The outcome of SARS-CoV-2 infection is highly variable with only a minority progressing to severe COVID-19, characterized by acute respiratory distress syndrome, multi-organ dysfunction, elevated inflammatory cytokines, lymphopenia, and other abnormalities of the immune system (Bonnet et al., 2021; Giamarellos-Bourboulis et al., 2020; Huang and Pranata, 2020; Kaneko et al., 2020; Kuri-Cervantes et al., 2020; Lucas et al., 2020; Mathew et al., 2020; Mudd et al., 2020; Zhou et al., 2020). The risk of severe COVID-19 and death in people infected with SARS-CoV-2 increases with age and is greater in men than in women (Alkhouli et al., 2020; Bunders and Altfeld, 2020; Gupta et al., 2021; Laxminarayan et al., 2020; Mauvais-Jarvis, 2020; O’Driscoll et al., 2021; Peckham et al., 2020; Richardson et al., 2020; Scully et al., 2020). These trends have been observed in people infected with SARS-CoV (Chen and Subbarao, 2007; Donnelly et al., 2003; Karlberg et al., 2004), or with MERS-CoV (Alghamdi et al., 2014), and in laboratory animals challenged with SARS-CoV or SARS-CoV-2 (Channappanavar et al., 2017; Leist et al., 2020). The mechanisms underlying these effects of age and sex on COVID-19 morbidity and mortality remain poorly understood.

The composition and function of the human immune system changes with age and exhibits sexual dimorphism (Darboe et al., 2020; Klein and Flanagan, 2016; Márquez et al., 2020; Patin et al., 2018; Solana et al., 2012), with consequences for survival of infection, response to vaccination, and susceptibility to autoimmune disease (Flanagan et al., 2017; Giefing-Kröll et al., 2015; Márquez et al., 2020; Mauvais-Jarvis, 2020; Patin et al., 2018; Piasecka et al., 2018). Better understanding of these effects might provide clues as to why the clinical outcome of SARS-CoV-2 infection is so variable, ranging from asymptomatic to lethal (Cevik et al., 2021; He et al., 2020; Jones et al., 2021; Lee et al., 2020; Lennon et al., 2020; Ra et al., 2021; Richardson et al., 2020; Yang et al., 2021).

Survival after infection with a pathogenic virus such as SARS-CoV-2 requires not only that the immune system control and eliminate the pathogen, but that disease tolerance mechanisms limit tissue damage caused by the pathogen or by host inflammatory responses (Ayres, 2020a; McCarville and Ayres, 2018; Medzhitov et al., 2012; Schneider and Ayres, 2008). Research with animal models has demonstrated that genetic and environmental factors can promote host fitness without directly inhibiting pathogen replication (Ayres, 2020a; Cumnock et al., 2018; Jhaveri et al., 2007; McCarville and Ayres, 2018; Medzhitov et al., 2012; Råberg et al., 2007; Sanchez et al., 2018; Schneider and Ayres, 2008; Wang et al., 2016). Although in most cases the underlying mechanism is unknown, some of these models suggest that subsets of innate lymphoid cells (ILCs) contribute to disease tolerance (Artis and Spits, 2015; Branzk et al., 2018; Califano et al., 2018; Diefenbach et al., 2020; McCarville and Ayres, 2018; Monticelli et al., 2015; Monticelli et al., 2011). Some ILC subsets produce the epidermal growth factor family member amphiregulin (AREG) that maintains the integrity of epithelial barriers in the lung and intestine (Branzk et al., 2018; Jamieson et al., 2013; Monticelli et al., 2015; Monticelli et al., 2011), and promotes tissue repair (Artis and Spits, 2015; Cherrier et al., 2018; Klose and Artis, 2016; Rak et al., 2016). In models of influenza infection in mice, homeostatic ILCs and exogenous AREG promote lung epithelial integrity, decrease disease severity, and increase survival, without decreasing pathogen burden (Califano et al., 2018; Jamieson et al., 2013; Monticelli et al., 2011).

Little is known about disease tolerance in the context of human infectious diseases. Interestingly, SARS-CoV-2 viral load does not reliably discriminate symptomatic from asymptomatic infection (Cevik et al., 2021; Jones et al., 2021; Lee et al., 2020; Lennon et al., 2021; Ra et al., 2021; Yang et al., 2021). This discrepancy between SARS-CoV-2 viral load and the severity of COVID-19 is especially pronounced in children, who rarely have severe COVID-19 (Bailey et al., 2021; Li et al., 2020; Lu et al., 2020; Poline et al., 2020), although viral load may be comparable to that in adults with severe COVID-19 (Heald-Sargent et al., 2020; LoTempio et al., 2021; Yonker et al., 2020). These observations suggest that age-dependent, disease tolerance mechanisms influence the severity of COVID-19. In mice, homeostatic ILCs decrease in abundance in the lung with increasing age, and lose their ability to maintain disease tolerance during influenza infection (D’Souza et al., 2019). Although the distribution of ILCs within human tissues differs from mice and is heterogeneous among individuals (Yudanin et al., 2019), human ILCs share many features with those in mice (Vivier et al., 2018) and therefore may perform similar roles in maintaining tissue homeostasis and disease tolerance.

ILCs in peripheral blood have been reported to be depleted in individuals with severe COVID-19 (García et al., 2020; Kuri-Cervantes et al., 2020), but it is difficult to determine the extent to which ILCs are decreased independently from the overall lymphopenia associated with COVID-19 (Chen et al., 2020; Huang et al., 2020; Huang and Pranata, 2020; Zhang et al., 2020; Zhao et al., 2020), or from changes in other blood cell lineages (Giamarellos-Bourboulis et al., 2020; Huang et al., 2020; Kuri-Cervantes et al., 2020; Lucas et al., 2020; Mathew et al., 2020; Mudd et al., 2020; Zheng et al., 2020). In addition, assessment of lymphoid cell abundance, in the context of a disease for which age and sex are risk factors for severity, is confounded by programmed differences in lymphocyte abundance with age and sex (Márquez et al., 2020; Patin et al., 2018). The goal of this study was to determine whether the abundance of any blood lymphoid cell population was altered in COVID-19, independent of age, sex, and global lymphopenia, and whether abundance of any lymphoid cell population correlated with clinical outcome in SARS-CoV-2 infection.

The outcome of SARS-CoV-2 infection ranges from entirely asymptomatic to lethal COVID-19 (Cevik et al., 2021; He et al., 2020; Jones et al., 2021; Lee et al., 2020; Lennon et al., 2020; Ra et al., 2021; Richardson et al., 2020; Yang et al., 2021). Yet, viral load does not reliably discriminate asymptomatic from symptomatic or hospitalized populations (Cevik et al., 2021; Jones et al., 2021; Lee et al., 2020; Lennon et al., 2020; Ra et al., 2021; Yang et al., 2021). In contrast, demographic factors, including increasing age and male sex, predict worse outcome of SARS-CoV-2 infection (Alkhouli et al., 2020; Bunders and Altfeld, 2020; Gupta et al., 2021; Laxminarayan et al., 2020; Mauvais-Jarvis, 2020; O’Driscoll et al., 2021; Peckham et al., 2020; Richardson et al., 2020; Scully et al., 2020). These demographic risk factors could be due to sexual dimorphism and changes with aging in composition and function of the human immune system (Darboe et al., 2020; Klein and Flanagan, 2016; Márquez et al., 2020; Patin et al., 2018; Solana et al., 2012). Therefore it is necessary to account for effects of age and sex to determine if there are additional, independent, effects of SARS-CoV-2-associated disease.

This study collected and analyzed 245 blood samples from 177 adult and 58 pediatric patients and controls, spanning the ages of 0.7–83 years, with approximately equal numbers of males and females. It was therefore possible to characterize the independent effects of age, sex, COVID-19, and MIS-C on blood lymphoid cell populations. After accounting for effects of age and sex, ILCs, but not CD4⁺ or CD8⁺ T cells, were lower in individuals hospitalized with COVID-19 when compared with controls (Table 2 and Figure 3A, B). Lower numbers of ILCs were also observed in children with COVID-19 (Table 5 and Figure 4A, B), as well as in an independent cohort of adult patients (Figure 3—figure supplement 2). Among adults infected with SARS-CoV-2, lower abundance of ILCs, but not of the other lymphoid cell subsets, was associated with increased odds of hospitalization, longer duration of hospitalization, and higher blood level of factors associated with systemic inflammation, including CRP (Tables 3 and 4, and Figure 3C). This inverse relationship between ILC abundance and CRP was also evident in children with COVID-19 or MIS-C (Figure 4C).

The identification of reduced ILC numbers as uniquely related to COVID-19 severity is important as these cells mediate disease tolerance in animal models (Artis and Spits, 2015; Branzk et al., 2018; Califano et al., 2018; Diefenbach et al., 2020; McCarville and Ayres, 2018; Monticelli et al., 2015; Monticelli et al., 2011). The results here therefore indicate that loss of ILCs from blood correlates with loss of ILC-associated homeostatic functions, thereby allowing more severe COVID-19. Although this study examined circulating blood lymphoid cells, and does not provide direct information about processes occurring within tissues, transcriptional and functional characterization of blood ILCs demonstrated that these cells are similar to ILCs isolated from lung tissue (Figure 5). Human ILCs circulate in lymphatic fluid draining from the tissues to the blood via the thoracic duct (Buggert et al., 2020), raising the possibility that some ILCs in the blood originate from, or traffic to, lung tissue. Further characterization of these blood ILCs showed that they are functional ILC2s capable of producing the protein AREG (Figure 6A and B). Given the tissue homeostatic role AREG plays in animal models of disease tolerance (Branzk et al., 2018; Diefenbach et al., 2020; Jamieson et al., 2013; McCarville and Ayres, 2018; Monticelli et al., 2015; Monticelli et al., 2011), the discovery here that males have a smaller fraction than females of blood ILCs capable of producing AREG (Figure 6C) could explain why males are at greater risk of death from SARS-CoV-2 infection (O’Driscoll et al., 2021). This sexual dimorphism in ILC function would be amplified further by the lower overall abundance of ILCs in males (Figure 2B and Table 2).

Although the inverse relationship between the number of blood ILCs and severity of COVID-19 suggests that loss of ILC homeostatic function results in breakdown of disease tolerance (Arpaia et al., 2015; Artis and Spits, 2015; Branzk et al., 2018; Diefenbach et al., 2020; McCarville and Ayres, 2018; Monticelli et al., 2015; Monticelli et al., 2011), this observational study cannot determine whether ILC depletion preceded SARS-CoV-2 infection or whether ILC numbers are depleted as a consequence of SARS-CoV-2 infection. However, several observations support the hypothesis that individuals with lower ILC numbers at the time of SARS-CoV-2 infection are at greater risk of developing severe disease. ILC numbers in uninfected controls decrease exponentially with age; this decrease is much larger than that seen with other lymphoid cell types (Figure 2A), and much more closely mirrors the exponential increase in COVID-19 mortality with age (O’Driscoll et al., 2021; Figure 2C). In addition, the greater risk of COVID-19 mortality in males (O’Driscoll et al., 2021) correlates with lower abundance of blood ILCs (Figure 2B and Table 2) and smaller fraction of ILCs capable of producing AREG (Figure 6C). Finally, patients hospitalized with COVID-19 have a smaller fraction of AREG⁺ ILCs than controls (Figure 6D) and conditions independently associated with lower ILC abundance, such as HIV-1 infection (Kløverpris et al., 2016; Wang et al., 2020) and obesity (Brestoff et al., 2015; Yudanin et al., 2019), increase the risk for worse outcomes from SARS-CoV-2 infection (Biccard et al., 2021; Kompaniyets et al., 2021; Tesoriero et al., 2021).

In contrast to individuals with COVID-19, children with MIS-C had lower numbers of T cells as well as ILCs (Table 5 and Figure 4A and B), and longitudinal follow-up samples for pediatric COVID-19 and MIS-C patients showed persistence of low ILC numbers after COVID-19, but normalization of all depleted cell types after recovery from MIS-C (Figure 4D and E and Figure 4—figure supplement 2). These differences imply that the reversible lymphopenia in MIS-C is due to different underlying processes than the more specific and persistent lower ILC abundance seen in individuals with COVID-19. This difference is made more interesting by the fact that none of the children with MIS-C had required hospitalization for COVID-19 and only one experienced any COVID-19 symptoms. The other children with MIS-C were therefore unaware that they had been infected. It is possible that children with pre-existing lower ILC numbers are at risk of developing COVID-19 if infected with SARS-CoV-2, while other factors such as prolonged exposure to SARS-CoV-2 antigens in the gastrointestinal tract (Yonker et al., 2021), or rare inborn errors of immunity (Sancho-Shimizu et al., 2021), promote inflammatory processes in MIS-C that drive nonspecific lymphoid cell depletion, which ultimately normalizes after recovery.

Although ILC depletion and recovery has been reported in rheumatoid arthritis (Rauber et al., 2017), inflammation-driven ILC-depletion is not necessarily reversible, as ILCs appear permanently depleted after HIV-1 infection, possibly by the high levels of common γ-chain cytokines that are present during acute infection (Wang et al., 2020). Better understanding of the processes that drive down ILC abundance in populations susceptible to COVID-19 could potentially allow for development of interventions that increase ILC abundance and restore homeostatic disease tolerance mechanisms.

In conclusion, considering the established functions of ILCs (Artis and Spits, 2015; Branzk et al., 2018; Klose and Artis, 2016; Monticelli et al., 2015; Monticelli et al., 2011), and the host homeostatic responses necessary to survive pathogenic infection (López-Otín and Kroemer, 2021; McCarville and Ayres, 2018; Medzhitov et al., 2012; Schneider and Ayres, 2008), the findings reported here support the hypothesis that loss of disease tolerance mechanisms attributable to ILCs increase the risk of morbidity and mortality with SARS-CoV-2 infection. The findings of this observational study warrant establishment of prospective cohorts to determine whether abundance of ILCs or of other lymphoid cell subsets associated with disease tolerance (Arpaia et al., 2015; Artis and Spits, 2015; Branzk et al., 2018; Diefenbach et al., 2020; McCarville and Ayres, 2018; Monticelli et al., 2015; Monticelli et al., 2011), predict clinical outcome for infection with SARS-CoV-2 or other lethal pathogens. Understanding the mechanisms that allow an individual to tolerate high-level viral replication without experiencing symptoms, and how these mechanisms can fail and thereby allow for progression to severe disease, will provide the foundation for development of therapeutic interventions that maintain health and improve survival of pathogenic viral infection (Ayres, 2020b).

The data that support the findings of this study are available within the manuscript and in its supplementary information data files. Bulk RNA-Seq datasets generated here can be found at: NCBI Gene Expression Omnibus (GEO): GSE168212. Bulk RNA-Seq data generated by previously published studies are available from NCBI GEO: GSE131031 and GSE126107. This study did not generate unique code.

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Author details

1. Noah J Silverstein

   1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
   2. Medical Scientist Training Program, University of Massachusetts Medical School, Worcester, United States
   3. Massachusetts Consortium on Pathogen Readiness, Boston, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Software, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Yetao Wang

   For correspondence

   noah.silverstein@umassmed.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5688-9978

2. Yetao Wang

   1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
   2. Massachusetts Consortium on Pathogen Readiness, Boston, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing – review and editing

   Contributed equally with

   Noah J Silverstein

   For correspondence

   yetao.wang@umassmed.edu

   Competing interests

   No competing interests declared

3. Zachary Manickas-Hill

   1. Massachusetts Consortium on Pathogen Readiness, Boston, United States
   2. Ragon Institute of MGH, MIT and Harvard, Cambridge, United States

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

4. Claudia Carbone

   Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Ann Dauphin

   Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

6. Brittany P Boribong

   1. Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, United States
   2. Massachusetts General Hospital, Department of Pediatrics, Boston, United States
   3. Harvard Medical School, Boston, United States

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

7. Maggie Loiselle

   Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, United States

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1051-2072

8. Jameson Davis

   Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, United States

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

9. Maureen M Leonard

   1. Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, United States
   2. Massachusetts General Hospital, Department of Pediatrics, Boston, United States
   3. Harvard Medical School, Boston, United States

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

10. Leticia Kuri-Cervantes

    1. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    2. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

    Contribution

    Data curation, Investigation

    Competing interests

    No competing interests declared

11. MGH COVID-19 Collection & Processing Team

    Contribution

    Resources

    Competing interests

    No competing interests declared

    1. Kendall Lavin-Parsons, Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
    2. Blair Parry, Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
    3. Brendan Lilley, Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
    4. Carl Lodenstein, Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
    5. Brenna McKaig, Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
    6. Nicole Charland, Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
    7. Hargun Khanna, Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
    8. Justin Margolin, Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
    9. Anna Gonye, Massachusetts General Hospital Cancer Center, Boston, United States
    10. Irena Gushterova, Massachusetts General Hospital Cancer Center, Boston, United States
    11. Tom Lasalle, Massachusetts General Hospital Cancer Center, Boston, United States
    12. Nihaarika Sharma, Massachusetts General Hospital Cancer Center, Boston, United States
    13. Brian C Russo, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States
    14. Maricarmen Rojas-Lopez, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States
    15. Moshe Sade-Feldman, Massachusetts General Hospital Center for Immunology and Inflammatory Diseases, Boston, United States
    16. Kasidet Manakongtreecheep, Massachusetts General Hospital Center for Immunology and Inflammatory Diseases, Boston, United States
    17. Jessica Tantivit, Massachusetts General Hospital Center for Immunology and Inflammatory Diseases, Boston, United States
    18. Molly Fisher Thomas, Massachusetts General Hospital Center for Immunology and Inflammatory Diseases, Boston, United States
    19. Betelihem A Abayneh, Massachusetts General Hospital, Boston, United States
    20. Patrick Allen, Massachusetts General Hospital, Boston, United States
    21. Diane Antille, Massachusetts General Hospital, Boston, United States
    22. Katrina Armstrong, Massachusetts General Hospital, Boston, United States
    23. Siobhan Boyce, Massachusetts General Hospital, Boston, United States
    24. Joan Braley, Massachusetts General Hospital, Boston, United States
    25. Karen Branch, Massachusetts General Hospital, Boston, United States
    26. Katherine Broderick, Massachusetts General Hospital, Boston, United States
    27. Julia Carney, Massachusetts General Hospital, Boston, United States
    28. Andrew Chan, Massachusetts General Hospital, Boston, United States
    29. Susan Davidson, Massachusetts General Hospital, Boston, United States
    30. Michael Dougan, Massachusetts General Hospital, Boston, United States
    31. David Drew, Massachusetts General Hospital, Boston, United States
    32. Ashley Elliman, Massachusetts General Hospital, Boston, United States
    33. Keith Flaherty, Massachusetts General Hospital, Boston, United States
    34. Jeanne Flannery, Massachusetts General Hospital, Boston, United States
    35. Pamela Forde, Massachusetts General Hospital, Boston, United States
    36. Elise Gettings, Massachusetts General Hospital, Boston, United States
    37. Amanda Griffin, Massachusetts General Hospital, Boston, United States
    38. Sheila Grimmel, Massachusetts General Hospital, Boston, United States
    39. Kathleen Grinke, Massachusetts General Hospital, Boston, United States
    40. Kathryn Hall, Massachusetts General Hospital, Boston, United States
    41. Meg Healy, Massachusetts General Hospital, Boston, United States
    42. Deborah Henault, Massachusetts General Hospital, Boston, United States
    43. Grace Holland, Massachusetts General Hospital, Boston, United States
    44. Chantal Kayitesi, Massachusetts General Hospital, Boston, United States
    45. Vlasta LaValle, Massachusetts General Hospital, Boston, United States
    46. Yuting Lu, Massachusetts General Hospital, Boston, United States
    47. Sarah Luthern, Massachusetts General Hospital, Boston, United States
    48. Jordan Marchewka, Massachusetts General Hospital, Boston, United States
    49. Brittani Martino, Massachusetts General Hospital, Boston, United States
    50. Roseann McNamara, Massachusetts General Hospital, Boston, United States
    51. Christian Nambu, Massachusetts General Hospital, Boston, United States
    52. Susan Nelson, Massachusetts General Hospital, Boston, United States
    53. Marjorie Noone, Massachusetts General Hospital, Boston, United States
    54. Christine Ommerborn, Massachusetts General Hospital, Boston, United States
    55. Lois Chris Pacheco, Massachusetts General Hospital, Boston, United States
    56. Nicole Phan, Massachusetts General Hospital, Boston, United States
    57. Falisha A Porto, Massachusetts General Hospital, Boston, United States
    58. Edward Ryan, Massachusetts General Hospital, Boston, United States
    59. Kathleen Selleck, Massachusetts General Hospital, Boston, United States
    60. Sue Slaughenhaupt, Massachusetts General Hospital, Boston, United States
    61. Kimberly Smith Sheppard, Massachusetts General Hospital, Boston, United States
    62. Elizabeth Suschana, Massachusetts General Hospital, Boston, United States
    63. Vivine Wilson, Massachusetts General Hospital, Boston, United States
    64. Galit Alter, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    65. Alejandro Balazs, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    66. Julia Bals, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    67. Max Barbash, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    68. Yannic Bartsch, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    69. Julie Boucau, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    70. Josh Chevalier, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    71. Fatema Chowdhury, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    72. Kevin Einkauf, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    73. Jon Fallon, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    74. Liz Fedirko, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    75. Kelsey Finn, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    76. Pilar Garcia-Broncano, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    77. Ciputra Hartana, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    78. Chenyang Jiang, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    79. Paulina Kaplonek, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    80. Marshall Karpell, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    81. Evan C Lam, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    82. Kristina Lefteri, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    83. Xiaodong Lian, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    84. Mathias Lichterfeld, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    85. Daniel Lingwood, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    86. Hang Liu, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    87. Jinqing Liu, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    88. Natasha Ly, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    89. Ashlin Michell, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    90. Ilan Millstrom, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    91. Noah Miranda, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    92. Claire O’Callaghan, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    93. Matthew Osborn, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    94. Shiv Pillai, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    95. Yelizaveta Rassadkina, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    96. Alexandra Reissis, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    97. Francis Ruzicka, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    98. Kyra Seiger, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    99. Libera Sessa, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    100. Christianne Sharr, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    101. Sally Shin, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    102. Nishant Singh, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    103. Weiwei Sun, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    104. Xiaoming Sun, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    105. Hannah Ticheli, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    106. Alicja Trocha-Piechocka, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    107. Daniel Worrall, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    108. Alex Zhu, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    109. George Daley, Harvard Medical School, Boston, United States
    110. David Golan, Harvard Medical School, Boston, United States
    111. Howard Heller, Harvard Medical School, Boston, United States
    112. Arlene Sharpe, Harvard Medical School, Boston, United States
    113. Nikolaus Jilg, Brigham and Women’s Hospital, Boston, United States
    114. Alex Rosenthal, Brigham and Women’s Hospital, Boston, United States
    115. Colline Wong, Brigham and Women’s Hospital, Boston, United States

12. Nuala J Meyer

    Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States

    Contribution

    Data curation, Resources

    Competing interests

    No competing interests declared

13. Michael R Betts

    1. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    2. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

    Contribution

    Data curation, Resources

    Competing interests

    No competing interests declared

14. Jonathan Z Li

    1. Massachusetts Consortium on Pathogen Readiness, Boston, United States
    2. Department of Medicine, Brigham and Women’s Hospital, Boston, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

15. Bruce D Walker

    1. Massachusetts Consortium on Pathogen Readiness, Boston, United States
    2. Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    3. Howard Hughes Medical Institute, Chevy Chase, United States
    4. Department of Biology and Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

16. Xu G Yu

    1. Massachusetts Consortium on Pathogen Readiness, Boston, United States
    2. Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    3. Department of Medicine, Brigham and Women’s Hospital, Boston, United States

    Contribution

    Data curation, Investigation, Resources, Writing – review and editing

    Competing interests

    No competing interests declared

17. Lael M Yonker

    1. Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, United States
    2. Massachusetts General Hospital, Department of Pediatrics, Boston, United States
    3. Harvard Medical School, Boston, United States

    Contribution

    Data curation, Funding acquisition, Investigation, Resources, Writing – original draft, Writing – review and editing

    Competing interests

    No competing interests declared

18. Jeremy Luban

    1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    2. Massachusetts Consortium on Pathogen Readiness, Boston, United States
    3. Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    4. Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, United States
    5. Broad Institute of Harvard and MIT, Cambridge, United States

    Contribution

    Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Writing – original draft, Writing – review and editing

    For correspondence

    jeremy.luban@umassmed.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5650-4054