Formation in COVID-19 Severe Respiratory Failure. Am J Respir Crit Care Med, 207, 349-350.

    7. Boumaza, A., Gay, L., Mezouar, S., Bestion, E., Diallo, A.B., Michel, M., Desnues, B., Raoult, D., La Scola, B., Halfon, P., Vitte, J., Olive, D., Mege, J.L., 2021. Monocytes and Macrophages, Targets of Severe Acute Respiratory Syndrome Coronavirus 2:The Clue for Coronavirus Disease 2019 Immunoparalysis. J Infect Dis, 224, 395-406.

    8. Budnevsky, A.V., Avdeev, S.N., Kosanovic, D., Shishkina, V.V., Filin, A.A., Esaulenko, D.I., Ovsyannikov, E.S., Samoylenko, T.V., Redkin, A.N., Suvorova, O.A., Perveeva, I.M., 2022. Role of mast cells in the pathogenesis of severe lung damage in COVID-19 patients. Respir Res, 23, 371.

    9. Bui, L.T., Winters, N.I., Chung, M.I., Joseph, C., Gutierrez, A.J., Habermann, A.C., Adams, T.S., Schupp, J.C., Poli, S., Peter, L.M., Taylor, C.J., Blackburn, J.B., Richmond, B.W., Nicholson, A.G., Rassl, D., Wallace, W.A., Rosas, I.O., Jenkins, R.G., Kaminski, N., Kropski, J.A., Banovich, N.E., Human Cell Atlas Lung Biological, N., 2021. Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity. Nat Commun, 12, 4314.

    10. Carroll-Portillo, A., Surviladze, Z., Cambi, A., Lidke, D.S., Wilson, B.S., 2012. Mast cell synapses and exosomes:membrane contacts for information exchange. Front Immunol, 3, 46.

    11. Carsana, L., Sonzogni, A., Nasr, A., Rossi, R.S., Pellegrinelli, A., Zerbi, P., Rech, R., Colombo, R., Antinori, S., Corbellino, M., Galli, M., Catena, E., Tosoni, A., Gianatti, A., Nebuloni, M., 2020. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy:a two-centre descriptive study. Lancet Infect Dis, 20, 1135-1140.

    12. Chaves, A.M., Braniff, O., Angelova, A., Deng, Y., Tremblay, M.E., 2023. Chronic inflammation, neuroglia dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome. Brain Res Bull, 201, 110702.

    13. Codo, A.C., Davanzo, G.G., Monteiro, L.B., De Souza, G.F., Muraro, S.P., Virgilio-Da-Silva, J.V., Prodonoff, J.S., Carregari, V.C., De Biagi Junior, C.a.O., Crunfli, F., Jimenez Restrepo, J.L., Vendramini, P.H., Reis-De-Oliveira, G., Bispo Dos Santos, K., Toledo-Teixeira, D.A., Parise, P.L., Martini, M.C., Marques, R.E., Carmo, H.R., Borin, A., Coimbra, L.D., Boldrini, V.O., Brunetti, N.S., Vieira, A.S., Mansour, E., Ulaf, R.G., Bernardes, A.F., Nunes, T.A., Ribeiro, L.C., Palma, A.C., Agrela, M.V., Moretti, M.L., Sposito, A.C., Pereira, F.B., Velloso, L.A., Vinolo, M.a.R., Damasio, A., Proença-Módena, J.L., Carvalho, R.F., Mori, M.A., Martins-De-Souza, D., Nakaya, H.I., Farias, A.S., Moraes-Vieira, P.M., 2020. Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis. Cell Metab, 32, 437-446.e435.

    14. Company, C., Piqueras, L., Naim Abu Nabah, Y., Escudero, P., Blanes, J.I., Jose, P.J., Morcillo, E.J., Sanz, M.J., 2011. Contributions of ACE and mast cell chymase to endogenous angiotensin II generation and leucocyte recruitment in vivo. Cardiovasc Res, 92, 48-56.

    15. Conti, P., Caraffa, A., Tete, G., Gallenga, C.E., Ross, R., Kritas, S.K., Frydas, I., Younes, A., Di Emidio, P., Ronconi, G., 2020. Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19. J Biol Regul Homeost Agents, 34, 1629-1632.

    16. Dorward, D.A., Russell, C.D., Um, I.H., Elshani, M., Armstrong, S.D., Penrice-Randal, R., Millar, T., Lerpiniere, C.E.B., Tagliavini, G., Hartley, C.S., Randle, N.P., Gachanja, N.N., Potey, P.M.D., Dong, X., Anderson, A.M., Campbell, V.L., Duguid, A.J., Al Qsous, W., Bouhaidar, R., Baillie, J.K., Dhaliwal, K., Wallace, W.A., Bellamy, C.O.C., Prost, S., Smith, C., Hiscox, J.A., Harrison, D.J., Lucas, C.D., 2021. Tissue-Specific Immunopathology in Fatal COVID-19. Am J Respir Crit Care Med, 203, 192-201.

    17. Dries, D.J., 2021. Coronavirus Disease 2019:From Intensive Care Unit to the Long Haul-Part 2. Air Med J, 40, 298-302.

    18. Dunbar, K.B., Agoston, A.T., Odze, R.D., Huo, X., Pham, T.H., Cipher, D.J., Castell, D.O., Genta, R.M., Souza, R.F., Spechler, S.J., 2016. Association of Acute Gastroesophageal Reflux Disease With Esophageal Histologic Changes. Jama, 315, 2104-2112.

    19. Elieh Ali Komi, D., Wohrl, S., Bielory, L., 2020. Mast Cell Biology at Molecular Level:a Comprehensive Review. Clin Rev Allergy Immunol, 58, 342-365.

    20. Galambos, C., Bush, D., Abman, S.H., 2021. Intrapulmonary bronchopulmonary anastomoses in COVID-19 respiratory failure. Eur Respir J, 58, 2004397.

    21. Gu, H., Chen, Q., Yang, G., He, L., Fan, H., Deng, Y.Q., Wang, Y., Teng, Y., Zhao, Z., Cui, Y., Li, Y., Li, X.F., Li, J., Zhang, N.N., Yang, X., Chen, S., Guo, Y., Zhao, G., Wang, X., Luo, D.Y., Wang, H., Yang, X., Li, Y., Han, G., He, Y., Zhou, X., Geng, S., Sheng, X., Jiang, S., Sun, S., Qin, C.F., Zhou, Y., 2020. Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy. Science, 369, 1603-1607.

    22. Guan, W.J., Liang, W.H., Zhao, Y., Liang, H.R., Chen, Z.S., Li, Y.M., Liu, X.Q., Chen, R.C., Tang, C.L., Wang, T., Ou, C.Q., Li, L., Chen, P.Y., Sang, L., Wang, W., Li, J.F., Li, C.C., Ou, L.M., Cheng, B., Xiong, S., Ni, Z.Y., Xiang, J., Hu, Y., Liu, L., Shan, H., Lei, C.L., Peng, Y.X., Wei, L., Liu, Y., Hu, Y.H., Peng, P., Wang, J.M., Liu, J.Y., Chen, Z., Li, G., Zheng, Z.J., Qiu, S.Q., Luo, J., Ye, C.J., Zhu, S.Y., Cheng, L.L., Ye, F., Li, S.Y., Zheng, J.P., Zhang, N.F., Zhong, N.S., He, J.X., 2020. Comorbidity and its impact on 1590 patients with COVID-19 in China:a nationwide analysis. Eur Respir J, 55, 2000547.

    23. Hou, Y.J., Chiba, S., Halfmann, P., Ehre, C., Kuroda, M., Dinnon, K.H., 3rd, Leist, S.R., Schäfer, A., Nakajima, N., Takahashi, K., Lee, R.E., Mascenik, T.M., Graham, R., Edwards, C.E., Tse, L.V., Okuda, K., Markmann, A.J., Bartelt, L., De Silva, A., Margolis, D.M., Boucher, R.C., Randell, S.H., Suzuki, T., Gralinski, L.E., Kawaoka, Y., Baric, R.S., 2020a. SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science, 370, 1464-1468.

    24. Hou, Y.J., Okuda, K., Edwards, C.E., Martinez, D.R., Asakura, T., Dinnon, K.H., 3rd, Kato, T., Lee, R.E., Yount, B.L., Mascenik, T.M., Chen, G., Olivier, K.N., Ghio, A., Tse, L.V., Leist, S.R., Gralinski, L.E., Schäfer, A., Dang, H., Gilmore, R., Nakano, S., Sun, L., Fulcher, M.L., Livraghi-Butrico, A., Nicely, N.I., Cameron, M., Cameron, C., Kelvin, D.J., De Silva, A., Margolis, D.M., Markmann, A., Bartelt, L., Zumwalt, R., Martinez, F.J., Salvatore, S.P., Borczuk, A., Tata, P.R., Sontake, V., Kimple, A., Jaspers, I., O'neal, W.K., Randell, S.H., Boucher, R.C., Baric, R.S., 2020b. SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract. Cell, 182, 429-446.e414.

    25. Imai, Y., Kuba, K., Rao, S., Huan, Y., Guo, F., Guan, B., Yang, P., Sarao, R., Wada, T., Leong-Poi, H., Crackower, M.A., Fukamizu, A., Hui, C.C., Hein, L., Uhlig, S., Slutsky, A.S., Jiang, C., Penninger, J.M., 2005. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature, 436, 112-116.

    26. Jiang, R.D., Liu, M.Q., Chen, Y., Shan, C., Zhou, Y.W., Shen, X.R., Li, Q., Zhang, L., Zhu, Y., Si, H.R., Wang, Q., Min, J., Wang, X., Zhang, W., Li, B., Zhang, H.J., Baric, R.S., Zhou, P., Yang, X.L., Shi, Z.L., 2020. Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2. Cell, 182, 50-58 e58.

    27. Jiang, S., Shi, Z.L., 2020. The First Disease X is Caused by a Highly Transmissible Acute Respiratory Syndrome Coronavirus. Virol Sin, 35, 263-265.

    28. Junqueira, C., Crespo, Â., Ranjbar, S., De Lacerda, L.B., Lewandrowski, M., Ingber, J., Parry, B., Ravid, S., Clark, S., Schrimpf, M.R., Ho, F., Beakes, C., Margolin, J., Russell, N., Kays, K., Boucau, J., Das Adhikari, U., Vora, S.M., Leger, V., Gehrke, L., Henderson, L.A., Janssen, E., Kwon, D., Sander, C., Abraham, J., Goldberg, M.B., Wu, H., Mehta, G., Bell, S., Goldfeld, A.E., Filbin, M.R., Lieberman, J., 2022. FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature, 606, 576-584.

    29. Khan, M., Yoo, S.J., Clijsters, M., Backaert, W., Vanstapel, A., Speleman, K., Lietaer, C., Choi, S., Hether, T.D., Marcelis, L., Nam, A., Pan, L., Reeves, J.W., Van Bulck, P., Zhou, H., Bourgeois, M., Debaveye, Y., De Munter, P., Gunst, J., Jorissen, M., Lagrou, K., Lorent, N., Neyrinck, A., Peetermans, M., Thal, D.R., Vandenbriele, C., Wauters, J., Mombaerts, P., Van Gerven, L., 2021. Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb. Cell, 184, 5932-5949.e5915.

    30. Knoll, R., Schultze, J.L., Schulte-Schrepping, J., 2021. Monocytes and Macrophages in COVID-19. Front Immunol, 12, 720109.

    31. Krysko, O., Bourne, J.H., Kondakova, E., Galova, E.A., Whitworth, K., Newby, M.L., Bachert, C., Hill, H., Crispin, M., Stamataki, Z., Cunningham, A.F., Pugh, M., Khan, A.O., Rayes, J., Vedunova, M., Krysko, D.V., Brill, A., 2022. Severity of SARS-CoV-2 infection is associated with high numbers of alveolar mast cells and their degranulation. Front Immunol, 13, 968981.

    32. Lam, H.Y., Tergaonkar, V., Kumar, A.P., Ahn, K.S., 2021. Mast cells:Therapeutic targets for COVID-19 and beyond. IUBMB Life, 73, 1278-1292.

    33. Lee, J.S., Koh, J.Y., Yi, K., Kim, Y.I., Park, S.J., Kim, E.H., Kim, S.M., Park, S.H., Ju, Y.S., Choi, Y.K., Park, S.H., 2021. Single-cell transcriptome of bronchoalveolar lavage fluid reveals sequential change of macrophages during SARS-CoV-2 infection in ferrets. Nat Commun, 12, 4567.

    34. Leung, J.M., Yang, C.X., Tam, A., Shaipanich, T., Hackett, T.L., Singhera, G.K., Dorscheid, D.R., Sin, D.D., 2020. ACE-2 expression in the small airway epithelia of smokers and COPD patients:implications for COVID-19. Eur Respir J, 55, 2000688.

    35. Li, J., Zhang, Y., Jiang, L., Cheng, H., Li, J., Li, L., Chen, Z., Tang, F., Fu, Y., Jin, Y., Lu, B., Zheng, J., Wang, Z., 2022. Similar aerosol emission rates and viral loads in upper respiratory tracts for COVID-19 patients with Delta and Omicron variant infection. Virol Sin, 37, 762-764.

    36. Li, S., Zhang, Y., Guan, Z., Li, H., Ye, M., Chen, X., Shen, J., Zhou, Y., Shi, Z.L., Zhou, P.,Peng, K., 2020. SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation. Signal Transduct Target Ther, 5, 235.

    37. Liu, F.L., Wu, K., Sun, J., Duan, Z., Quan, X., Kuang, J., Chu, S., Pang, W., Gao, H., Xu, L., Li, Y.C., Zhang, H.L., Wang, X.H., Luo, R.H., Feng, X.L., Schöler, H.R., Chen, X., Pei, D., Wu, G., Zheng, Y.T.,Chen, J., 2021. Rapid generation of ACE2 humanized inbred mouse model for COVID-19 with tetraploid complementation. Natl Sci Rev, 8, nwaa285.

    38. Liu, Z., Xu, W., Xia, S., Gu, C., Wang, X., Wang, Q., Zhou, J., Wu, Y., Cai, X., Qu, D., Ying, T., Xie, Y., Lu, L., Yuan, Z., Jiang, S., 2020. RBD-Fc-based COVID-19 vaccine candidate induces highly potent SARS-CoV-2 neutralizing antibody response. Signal Transduct Target Ther, 5, 282.

    39. Luo, W., Zhang, J.W., Zhang, W., Lin, Y.L., Wang, Q., 2021. Circulating levels of IL-2, IL-4, TNF-α, IFN-γ, and C-reactive protein are not associated with severity of COVID-19 symptoms. J Med Virol, 93, 89-91.

    40. Malkoc, A., Gill, H., Liu, N., Nguyen, D.T., Phan, A.T., Nguyen, A., Toporoff, B., 2022. Bronchopulmonary Fistula Development in an Elderly Male With COVID-19 Infection. Cureus, 14, e31686.

    41. Malone, R.W., Tisdall, P., Fremont-Smith, P., Liu, Y., Huang, X.P., White, K.M., Miorin, L., Moreno, E., Alon, A., Delaforge, E., Hennecker, C.D., Wang, G., Pottel, J., Blair, R.V., Roy, C.J., Smith, N., Hall, J.M., Tomera, K.M., Shapiro, G., Mittermaier, A., Kruse, A.C., Garcia-Sastre, A., Roth, B.L., Glasspool-Malone, J., Ricke, D.O., 2021. COVID-19:Famotidine, Histamine, Mast Cells, and Mechanisms. Front Pharmacol, 12, 633680.

    42. Marshall, G.D., Jr., 2023. The pathophysiology of postacute sequelae of COVID-19 (PASC):Possible role for persistent inflammation. Asia Pac Allergy, 13, 77-84.

    43. Marshall, J.S., Portales-Cervantes, L.,Leong, E., 2019. Mast Cell Responses to Viruses and Pathogen Products. Int J Mol Sci, 20, 4241.

    44. Mehandru, S., Merad, M., 2022. Pathological sequelae of long-haul COVID. Nat Immunol, 23, 194-202.

    45. Mehta, P., Mcauley, D.F., Brown, M., Sanchez, E., Tattersall, R.S., Manson, J.J., 2020a. COVID-19:consider cytokine storm syndromes and immunosuppression. Lancet, 395, 1033-1034.

    46. Mehta, P., Porter, J.C., Manson, J.J., Isaacs, J.D., Openshaw, P.J.M., Mcinnes, I.B., Summers, C., Chambers, R.C., 2020b. Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation:challenges and opportunities. Lancet Respir Med, 8, 822-830.

    47. Mohandas, S., Jagannathan, P., Henrich, T.J., Sherif, Z.A., Bime, C., Quinlan, E., Portman, M.A., Gennaro, M., Rehman, J., Force, R.M.P.T., 2023. Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC). Elife, 12, e86014.

    48. Morrison, C.B., Edwards, C.E., Shaffer, K.M., Araba, K.C., Wykoff, J.A., Williams, D.R., Asakura, T., Dang, H., Morton, L.C., Gilmore, R.C., O'neal, W.K., Boucher, R.C., Baric, R.S., Ehre, C., 2022. SARS-CoV-2 infection of airway cells causes intense viral and cell shedding, two spreading mechanisms affected by IL-13. Proc Natl Acad Sci U S A, 119, e2119680119.

    49. Motta Junior, J.D.S., Miggiolaro, A., Nagashima, S., De Paula, C.B.V., Baena, C.P., Scharfstein, J., De Noronha, L., 2020. Mast Cells in Alveolar Septa of COVID-19 Patients:A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis. Front Immunol, 11, 574862.

    50. Munnur, D., Teo, Q., Eggermont, D., Lee, H.H.Y., Thery, F., Ho, J., Van Leur, S.W., Ng, W.W.S., Siu, L.Y.L., Beling, A., Ploegh, H., Pinto-Fernandez, A., Damianou, A., Kessler, B., Impens, F., Mok, C.K.P., Sanyal, S., 2021. Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection. Nat Immunol, 22, 1416-1427.

    51. Potashnikova, D.M., Sotnikova, T.N., Shirokova, O.M., Zayratyants, O.V., Vasilieva, E.Y., Sheval, E.V., 2023. Cilia impairment in bronchial epithelial cells detected in autopsy material of SARS-CoV-2-infected patient. Ultrastruct Pathol, 47, 382-387.

    52. Ramasamy, S., Subbian, S., 2021. Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis. Clin Microbiol Rev, 34, e00299-20.

    53. Ribeiro Dos Santos Miggiolaro, A.F., Da Silva Motta Junior, J., Busatta Vaz De Paula, C., Nagashima, S., Alessandra Scaranello Malaquias, M., Baena Carstens, L., A, N.M.-A., Pellegrino Baena, C., De Noronha, L., 2020. Covid-19 cytokine storm in pulmonary tissue:Anatomopathological and immunohistochemical findings. Respir Med Case Rep, 31, 101292.

    54. Robinot, R., Hubert, M., De Melo, G.D., Lazarini, F., Bruel, T., Smith, N., Levallois, S., Larrous, F., Fernandes, J., Gellenoncourt, S., Rigaud, S., Gorgette, O., Thouvenot, C., Trebeau, C., Mallet, A., Dumenil, G., Gobaa, S., Etournay, R., Lledo, P.M., Lecuit, M., Bourhy, H., Duffy, D., Michel, V., Schwartz, O., Chakrabarti, L.A., 2021. SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance. Nat Commun, 12, 4354.

    55. Ryan, F.J., Hope, C.M., Masavuli, M.G., Lynn, M.A., Mekonnen, Z.A., Yeow, A.E.L., Garcia-Valtanen, P., Al-Delfi, Z., Gummow, J., Ferguson, C., O'connor, S., Reddi, B.a.J., Hissaria, P., Shaw, D., Kok-Lim, C., Gleadle, J.M., Beard, M.R., Barry, S.C., Grubor-Bauk, B., Lynn, D.J., 2022. Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection. BMC Med, 20, 26.

    56. Schaller, T., Markl, B., Claus, R., Sholl, L., Hornick, J.L., Giannetti, M.P., Schweizer, L., Mann, M., Castells, M., 2022. Mast cells in lung damage of COVID-19 autopsies:A descriptive study. Allergy, 77, 2237-2239.

    57. Song, T.Z., Zheng, H.Y., Han, J.B., Jin, L., Yang, X., Liu, F.L., Luo, R.H., Tian, R.R., Cai, H.R., Feng, X.L., Liu, C., Li, M.H., Zheng, Y.T., 2020. Delayed severe cytokine storm and immune cell infiltration in SARS-CoV-2-infected aged Chinese rhesus macaques. Zool Res, 41, 503-516.

    58. Song, W.J., Hui, C.K.M., Hull, J.H., Birring, S.S., Mcgarvey, L., Mazzone, S.B., Chung, K.F., 2021. Confronting COVID-19-associated cough and the post-COVID syndrome:role of viral neurotropism, neuroinflammation, and neuroimmune responses. Lancet Respir Med, 9, 533-544.

    59. Stein, S.R., Ramelli, S.C., Grazioli, A., Chung, J.Y., Singh, M., Yinda, C.K., Winkler, C.W., Sun, J., Dickey, J.M., Ylaya, K., Ko, S.H., Platt, A.P., Burbelo, P.D., Quezado, M., Pittaluga, S., Purcell, M., Munster, V.J., Belinky, F., Ramos-Benitez, M.J., Boritz, E.A., Lach, I.A., Herr, D.L., Rabin, J., Saharia, K.K., Madathil, R.J., Tabatabai, A., Soherwardi, S., Mccurdy, M.T., Peterson, K.E., Cohen, J.I., De Wit, E., Vannella, K.M., Hewitt, S.M., Kleiner, D.E., Chertow, D.S., 2022. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature, 612, 758-763.

    60. Tan, J.Y., Anderson, D.E., Rathore, A.P., O'neill, A., Mantri, C.K., Saron, W.A., Lee, C.Q., Cui, C.W., Kang, A.E., Foo, R., Kalimuddin, S., Low, J.G., Ho, L., Tambyah, P., Burke, T.W., Woods, C.W., Chan, K.R., Karhausen, J., St John, A.L., 2023. Mast cell activation in lungs during SARS-CoV-2 infection associated with lung pathology and severe COVID-19. J Clin Invest, 133, e149834.

    61. Wechsler, J.B., Butuci, M., Wong, A., Kamboj, A.P., Youngblood, B.A., 2022. Mast cell activation is associated with post-acute COVID-19 syndrome. Allergy, 77, 1288-1291.

    62. Wu, F., Zhao, S., Yu, B., Chen, Y.M., Wang, W., Song, Z.G., Hu, Y., Tao, Z.W., Tian, J.H., Pei, Y.Y., Yuan, M.L., Zhang, Y.L., Dai, F.H., Liu, Y., Wang, Q.M., Zheng, J.J., Xu, L., Holmes, E.C., Zhang, Y.Z., 2020. A new coronavirus associated with human respiratory disease in China. Nature, 579, 265-269.

    63. Wu, M.L., Liu, F.L., Sun, J., Li, X., He, X.Y., Zheng, H.Y., Zhou, Y.H., Yan, Q., Chen, L., Yu, G.Y., Chang, J., Jin, X., Zhao, J., Chen, X.W., Zheng, Y.T., Wang, J.H., 2021. SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury. Signal Transduct Target Ther, 6, 428.

    64. Wu, M.L., Liu, F.L., Sun, J., Li, X., Qin, J.R., Yan, Q.H., Jin, X., Chen, X.W., Zheng, Y.T., Zhao, J.C., Wang, J.H., 2022. Combinational benefit of antihistamines and remdesivir for reducing SARS-CoV-2 replication and alleviating inflammation-induced lung injury in mice. Zool Res, 43, 457-468.

    65. Zhang, F., Mears, J.R., Shakib, L., Beynor, J.I., Shanaj, S., Korsunsky, I., Nathan, A., Donlin, L.T., Raychaudhuri, S., 2021. IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation. Genome Med, 13, 64.

    66. Zheng, J., Wang, Y., Li, K., Meyerholz, D.K., Allamargot, C., Perlman, S., 2021. Severe Acute Respiratory Syndrome Coronavirus 2-Induced Immune Activation and Death of Monocyte-Derived Human Macrophages and Dendritic Cells. J Infect Dis, 223, 785-795.

    67. Zhou, P., Yang, X.L., Wang, X.G., Hu, B., Zhang, L., Zhang, W., Si, H.R., Zhu, Y., Li, B., Huang, C.L., Chen, H.D., Chen, J., Luo, Y., Guo, H., Jiang, R.D., Liu, M.Q., Chen, Y., Shen, X.R., Wang, X., Zheng, X.S., Zhao, K., Chen, Q.J., Deng, F., Liu, L.L., Yan, B., Zhan, F.X., Wang, Y.Y., Xiao, G.F., Shi, Z.L., 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579, 270-273.

    68. Zhou, Y., Zhou, B., Pache, L., Chang, M., Khodabakhshi, A.H., Tanaseichuk, O., Benner, C., Chanda, S.K., 2019. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun, 10, 1523.

    69. Zhu, N., Wang, W., Liu, Z., Liang, C., Wang, W., Ye, F., Huang, B., Zhao, L., Wang, H., Zhou, W., Deng, Y., Mao, L., Su, C., Qiang, G., Jiang, T., Zhao, J., Wu, G., Song, J., Tan, W., 2020. Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells. Nat Commun, 11, 3910.

  • 加载中

Article Metrics

Article views(464) PDF downloads(8) Cited by()

Related
Proportional views

    Mast cell degranulation-triggered by SARS-CoV-2 induces tracheal-bronchial epithelial inflammation and injury

      Corresponding author: Yong-Tang Zheng, zhengyt@mail.kiz.ac.cn
      Corresponding author: Jian-Hua Wang, wang_jianhua@gibh.ac.cn
    • a. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
    • b. School of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China;
    • c. Key Laboratory of Bioactive Peptides of Yunnan Province, Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;
    • d. University of Chinese Academy of Sciences, Beijing 101408, China

    Abstract: SARS-CoV-2 infection-induced hyper-inflammation is a key pathogenic factor of COVID-19. Our research, along with others', has demonstrated that mast cells (MCs) play a vital role in the initiation of hyper-inflammation caused by SARS-CoV-2. In previous study, we observed that SARS-CoV-2 infection induced the accumulation of MCs in the peri-bronchus and bronchioalveolar-duct junction in humanized mice. Additionally, we found that MC degranulation triggered by the spike protein resulted in inflammation in alveolar epithelial cells and capillary endothelial cells, leading to subsequent lung injury. The trachea and bronchus are the routes for SARS-CoV-2 transmission after virus inhalation, and inflammation in these regions could promote viral spread. MCs are widely distributed throughout the respiratory tract. Thus, in this study, we investigated the role of MCs and their degranulation in the development of inflammation in tracheal-bronchial epithelium. Histological analyses showed the accumulation and degranulation of MCs in the peri-trachea of humanized mice infected with SARS-CoV-2. MC degranulation caused lesions in trachea, and the formation of papillary hyperplasia was observed. Through transcriptome analysis in bronchial epithelial cells, we found that MC degranulation significantly altered multiple cellular signaling, particularly, leading to upregulated immune responses and inflammation. The administration of ebastine or loratadine effectively suppressed the induction of inflammatory factors in bronchial epithelial cells and alleviated tracheal injury in mice. Taken together, our findings confirm the essential role of MC degranulation in SARS-CoV-2-induced hyper-inflammation and the subsequent tissue lesions. Furthermore, our results support the use of ebastine or loratadine to inhibit SARS-CoV-2-triggered degranulation, thereby preventing tissue damage caused by hyper-inflammation.

    Reference (69) Relative (20)

    目录

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return