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Abstract

Emerging and re-emerging respiratory viral infections pose a tremendous threat to human society, as exemplified by the ongoing COVID-19 pandemic. Upon viral invasion of the respiratory tract, the host initiates coordinated innate and adaptive immune responses to defend against the virus and to promote repair of the damaged tissue. However, dysregulated host immunity can also cause acute morbidity, hamper lung regeneration, and/or lead to chronic tissue sequelae. Here, we review our current knowledge of the immune mechanisms regulating antiviral protection, host pathogenesis, inflammation resolution, and lung regeneration following respiratory viral infections, mainly using influenza virus and SARS-CoV-2 infections as examples. We hope that this review sheds light on future research directions to elucidate the cellular and molecular cross talk regulating host recovery and to pave the way to the development of pro-repair therapeutics to augment lung regeneration following viral injury.

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2023-04-26
2024-04-26
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Literature Cited

  1. 1.
    Gambotto A, Barratt-Boyes SM, de Jong MD, Neumann G, Kawaoka Y. 2008. Human infection with highly pathogenic H5N1 influenza virus. Lancet 371:1464–75
    [Google Scholar]
  2. 2.
    Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S et al. 2020. Extrapulmonary manifestations of COVID-19. Nat. Med. 26:1017–32
    [Google Scholar]
  3. 3.
    Flerlage T, Boyd DF, Meliopoulos V, Thomas PG, Schultz-Cherry S. 2021. Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract. Nat. Rev. Microbiol. 19:425–41
    [Google Scholar]
  4. 4.
    Schneider DS, Ayres JS. 2008. Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat. Rev. Immunol. 8:889–95
    [Google Scholar]
  5. 5.
    Iwasaki A, Pillai PS. 2014. Innate immunity to influenza virus infection. Nat. Rev. Immunol. 14:315–28
    [Google Scholar]
  6. 6.
    Merad M, Blish CA, Sallusto F, Iwasaki A. 2022. The immunology and immunopathology of COVID-19. Science 375:1122–27
    [Google Scholar]
  7. 7.
    Pang IK, Iwasaki A. 2012. Control of antiviral immunity by pattern recognition and the microbiome. Immunol. Rev. 245:209–26
    [Google Scholar]
  8. 8.
    Malik G, Zhou Y. 2020. Innate immune sensing of influenza A virus. Viruses 12:7755
    [Google Scholar]
  9. 9.
    Webb LG, Fernandez-Sesma A. 2022. RNA viruses and the cGAS-STING pathway: reframing our understanding of innate immune sensing. Curr. Opin. Virol. 53:101206
    [Google Scholar]
  10. 10.
    Hussell T, Bell TJ. 2014. Alveolar macrophages: plasticity in a tissue-specific context. Nat. Rev. Immunol. 14:81–93
    [Google Scholar]
  11. 11.
    Divangahi M, King IL, Pernet E. 2015. Alveolar macrophages and type I IFN in airway homeostasis and immunity. Trends Immunol. 36:307–14
    [Google Scholar]
  12. 12.
    Kumagai Y, Takeuchi O, Kato H, Kumar H, Matsui K et al. 2007. Alveolar macrophages are the primary interferon-α producer in pulmonary infection with RNA viruses. Immunity 27:240–52
    [Google Scholar]
  13. 13.
    Wang J, Nikrad MP, Travanty EA, Zhou B, Phang T et al. 2012. Innate immune response of human alveolar macrophages during influenza A infection. PLOS ONE 7:e29879
    [Google Scholar]
  14. 14.
    Tate MD, Pickett DL, van Rooijen N, Brooks AG, Reading PC. 2010. Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J. Virol. 84:7569–80
    [Google Scholar]
  15. 15.
    Huot N, Planchais C, Contreras V, Jacquelin B, Petitdemange C et al. 2022. Adaptive MHC-E restricted tissue-resident NK cells are associated with persistent low antigen load in alveolar macrophages after SARS-CoV-2 infection. Version 1. Research Square. https://doi.org/10.21203/rs.3.rs-1561222/v1
  16. 16.
    Chu H, Chan JF, Wang Y, Yuen TT, Chai Y et al. 2020. Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19. Clin. Infect. Dis. 71:1400–9
    [Google Scholar]
  17. 17.
    Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D et al. 2020. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 181:1036–45.e9
    [Google Scholar]
  18. 18.
    Ural BB, Yeung ST, Damani-Yokota P, Devlin JC, de Vries M et al. 2020. Identification of a nerve-associated, lung-resident interstitial macrophage subset with distinct localization and immunoregulatory properties. Sci. Immunol. 5:45eaax8756
    [Google Scholar]
  19. 19.
    Lee AJ, Chen B, Chew MV, Barra NG, Shenouda MM et al. 2017. Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection. J. Exp. Med. 214:1153–67
    [Google Scholar]
  20. 20.
    Aldridge JR Jr., Moseley CE, Boltz DA, Negovetich NJ, Reynolds C et al. 2009. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. PNAS 106:5306–11
    [Google Scholar]
  21. 21.
    Kim TS, Braciale TJ. 2009. Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8+ T cell responses. PLOS ONE 4:e4204
    [Google Scholar]
  22. 22.
    Junqueira C, Crespo A, Ranjbar S, de Lacerda LB, Lewandrowski M et al. 2022. FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature 606:576–84
    [Google Scholar]
  23. 23.
    Freeman CM, Curtis JL. 2017. Lung dendritic cells: shaping immune responses throughout chronic obstructive pulmonary disease progression. Am. J. Respir. Cell Mol. Biol. 56:152–59
    [Google Scholar]
  24. 24.
    Eisenbarth SC. 2019. Dendritic cell subsets in T cell programming: location dictates function. Nat. Rev. Immunol. 19:89–103
    [Google Scholar]
  25. 25.
    Sanchez-Cerrillo I, Landete P, Aldave B, Sanchez-Alonso S, Sanchez-Azofra A et al. 2020. COVID-19 severity associates with pulmonary redistribution of CD1c+ DCs and inflammatory transitional and nonclassical monocytes. J. Clin. Investig. 130:6290–300
    [Google Scholar]
  26. 26.
    Zhao J, Zhao J, Legge K, Perlman S. 2011. Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J. Clin. Investig. 121:4921–30
    [Google Scholar]
  27. 27.
    Roy Wong L-Y, Zheng J, Wilhelmsen K, Li K, Ortiz ME et al. 2022. Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19. Nature 605:146–51
    [Google Scholar]
  28. 28.
    Smit JJ, Rudd BD, Lukacs NW. 2006. Plasmacytoid dendritic cells inhibit pulmonary immunopathology and promote clearance of respiratory syncytial virus. J. Exp. Med. 203:1153–59
    [Google Scholar]
  29. 29.
    GeurtsvanKessel CH, Willart MA, van Rijt LS, Muskens F, Kool M et al. 2008. Clearance of influenza virus from the lung depends on migratory langerin+CD11b but not plasmacytoid dendritic cells. J. Exp. Med. 205:1621–34
    [Google Scholar]
  30. 30.
    Arunachalam PS, Wimmers F, Mok CKP, Perera R, Scott M et al. 2020. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science 369:1210–20
    [Google Scholar]
  31. 31.
    Culley FJ. 2009. Natural killer cells in infection and inflammation of the lung. Immunology 128:151–63
    [Google Scholar]
  32. 32.
    Bi J. 2022. NK cell dysfunction in patients with COVID-19. Cell Mol. Immunol. 19:127–29
    [Google Scholar]
  33. 33.
    Lujan RA, Vrba SM, Hickman HD. 2022. Antiviral activities of group I innate lymphoid cells. J. Mol. Biol. 434:167266
    [Google Scholar]
  34. 34.
    Newton AH, Cardani A, Braciale TJ. 2016. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin. Immunopathol. 38:471–82
    [Google Scholar]
  35. 35.
    Brown DM, Lee S, Garcia-Hernandez ML, Swain SL 2012. Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J. Virol. 86:6792–803
    [Google Scholar]
  36. 36.
    Hua L, Yao S, Pham D, Jiang L, Wright J et al. 2013. Cytokine-dependent induction of CD4+ T cells with cytotoxic potential during influenza virus infection. J. Virol. 87:11884–93
    [Google Scholar]
  37. 37.
    Hufford MM, Kim TS, Sun J, Braciale TJ. 2011. Antiviral CD8+ T cell effector activities in situ are regulated by target cell type. J. Exp. Med. 208:167–80
    [Google Scholar]
  38. 38.
    Sun J, Madan R, Karp CL, Braciale TJ. 2009. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat. Med. 15:277–84
    [Google Scholar]
  39. 39.
    Szabo PA, Miron M, Farber DL. 2019. Location, location, location: tissue resident memory T cells in mice and humans. Sci. Immunol. 4:34eaas9673
    [Google Scholar]
  40. 40.
    Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM et al. 2020. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 181:1489–501.e15
    [Google Scholar]
  41. 41.
    Sekine T, Perez-Potti A, Rivera-Ballesteros O, Stralin K, Gorin JB et al. 2020. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell 183:158–68.e14
    [Google Scholar]
  42. 42.
    Westmeier J, Paniskaki K, Karakose Z, Werner T, Sutter K et al. 2020. Impaired cytotoxic CD8+ T cell response in elderly COVID-19 patients. mBio 11:5e02243–20
    [Google Scholar]
  43. 43.
    Rydyznski Moderbacher C, Ramirez SI, Dan JM, Grifoni A, Hastie KM et al. 2020. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell 183:996–1012.e19
    [Google Scholar]
  44. 44.
    Cheon IS, Li C, Son YM, Goplen NP, Wu Y et al. 2021. Immune signatures underlying post-acute COVID-19 lung sequelae. Sci. Immunol. 6:eabk1741
    [Google Scholar]
  45. 45.
    Poon MML, Rybkina K, Kato Y, Kubota M, Matsumoto R et al. 2021. SARS-CoV-2 infection generates tissue-localized immunological memory in humans. Sci. Immunol. 6:eabl9105
    [Google Scholar]
  46. 46.
    Tang J, Zeng C, Cox TM, Li C, Son YM et al. 2022. Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination. Sci. Immunol. 7:7674
    [Google Scholar]
  47. 47.
    Jarjour NN, Masopust D, Jameson SC. 2021. T cell memory: understanding COVID-19. Immunity 54:14–18
    [Google Scholar]
  48. 48.
    Grant EJ, Quinones-Parra SM, Clemens EB, Kedzierska K 2016. Human influenza viruses and CD8+ T cell responses. Curr. Opin. Virol. 16:132–42
    [Google Scholar]
  49. 49.
    Vinuesa CG, Linterman MA, Yu D, MacLennan IC 2016. Follicular helper T cells. Annu. Rev. Immunol. 34:335–68
    [Google Scholar]
  50. 50.
    Yoo JK, Fish EN, Braciale TJ. 2012. LAPCs promote follicular helper T cell differentiation of Ag-primed CD4+ T cells during respiratory virus infection. J. Exp. Med. 209:1853–67
    [Google Scholar]
  51. 51.
    Piccoli L, Park YJ, Tortorici MA, Czudnochowski N, Walls AC et al. 2020. Mapping neutralizing and immunodominant sites on the SARS-CoV-2 spike receptor-binding domain by structure-guided high-resolution serology. Cell 183:1024–42.e21
    [Google Scholar]
  52. 52.
    Cele S, Gazy I, Jackson L, Hwa SH, Tegally H et al. 2021. Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. Nature 593:142–46
    [Google Scholar]
  53. 53.
    Garcia-Beltran WF, Lam EC, St. Denis K, Nitido AD, Garcia ZH et al. 2021. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell 184:2372–83.e9
    [Google Scholar]
  54. 54.
    Waffarn EE, Baumgarth N. 2011. Protective B cell responses to flu—no fluke!. J. Immunol. 186:3823–29
    [Google Scholar]
  55. 55.
    Sautto GA, Kirchenbaum GA, Ross TM. 2018. Towards a universal influenza vaccine: different approaches for one goal. Virol. J. 15:17
    [Google Scholar]
  56. 56.
    Burton DR. 2002. Antibodies, viruses and vaccines. Nat. Rev. Immunol. 2:706–13
    [Google Scholar]
  57. 57.
    Godfrey DI, Uldrich AP, McCluskey J, Rossjohn J, Moody DB. 2015. The burgeoning family of unconventional T cells. Nat. Immunol. 16:1114–23
    [Google Scholar]
  58. 58.
    Loh L, Wang Z, Sant S, Koutsakos M, Jegaskanda S et al. 2016. Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation. PNAS 113:10133–38
    [Google Scholar]
  59. 59.
    Li H, Xiang Z, Feng T, Li J, Liu Y et al. 2013. Human V9Vδ2-T cells efficiently kill influenza virus-infected lung alveolar epithelial cells. Cell Mol. Immunol. 10:159–64
    [Google Scholar]
  60. 60.
    De Santo C, Salio M, Masri SH, Lee LY, Dong T et al. 2008. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J. Clin. Investig. 118:4036–48
    [Google Scholar]
  61. 61.
    Parrot T, Gorin JB, Ponzetta A, Maleki KT, Kammann T et al. 2020. MAIT cell activation and dynamics associated with COVID-19 disease severity. Sci. Immunol. 5:51eabe1670
    [Google Scholar]
  62. 62.
    Jouan Y, Guillon A, Gonzalez L, Perez Y, Boisseau C et al. 2020. Phenotypical and functional alteration of unconventional T cells in severe COVID-19 patients. J. Exp. Med. 217:12e20200872
    [Google Scholar]
  63. 63.
    Zingaropoli MA, Perri V, Pasculli P, Cogliati Dezza F, Nijhawan P et al. 2021. Major reduction of NKT cells in patients with severe COVID-19 pneumonia. Clin. Immunol. 222:108630
    [Google Scholar]
  64. 64.
    Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF et al. 2003. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 361:1767–72
    [Google Scholar]
  65. 65.
    Memish ZA, Perlman S, Van Kerkhove MD, Zumla A. 2020. Middle East respiratory syndrome. Lancet 395:1063–77
    [Google Scholar]
  66. 66.
    Wolfel R, Corman VM, Guggemos W, Seilmaier M, Zange S et al. 2020. Virological assessment of hospitalized patients with COVID-2019. Nature 581:465–69
    [Google Scholar]
  67. 67.
    Oshansky CM, Gartland AJ, Wong SS, Jeevan T, Wang D et al. 2014. Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load. Am. J. Respir. Crit. Care Med. 189:449–62
    [Google Scholar]
  68. 68.
    Davidson S, Crotta S, McCabe TM, Wack A. 2014. Pathogenic potential of interferon αβ in acute influenza infection. Nat. Commun. 5:3864
    [Google Scholar]
  69. 69.
    Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J et al. 2016. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe 19:181–93
    [Google Scholar]
  70. 70.
    Broggi A, Ghosh S, Sposito B, Spreafico R, Balzarini F et al. 2020. Type III interferons disrupt the lung epithelial barrier upon viral recognition. Science 369:706–12
    [Google Scholar]
  71. 71.
    Major J, Crotta S, Llorian M, McCabe TM, Gad HH et al. 2020. Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. Science 369:712–17
    [Google Scholar]
  72. 72.
    Mangalmurti N, Hunter CA. 2020. Cytokine storms: understanding COVID-19. Immunity 53:19–25
    [Google Scholar]
  73. 73.
    Gu SX, Tyagi T, Jain K, Gu VW, Lee SH et al. 2021. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat. Rev. Cardiol. 18:194–209
    [Google Scholar]
  74. 74.
    Salomon R, Hoffmann E, Webster RG. 2007. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. PNAS 104:12479–81
    [Google Scholar]
  75. 75.
    Zhao M. 2020. Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies. Int. J. Antimicrob. Agents 55:105982
    [Google Scholar]
  76. 76.
    Afzali B, Noris M, Lambrecht BN, Kemper C. 2022. The state of complement in COVID-19. Nat. Rev. Immunol. 22:77–84
    [Google Scholar]
  77. 77.
    Jiang Y, Zhao G, Song N, Li P, Chen Y et al. 2018. Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV. Emerg. Microbes Infect. 7:77
    [Google Scholar]
  78. 78.
    Sun S, Zhao G, Liu C, Wu X, Guo Y et al. 2013. Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection. Am. J. Respir. Cell Mol. Biol. 49:221–30
    [Google Scholar]
  79. 79.
    Narasimhan B, Lorente-Ros M, Aguilar-Gallardo JS, Lizardo CP, Narasimhan H et al. 2021. Anticoagulation in COVID-19: a review of current literature and guidelines. Hospital. Pract. 49:307–24
    [Google Scholar]
  80. 80.
    Zhu B, Wu Y, Huang S, Zhang R, Son YM et al. 2021. Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection. Immunity 54:1200–18.e9
    [Google Scholar]
  81. 81.
    Hoepel W, Chen HJ, Geyer CE, Allahverdiyeva S, Manz XD et al. 2021. High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages. Sci. Transl. Med. 13:596eabf8654
    [Google Scholar]
  82. 82.
    Alon R, Sportiello M, Kozlovski S, Kumar A, Reilly EC et al. 2021. Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19. Nat. Rev. Immunol. 21:49–64
    [Google Scholar]
  83. 83.
    Channappanavar R, Perlman S. 2017. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 39:529–39
    [Google Scholar]
  84. 84.
    Zhou Y, Fu B, Zheng X, Wang D, Zhao C et al. 2020. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl. Sci. Rev. 7:998–1002
    [Google Scholar]
  85. 85.
    Sefik E, Qu R, Junqueira C, Kaffe E, Mirza H et al. 2022. Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature 606:585–93
    [Google Scholar]
  86. 86.
    Johansson C, Kirsebom FCM. 2021. Neutrophils in respiratory viral infections. Mucosal Immunol. 14:815–27
    [Google Scholar]
  87. 87.
    Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M et al. 2020. Neutrophil extracellular traps in COVID-19. JCI Insight 5:11e138999
    [Google Scholar]
  88. 88.
    Lucas C, Wong P, Klein J, Castro TBR, Silva J et al. 2020. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 584:463–69
    [Google Scholar]
  89. 89.
    Tang BM, Shojaei M, Teoh S, Meyers A, Ho J et al. 2019. Neutrophils-related host factors associated with severe disease and fatality in patients with influenza infection. Nat. Commun. 10:3422
    [Google Scholar]
  90. 90.
    Twaddell SH, Baines KJ, Grainge C, Gibson PG. 2019. The emerging role of neutrophil extracellular traps in respiratory disease. Chest 156:774–82
    [Google Scholar]
  91. 91.
    Kulkarni U, Zemans RL, Smith CA, Wood SC, Deng JC, Goldstein DR. 2019. Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality. Mucosal Immunol. 12:545–54
    [Google Scholar]
  92. 92.
    Zhu B, Zhang R, Li C, Jiang L, Xiang M et al. 2019. BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection. PNAS 116:11888–93
    [Google Scholar]
  93. 93.
    Wu ML, Liu FL, Sun J, Li X, He XY et al. 2021. SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury. Signal Transduct. Target. Ther. 6:428
    [Google Scholar]
  94. 94.
    Hu Y, Jin Y, Han D, Zhang G, Cao S et al. 2012. Mast cell-induced lung injury in mice infected with H5N1 influenza virus. J. Virol. 86:3347–56
    [Google Scholar]
  95. 95.
    Kim TS, Hufford MM, Sun J, Fu YX, Braciale TJ. 2010. Antigen persistence and the control of local T cell memory by migrant respiratory dendritic cells after acute virus infection. J. Exp. Med. 207:1161–72
    [Google Scholar]
  96. 96.
    Guo K, Yombo DJ, Xu J, Wang Z, Schmit T et al. 2022. The chemokine receptor CXCR3 promotes CD8+ T cell-dependent lung pathology during influenza pathogenesis. bioRxiv 2022.02.14.480379, Feb. 14
  97. 97.
    Oja AE, Saris A, Ghandour CA, Kragten NAM, Hogema BM et al. 2020. Divergent SARS-CoV-2-specific T- and B-cell responses in severe but not mild COVID-19 patients. Eur. J. Immunol. 50:1998–2012
    [Google Scholar]
  98. 98.
    Zhao Y, Kilian C, Turner JE, Bosurgi L, Roedl K et al. 2021. Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients. Sci. Immunol. 6:56eabf6692
    [Google Scholar]
  99. 99.
    Liao M, Liu Y, Yuan J, Wen Y, Xu G et al. 2020. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat. Med. 26:842–44
    [Google Scholar]
  100. 100.
    Georg P, Astaburuaga-Garcia R, Bonaguro L, Brumhard S, Michalick L et al. 2022. Complement activation induces excessive T cell cytotoxicity in severe COVID-19. Cell 185:493–512.e25
    [Google Scholar]
  101. 101.
    Zhivaki D, Lemoine S, Lim A, Morva A, Vidalain PO et al. 2017. Respiratory syncytial virus infects regulatory B cells in human neonates via chemokine receptor CX3CR1 and promotes lung disease severity. Immunity 46:301–14
    [Google Scholar]
  102. 102.
    Woodruff MC, Ramonell RP, Nguyen DC, Cashman KS, Saini AS et al. 2020. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat. Immunol. 21:1506–16
    [Google Scholar]
  103. 103.
    Kaneko N, Kuo HH, Boucau J, Farmer JR, Allard-Chamard H et al. 2020. Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19. Cell 183:143–57.e13
    [Google Scholar]
  104. 104.
    Chakraborty S, Gonzalez J, Edwards K, Mallajosyula V, Buzzanco AS et al. 2021. Proinflammatory IgG Fc structures in patients with severe COVID-19. Nat. Immunol. 22:67–73
    [Google Scholar]
  105. 105.
    Larsen MD, de Graaf EL, Sonneveld ME, Plomp HR, Nouta J et al. 2021. Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity. Science 371:6532eabc8378
    [Google Scholar]
  106. 106.
    Snelgrove RJ, Goulding J, Didierlaurent AM, Lyonga D, Vekaria S et al. 2008. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nat. Immunol. 9:1074–83
    [Google Scholar]
  107. 107.
    Kvedaraite E, Hertwig L, Sinha I, Ponzetta A, Hed Myrberg I et al. 2021. Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity. PNAS 118:6e2018587118
    [Google Scholar]
  108. 108.
    Schneider C, Nobs SP, Kurrer M, Rehrauer H, Thiele C, Kopf M. 2014. Induction of the nuclear receptor PPAR-gamma by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat. Immunol. 15:1026–37
    [Google Scholar]
  109. 109.
    Huang S, Zhu B, Cheon IS, Goplen NP, Jiang L et al. 2019. PPAR-γ in macrophages limits pulmonary inflammation and promotes host recovery following respiratory viral infection. J. Virol. 93:9e00030–19
    [Google Scholar]
  110. 110.
    Li F, Piattini F, Pohlmeier L, Feng Q, Rehrauer H, Kopf M. 2022. Monocyte-derived alveolar macrophages autonomously determine severe outcome of respiratory viral infection. Sci. Immunol. 7:eabj5761
    [Google Scholar]
  111. 111.
    Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB et al. 2013. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38:792–804
    [Google Scholar]
  112. 112.
    Delorey TM, Ziegler CGK, Heimberg G, Normand R, Yang Y et al. 2021. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature 595:107–13
    [Google Scholar]
  113. 113.
    Chen ST, Park MD, Del Valle DM, Buckup M, Tabachnikova A et al. 2022. A shift in lung macrophage composition is associated with COVID-19 severity and recovery. Science Transl. Med. 14:eabn5168
    [Google Scholar]
  114. 114.
    Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG et al. 2011. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12:1045–54
    [Google Scholar]
  115. 115.
    Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM et al. 2011. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. 12:1055–62
    [Google Scholar]
  116. 116.
    Le Goffic R, Arshad MI, Rauch M, L'Helgoualc'h A, Delmas B et al. 2011. Infection with influenza virus induces IL-33 in murine lungs. Am. J. Respir. Cell Mol. Biol. 45:1125–32
    [Google Scholar]
  117. 117.
    Wu X, Kasmani MY, Zheng S, Khatun A, Chen Y et al. 2022. BATF promotes group 2 innate lymphoid cell-mediated lung tissue protection during acute respiratory virus infection. Sci. Immunol. 7:eabc9934
    [Google Scholar]
  118. 118.
    Califano D, Furuya Y, Roberts S, Avram D, McKenzie ANJ, Metzger DW 2018. IFN-gamma increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells. Mucosal Immunol. 11:209–19
    [Google Scholar]
  119. 119.
    Jamieson AM, Pasman L, Yu S, Gamradt P, Homer RJ et al. 2013. Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science 340:1230–34
    [Google Scholar]
  120. 120.
    Duerr CU, McCarthy CD, Mindt BC, Rubio M, Meli AP et al. 2016. Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells. Nat. Immunol. 17:65–75
    [Google Scholar]
  121. 121.
    Kuri-Cervantes L, Pampena MB, Meng W, Rosenfeld AM, Ittner CAG et al. 2020. Comprehensive mapping of immune perturbations associated with severe COVID-19. Sci. Immunol. 5:49eabd7114
    [Google Scholar]
  122. 122.
    Silverstein NJ, Wang Y, Manickas-Hill Z, Carbone C, Dauphin A et al. 2022. Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection. eLife 11:e74681
    [Google Scholar]
  123. 123.
    Gomez-Cadena A, Spehner L, Kroemer M, Khelil MB, Bouiller K et al. 2021. Severe COVID-19 patients exhibit an ILC2 NKG2D+ population in their impaired ILC compartment. Cell Mol. Immunol. 18:484–86
    [Google Scholar]
  124. 124.
    Sasson J, Donlan AN, Ma JZ, Haughey HM, Coleman R et al. 2022. Safety and efficacy of dupilumab for the treatment of hospitalized patients with moderate to severe coronavirus disease 2019: a phase 2a trial. Open Forum Infect. Dis. 9:8ofac343
    [Google Scholar]
  125. 125.
    Sonnenberg GF, Fouser LA, Artis D. 2011. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12:383–90
    [Google Scholar]
  126. 126.
    Pociask DA, Scheller EV, Mandalapu S, McHugh KJ, Enelow RI et al. 2013. IL-22 is essential for lung epithelial repair following influenza infection. Am. J. Pathol. 182:1286–96
    [Google Scholar]
  127. 127.
    Ivanov S, Renneson J, Fontaine J, Barthelemy A, Paget C et al. 2013. Interleukin-22 reduces lung inflammation during influenza A virus infection and protects against secondary bacterial infection. J. Virol. 87:6911–24
    [Google Scholar]
  128. 128.
    Moser EK, Hufford MM, Braciale TJ. 2014. Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP3+ regulatory T cell dependent manner. PLOS Pathog. 10:e1004315
    [Google Scholar]
  129. 129.
    Antunes I, Kassiotis G. 2010. Suppression of innate immune pathology by regulatory T cells during Influenza A virus infection of immunodeficient mice. J. Virol. 84:12564–75
    [Google Scholar]
  130. 130.
    Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. 2009. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10:595–602
    [Google Scholar]
  131. 131.
    Cretney E, Xin A, Shi W, Minnich M, Masson F et al. 2011. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat. Immunol. 12:304–11
    [Google Scholar]
  132. 132.
    Sadeghi A, Tahmasebi S, Mahmood A, Kuznetsova M, Valizadeh H et al. 2021. Th17 and Treg cells function in SARS-CoV2 patients compared with healthy controls. J. Cell Physiol. 236:2829–39
    [Google Scholar]
  133. 133.
    Szabo PA, Dogra P, Gray JI, Wells SB, Connors TJ et al. 2021. Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19. Immunity 54:797–814.e6
    [Google Scholar]
  134. 134.
    Vick SC, Frutoso M, Mair F, Konecny AJ, Greene E et al. 2021. A regulatory T cell signature distinguishes the immune landscape of COVID-19 patients from those with other respiratory infections. Sci. Adv. 7:eabj0274
    [Google Scholar]
  135. 135.
    Galvan-Pena S, Leon J, Chowdhary K, Michelson DA, Vijaykumar B et al. 2021. Profound Treg perturbations correlate with COVID-19 severity. PNAS 118:37e2111315118
    [Google Scholar]
  136. 136.
    Panduro M, Benoist C, Mathis D. 2016. Tissue Tregs. Annu. Rev. Immunol. 34:609–33
    [Google Scholar]
  137. 137.
    Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, Treuting PM, Rudensky AY. 2015. A distinct function of regulatory T cells in tissue protection. Cell 162:1078–89
    [Google Scholar]
  138. 138.
    Harb H, Benamar M, Lai PS, Contini P, Griffith JW et al. 2021. Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections. Immunity 54:1186–99.e7
    [Google Scholar]
  139. 139.
    Morales-Nebreda L, Helmin KA, Torres Acosta MA, Markov NS, Hu JY et al. 2021. Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia. JCI Insight 6:e141690
    [Google Scholar]
  140. 140.
    Sun J, Cardani A, Sharma AK, Laubach VE, Jack RS et al. 2011. Autocrine regulation of pulmonary inflammation by effector T-cell derived IL-10 during infection with respiratory syncytial virus. PLOS Pathog 7:e1002173
    [Google Scholar]
  141. 141.
    Loebbermann J, Schnoeller C, Thornton H, Durant L, Sweeney NP et al. 2012. IL-10 regulates viral lung immunopathology during acute respiratory syncytial virus infection in mice. PLOS ONE 7:e32371
    [Google Scholar]
  142. 142.
    Sun J, Dodd H, Moser EK, Sharma R, Braciale TJ. 2011. CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat. Immunol. 12:327–34
    [Google Scholar]
  143. 143.
    Knowles MR, Boucher RC. 2002. Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Investig. 109:571–77
    [Google Scholar]
  144. 144.
    Adam D, Perotin JM, Lebargy F, Birembaut P, Deslée G, Coraux C. 2014. Régénération de l'épithélium des voies aériennes. Rev. Maladies Respir. 31:300–11
    [Google Scholar]
  145. 145.
    Rock JR, Gao X, Xue Y, Randell SH, Kong YY, Hogan BL. 2011. Notch-dependent differentiation of adult airway basal stem cells. Cell Stem Cell 8:639–48
    [Google Scholar]
  146. 146.
    Stupnikov MR, Yang Y, Mori M, Lu J, Cardoso WV. 2019. Jagged and Delta-like ligands control distinct events during airway progenitor cell differentiation. eLife 8:e50487
    [Google Scholar]
  147. 147.
    Mori M, Mahoney JE, Stupnikov MR, Paez-Cortez JR, Szymaniak AD et al. 2015. Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development 142:258–67
    [Google Scholar]
  148. 148.
    Pardo-Saganta A, Law BM, Tata PR, Villoria J, Saez B et al. 2015. Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations. Cell Stem Cell 16:184–97
    [Google Scholar]
  149. 149.
    Rawlins EL, Okubo T, Xue Y, Brass DM, Auten RL et al. 2009. The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4:525–34
    [Google Scholar]
  150. 150.
    Basil MC, Katzen J, Engler AE, Guo M, Herriges MJ et al. 2020. The cellular and physiological basis for lung repair and regeneration: past, present, and future. Cell Stem Cell 26:482–502
    [Google Scholar]
  151. 151.
    Zepp JA, Morrisey EE. 2019. Cellular crosstalk in the development and regeneration of the respiratory system. Nat. Rev. Mol. Cell Biol. 20:551–66
    [Google Scholar]
  152. 152.
    Zacharias WJ, Frank DB, Zepp JA, Morley MP, Alkhaleel FA et al. 2018. Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 555:251–55
    [Google Scholar]
  153. 153.
    Nabhan AN, Brownfield DG, Harbury PB, Krasnow MA, Desai TJ. 2018. Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science 359:1118–23
    [Google Scholar]
  154. 154.
    Hung L-Y, Sen D, Oniskey TK, Katzen J, Cohen NA et al. 2019. Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism. Mucosal. Immunol. 12:64–76
    [Google Scholar]
  155. 155.
    Choi J, Park JE, Tsagkogeorga G, Yanagita M, Koo BK et al. 2020. Inflammatory signals induce AT2 cell-derived damage-associated transient progenitors that mediate alveolar regeneration. Cell Stem Cell 27:366–82.e7
    [Google Scholar]
  156. 156.
    Kobayashi Y, Tata A, Konkimalla A, Katsura H, Lee RF et al. 2020. Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat. Cell Biol. 22:934–46
    [Google Scholar]
  157. 157.
    Strunz M, Simon LM, Ansari M, Kathiriya JJ, Angelidis I et al. 2020. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat. Commun. 11:3559
    [Google Scholar]
  158. 158.
    Katsura H, Kobayashi Y, Tata PR, Hogan BLM. 2019. IL-1 and TNFα contribute to the inflammatory niche to enhance alveolar regeneration. Stem Cell Rep. 12:657–66
    [Google Scholar]
  159. 159.
    Taylor MS, Chivukula RR, Myers LC, Jeck WR, Waghray A et al. 2018. A conserved distal lung regenerative pathway in acute lung injury. Am. J. Pathol. 188:1149–60
    [Google Scholar]
  160. 160.
    Kumar PA, Hu Y, Yamamoto Y, Hoe NB, Wei TS et al. 2011. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 147:525–38
    [Google Scholar]
  161. 161.
    Zuo W, Zhang T, Wu DZ, Guan SP, Liew AA et al. 2015. p63+Krt5+ distal airway stem cells are essential for lung regeneration. Nature 517:616–20
    [Google Scholar]
  162. 162.
    Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG et al. 2015. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517:621–25
    [Google Scholar]
  163. 163.
    Liu K, Tang M, Liu Q, Han X, Jin H et al. 2020. Bi-directional differentiation of single bronchioalveolar stem cells during lung repair. Cell Discov. 6:1
    [Google Scholar]
  164. 164.
    Kim CFB, Jackson EL, Woolfenden AE, Lawrence S, Babar I et al. 2005. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121:823–35
    [Google Scholar]
  165. 165.
    Salwig I, Spitznagel B, Vazquez-Armendariz AI, Khalooghi K, Guenther S et al. 2019. Bronchioalveolar stem cells are a main source for regeneration of distal lung epithelia in vivo. EMBO J. 38:e102099
    [Google Scholar]
  166. 166.
    Basil MC, Cardenas-Diaz FL, Kathiriya JJ, Morley MP, Carl J et al. 2022. Human distal airways contain a multipotent secretory cell that can regenerate alveoli. Nature 604:120–26
    [Google Scholar]
  167. 167.
    Kadur Lakshminarasimha Murthy P, Sontake V, Tata A, Kobayashi Y, Macadlo L et al. 2022. Human distal lung maps and lineage hierarchies reveal a bipotent progenitor. Nature 604:111–19
    [Google Scholar]
  168. 168.
    Kathiriya JJ, Brumwell AN, Jackson JR, Tang X, Chapman HA. 2020. Distinct airway epithelial stem cells hide among club cells but mobilize to promote alveolar regeneration. Cell Stem Cell 26:346–58.e4
    [Google Scholar]
  169. 169.
    Ushakumary MG, Riccetti M, Perl A-KT. 2021. Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration. Stem Cells Transl. Med. 10:1021–32
    [Google Scholar]
  170. 170.
    White ES. 2015. Lung extracellular matrix and fibroblast function. Ann. Am. Thorac. Soc. 12:Suppl. 1S30–33
    [Google Scholar]
  171. 171.
    Lechner AJ, Driver IH, Lee J, Conroy CM, Nagle A et al. 2017. Recruited monocytes and type 2 immunity promote lung regeneration following pneumonectomy. Cell Stem Cell 21:120–34.e7
    [Google Scholar]
  172. 172.
    Zepp JA, Zacharias WJ, Frank DB, Cavanaugh CA, Zhou S et al. 2017. Distinct mesenchymal lineages and niches promote epithelial self-renewal and myofibrogenesis in the lung. Cell 170:1134–48.e10
    [Google Scholar]
  173. 173.
    Lee J-H, Tammela T, Hofree M, Choi J, Marjanovic ND et al. 2017. Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6. Cell 170:1149–63.e12
    [Google Scholar]
  174. 174.
    Boyd DF, Allen EK, Randolph AG, Guo X-ZJ, Weng Y et al. 2020. Exuberant fibroblast activity compromises lung function via ADAMTS4. Nature 587:466–71. Erratum. 2020 Nature 588:E5
    [Google Scholar]
  175. 175.
    Alvarez DF, Huang L, King JA, ElZarrad MK, Yoder MC, Stevens T. 2008. Lung microvascular endothelium is enriched with progenitor cells that exhibit vasculogenic capacity. Am. J. Physiol.-Lung Cell. Mol. Physiol. 294:L419–30
    [Google Scholar]
  176. 176.
    Zhao G, Weiner AI, Neupauer KM, de Mello Costa MF, Palashikar G et al. 2020. Regeneration of the pulmonary vascular endothelium after viral pneumonia requires COUP-TF2. Sci. Adv. 6:eabc4493
    [Google Scholar]
  177. 177.
    Niethamer TK, Stabler CT, Leach JP, Zepp JA, Morley MP et al. 2020. Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury. eLife 9:e53072
    [Google Scholar]
  178. 178.
    Xie Y, Bowe B, Al-Aly Z. 2021. Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status. Nat. Commun. 12:6571
    [Google Scholar]
  179. 179.
    Narasimhan H, Wu Y, Goplen NP, Sun J. 2022. Immune determinants of chronic sequelae after respiratory viral infection. Sci. Immunol. 7:eabm7996
    [Google Scholar]
  180. 180.
    Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C et al. 2021. Post-acute COVID-19 syndrome. Nat. Med. 27:601–15
    [Google Scholar]
  181. 181.
    Wu X, Liu X, Zhou Y, Yu H, Li R et al. 2021. 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study. Lancet Respir. Med. 9:747–54
    [Google Scholar]
  182. 182.
    Huang L, Li X, Gu X, Zhang H, Ren L et al. 2022. Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study. Lancet Respir. Med. 10:9863–76
    [Google Scholar]
  183. 183.
    Choutka J, Jansari V, Hornig M, Iwasaki A. 2022. Unexplained post-acute infection syndromes. Nat. Med. 28:911–23
    [Google Scholar]
  184. 184.
    Vijayakumar B, Boustani K, Ogger PP, Papadaki A, Tonkin J et al. 2022. Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVID-19 respiratory disease. Immunity 55:542–56.e5
    [Google Scholar]
  185. 185.
    Wendisch D, Dietrich O, Mari T, von Stillfried S, Ibarra IL et al. 2021. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell 184:6243–61.e27
    [Google Scholar]
  186. 186.
    Melms JC, Biermann J, Huang H, Wang Y, Nair A et al. 2021. A molecular single-cell lung atlas of lethal COVID-19. Nature 595:114–19
    [Google Scholar]
  187. 187.
    Phetsouphanh C, Darley DR, Wilson DB, Howe A, Munier CML et al. 2022. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat. Immunol. 23:210–16
    [Google Scholar]
  188. 188.
    Su Y, Yuan D, Chen DG, Ng RH, Wang K et al. 2022. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell 185:881–95.e20
    [Google Scholar]
  189. 189.
    Wang EY, Mao T, Klein J, Dai Y, Huck JD et al. 2021. Diverse functional autoantibodies in patients with COVID-19. Nature 595:283–88
    [Google Scholar]
  190. 190.
    Arthur JM, Forrest JC, Boehme KW, Kennedy JL, Owens S et al. 2021. Development of ACE2 autoantibodies after SARS-CoV-2 infection. PLOS ONE 16:e0257016
    [Google Scholar]
  191. 191.
    Chang SE, Feng A, Meng W, Apostolidis SA, Mack E et al. 2021. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat. Commun. 12:5417
    [Google Scholar]
  192. 192.
    Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann H-H et al. 2020. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370:eabd4585
    [Google Scholar]
  193. 193.
    Goplen NP, Wu Y, Son YM, Li C, Wang Z et al. 2020. Tissue-resident CD8+ T cells drive age-associated chronic lung sequelae after viral pneumonia. Sci. Immunol. 5:eabc4557
    [Google Scholar]
  194. 194.
    Booth A, Reed AB, Ponzo S, Yassaee A, Aral M et al. 2021. Population risk factors for severe disease and mortality in COVID-19: a global systematic review and meta-analysis. PLOS ONE 16:e0247461
    [Google Scholar]
  195. 195.
    Brodin P. 2021. Immune determinants of COVID-19 disease presentation and severity. Nat. Med. 27:28–33
    [Google Scholar]
  196. 196.
    Saxton RA, Henneberg LT, Calafiore M, Su L, Jude KM et al. 2021. The tissue protective functions of interleukin-22 can be decoupled from pro-inflammatory actions through structure-based design. Immunity 54:660–72.e9
    [Google Scholar]
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