Phospholipid scramblase 1 (PLSCR1) regulates interferon-lambda receptor 1 (IFN-λR1) and IFN-λ signaling in influenza A virus (IAV) infection

Influenza A virus (IAV) is highly contagious and causes acute respiratory infectious disease transmitted by virus-containing droplets. Its segmented gene and wide host range facilitate frequent antigenic shift during coinfection, posing a significant threat to human health. IAV has caused several pandemics in human history, and seasonal flu remains a major health burden in present days, despite annual vaccination efforts (Holbach, 2016). Existing anti-flu drugs mainly target influenza virus proteins: (1) penetration and shelling inhibitors, such as Gocovri (amantadine) and Flumadine (Rimantadine); (2) neuraminidase inhibitors, such as Relenza (zanamivir), Tamiflu (oseltamivir phosphate), Rapivab (peramivir), and Xofluza (baloxavir marboxil) (The Medical Letter on Drugs and Therapeutics, 2020). However, the emergence of drug-resistant variant strains is common. Moreover, these direct antivirals have a short therapeutic window and are the most effective only if given within the first 48 hr after the initial infection (The Medical Letter on Drugs and Therapeutics, 2020). In addition, IAV-induced acute inflammation could persist, leading to severe complications, such as life-threatening pneumonia, immunopathology, and acute respiratory distress syndrome (ARDS). Therefore, there is a pressing need to understand host immune responses and develop anti-influenza drugs targeting host factors.

At the center of anti-flu immunity are the interferon (IFN) pathways. Discovered a mere two decades ago, type 3 IFNs were initially perceived as redundant to type 1 IFNs, given their shared intracellular signaling pathways and antiviral activities. However, recent studies have revealed their unique properties, notably their signaling through a pair of heterodimer receptors (IFN-λR1/IL-10R2) distinct from type 1 IFN receptor complex (IFN-αR1/IFN-αR2) (Sheppard et al., 2003; Donnelly et al., 2004). First of all, IFN-λ exhibits a more constrained expression pattern compared to type 1 IFNs. While the cellular sources of type 1 IFNs in viral infections depend on the infection route and the tissue tropism, they can be produced by a large variety of cell types, including epithelial, parenchymal, immune, and stromal cells, to combat infections in the skin, mucosal, organ, lymph node, and at the systemic level (Swiecki and Colonna, 2011). In contrast, IFN-λ is primarily secreted by cells at barrier surfaces, such as respiratory and gastrointestinal epithelial cells, DCs, and macrophages (Coccia et al., 2004; Sommereyns et al., 2008). Moreover, their receptor distributions are vastly different. IFN-αR1/IFN-αR2 complex is present on nearly all cell types, but IFN-λR1/IL-10R2 complex is expressed exclusively on epithelial cells and a few immune cells, including neutrophils and subsets of dendritic cells (Broggi et al., 2017; Yin et al., 2012). Most importantly, IFN-λ is produced earlier than type 1 interferons in IAV infection and can elicit effective antiviral responses without inflammation, such as the release of tissue-damaging mediators, such as tumor necrosis factor (TNF) and IL-1β from neutrophils. In fact, only under a high dose of IAV are type 1 interferons detected, contributing to tissue immunopathology (Galani et al., 2017). Another exclusive anti-flu mechanism of IFN-λ is its role in preventing viral transmission from the upper airways to the lungs (Klinkhammer et al., 2018). Taken together, IFN-λ provides a non-redundant front-line shield against influenza virus.

IFNs secreted by infected cells signal neighboring cells to enter an antiviral state by inducing the expression of hundreds of ISGs (Chen et al., 2018). PLSCR1, the most studied member of the phospholipid scramblase protein family, is one such ISG, with its expression highly induced by type 1, 2, and 3 interferons in various viral infections (Zhou et al., 2000; Lu et al., 2007; Xu et al., 2023). It is a type II transmembrane protein generally located on the cell membrane, but can be imported into the nucleus and act as a transcriptional factor to regulate several gene expressions by directly binding to their promoter regions (Zhou et al., 2005; Huang et al., 2020). PLSCR1 is detected in all tissues and has a relatively high expression in the lung. Although it is universally expressed across various cell types in the lung, including alveolar epithelial cells and lymphocytes, macrophages have the highest expression, followed by endothelial cells and respiratory ciliated cells (Karlsson et al., 2021). The main function of PLSCR1 is to catalyze Ca²⁺-dependent, ATP-independent, bidirectional, and non-specific translocation of phospholipids between inner & outer leaflet of plasma membrane. Scrambling of membrane phospholipids results in the externalization of phosphatidylserine (PS), which acts as a docking site for many biological processes, including coagulation, apoptosis, and activation (Bassé et al., 1996).

Previous studies have described some critical anti-influenza activities of PLSCR1. For example, PLSCR1 interacts with the nucleoprotein (NP) of IAV, impairing its nuclear import and thereby suppressing virus replication in A549 cells (Luo et al., 2018). In addition, Plscr1 competes with immunoglobulin-like domain-containing receptor 1 (ILDR1) for NP binding, inhibiting swine influenza virus (SIV) infection in mice (Liu et al., 2022). Besides direct interactions with the virus, PLSCR1 interacts with toll-like receptor (TLR) 9 and regulates its trafficking and ability to induce type I interferon production in plasmacytoid dendritic cells (Talukder et al., 2012). Furthermore, PLSCR1 is required to potentiate the expression of numerous other ISGs in response to IFN-β in Hey1B cells, including p56, ISG15, and OAS (Dong et al., 2004). The goals of this project are to determine the roles of Plscr1 in an IAV-infected mouse model, to implicate its involvement in IFN-λ signaling, and to elucidate the cell types responsible for Plscr1-mediated anti-influenza activities.

To address this knowledge gap, we have employed a systematic approach, leveraging both global and cell type-specific Plscr1^-/- and Plscr1 knock-in overexpression mice infected with mouse-adapted human IAV. Human respiratory epithelial cell lines harboring PLSCR1 mutations have also been used to elucidate the subcellular roles of PLSCR1. Our findings demonstrate that Plscr1 is an IFN-λ-stimulated gene, and it protects mice against IAV infection by regulating IFNLR1 gene expression in the nucleus and interacting with IFN-λR1 protein on the cell membrane in ciliated airway epithelial cells. Our research will aid in the understanding of virus-host interactions and the development of novel anti-influenza therapeutics targeting human components, preventing the emergence of drug-resistant IAV strains.

We are the first group to demonstrate the roles of Plscr1 in a mouse-adapted human IAV-infected mouse model, to implicate its IFN-λ signaling-related mechanisms, and to elucidate the cell types that are responsible for Plscr1-mediated anti-influenza activities. We established Plscr1^-/- mice and found them more susceptible to IAV (WSN) compared to WT mice, as evidenced by greater weight loss in both sublethal and lethal infection and poorer survival in a lethal infection. Further examination of infected lungs provided the first in vivo evidence demonstrating that Plscr1 suppressed human IAV replication. This observation aligns with a previous report indicating that PLSCR1 interacts with the IAV NP, thereby impairing its nuclear import in vitro (Luo et al., 2018). Notably, while differences in viral copy numbers were only observed at the early stages of infection, coinciding with a significant increase in Plscr1 transcription, these changes had profound implications for host fitness. Therefore, as one of the earliest induced ISGs, Plscr1 constitutes the frontline defense against influenza infection.

While the only previously published Plscr1^-/- mouse flu model focused on an H1N1 SIV infection (Liu et al., 2022), our data showed both similarities and discrepancies. First, while both studies observed that Plscr1 promoted survival during IAV infection, SIV-infected Plscr1^-/- mice exhibited weight loss similar to WT mice. Furthermore, while both models attributed the lower survival rate in Plscr1^-/- mice to increased viral replication, SIV-infected Plscr1^-/- lungs exhibited higher viral titers across all examined time points, from 1 to 7 dpi. Intriguingly, contrary to our observations, Plscr1 expression was markedly decreased in SIV infection. Given previous in vitro studies demonstrating PLSCR1 induction by IAV (WSN) (Luo et al., 2018) and type 1 IFNs (Zhou et al., 2000; Dong et al., 2004; Lizak and Yarovinsky, 2012), we propose that the contradictory trend observed by Liu et al. may be attributed to distinct properties of SIV, such as viral replication rate, both the cellular tropism and the tissue tropism (proximal or distal lung), or antigen variation which may affect direct interaction with PLSCR1, innate sensing of the infection, or recognition by the adaptive immune response.

The delicate balance between immunity and immunopathology plays a pivotal role in determining host fitness during viral infections. To interrogate immunopathology in the lungs, we accessed the BAL, histology, and interferon expressions. BAL from Plscr1^-/- mice were highly enriched with inflammatory neutrophils and lymphocytes, which were likely attracted by robust IFNs and other chemokines. Consistently, Plscr1^-/- mice exhibited more severe lung damage and a greater extent of affected areas. These findings indicate that Plscr1 not only enhances immunity but also mitigates immunopathology. Importantly, regardless of excessive production of antiviral IFNs in Plscr1^-/- mice, they failed to effectively control the initial viral infection. This suggests that the absence of Plscr1 impairs the IFN signaling pathway, highlighting the crucial role of Plscr1 in facilitating effective antiviral responses.

Although type 1 and 3 IFNs may share similar downstream pathways, they rely on distinct receptors for signaling. Consistent with previous findings (Sheppard et al., 2003), Ifn-λr1 was detected in respiratory epithelium, including ciliated epithelial cells, club cells, and AT2 cells during infection. Loss of Plscr1 impaired Ifnlr1 transcription in IAV infection, with this transcriptional difference translating into protein expression. IFN-λ is crucial for early viral control within the initial days of infection without igniting unnecessary inflammation and compromising host fitness (Galani et al., 2017). With limited Ifn-λr1 expression, Plscr1^-/- mice were unable to mount a robust type 3 IFN response to control early viral infection. Instead, they relied largely on type 1 interferons, which succeeded in eliminating IAV at later time points, but led to exaggerated immunopathology. Furthermore, our observations of enhanced neutrophilia, lung injury, and lethality in Plscr1^-/- mice align with findings reported in Ifnlr1^-/- mice in IAV infection (Galani et al., 2017). However, a discrepancy in Ifnlr1 expression over the course of infection was observed between the RNA sequencing and the qRT-PCR data. While RNA-seq showed further upregulation of Ifnlr1 at 7 dpi (Figure 3A), qRT-PCR indicated a rapid downregulation at the same time point (Figure 3B). The reason for this time-dependent discrepancy remains unclear and warrants further investigation. In addition, this study did not definitively establish causality between reduced Ifn-λ signaling and the observed in vivo phenotype. The increased morbidity and mortality in Plscr1^-/- mice could also be attributed to elevated Tnf-α levels and associated lung damage. Given that proinflammatory cytokines and/or enhanced lung damage are known contributors to influenza morbidity and mortality, future work will be needed to disentangle the impacts of TNF-α, IL-1β, and other inflammatory cytokines from those of the IFN pathway to fully clarify the role of Plscr1 in antiviral defense.

PLSCR1 expression was increased in response to IFN-λ in human airway epithelial cells, consistent with previous studies (Xu et al., 2023). While PLSCR1 typically localizes on the cell membrane and in the cytoplasm, it translocates into nucleus to bind the IFNLR1 promoter upon IAV infection, thereby regulating IFNLR1 transcription. The nuclear localization and functions of PLSCR1 have been extensively documented in previous studies (Huang et al., 2020; Chen et al., 2013; Wyles et al., 2007; Huang et al., 2015). Relevantly, IFN-α promotes the nuclear translocation of PLSCR1 in breast cancer cells (Wiedmer et al., 2003). Therefore, it is highly plausible that the nuclear trafficking of PLSCR1 in airway epithelial cells is similarly stimulated by IFN-α produced during IAV infection, but further evidence is demanded. Additionally, the precise binding site for PLSCR1 within the IFNLR1 promoter and the binding motif on PLSCR1 remain unknown. Previous bioinformatics predictions revealed that the –430~–421 segment of IFNLR1 promoter likely contains binding sites for a number of transcription factors (TFs) with important regulatory functions (Ding et al., 2014). Further mutagenesis studies, such as truncations or single-nucleotide mutations within these sequences, could be done to identify the specific motif for PLSCR1 binding. Finally, it is not clear whether PLSCR1 directly activates IFNLR1 expression by acting as a TF, or as a co-factor enhancing other TF’s transcriptional activity. Co-immunoprecipitations could be pursued in future to explore the binding potential between PLSCR1 and other known TFs for IFNLR1, such as NF-Y (Ding et al., 2014).

In addition to activities in the nucleus, PLSCR1 has been shown to interact with multiple proteins on the plasma or endosomal membrane (Talukder et al., 2012; Guo et al., 2020; Sun et al., 2002; Li et al., 2006; Amir-Moazami et al., 2008). Here, we reported a novel interaction between PLSCR1 and IFN-λR1 on airway epithelial cell membrane in vivo and in vitro, confirmed with both coimmunoprecipitation and immunofluorescence. Since their interaction was significantly enhanced after IAV infection, we speculate that membrane-bound PLSCR1 is a positive regulator of IFN-λR1 signaling. One plausible mechanism is that PLSCR1 facilitates the intracellular trafficking of IFN-λR1, akin to its role in assisting the trafficking of other membrane receptors (Talukder et al., 2012; Sun et al., 2002; Kametaka et al., 2003).

The subcellular location of PLSCR1 is vital not only for interactions with host components, but also for direct viral control. We found that nuclear PLSCR1 is both necessary and sufficient for viral control in airway epithelial cells, whereas membrane PLSCR1 provides only partial protection against IAV infection. These findings are not surprising, as the previously reported anti-flu mechanism of PLSCR1 also relies on its nuclear localization signal to restrict the import of IAV NP (Luo et al., 2018). Furthermore, besides IFNLR1, PLSCR1 enhances the expression of a select subset of ISGs in IAV infection as well, a mechanism potentially mediated by nuclear PLSCR1 on ISG gene transcription (Dong et al., 2004). On the other hand, membrane PLSCR1 may modulate the JAK/STAT signaling pathway, thereby augmenting the optimal anti-viral activity of these ISGs (Dong et al., 2004). We found that membrane PLSCR1 interacts with IFN-λR1 protein in IAV infection, suggesting that it could facilitate viral elimination to some extent.

PLSCR1 is most well-known for its scramblase activity that favors PS exposure, apoptosis, and phagocytosis (Guo et al., 2020; Zhao et al., 1998). Using an enzymatically inactive mutant of PLSCR1, we uncoupled its lipid scramblase activity from anti-influenza activity. There are several potential explanations for this finding. First, our epithelial cell culture lacked phagocytes, therefore, the impact of apoptosis followed by phagocytosis induced by PLSCR1 is minimal. Future studies using mice that harbor Plscr1(F281A) mutation would be needed to verify the role of lipid scramblase activity and epithelial cell apoptosis in the presence of phagocytes. Second, PLSCR1 exhibits only weak enzymatic activities compared to other members of lipid scramblase family, possibly due to its vastly different central β-barrel structure (Xu et al., 2023; Tang et al., 2022). PS externalization may be compensated by other more potent scramblases. Importantly, the lipid scramblase activity of PLSCR1 has been shown to be dispensable for its anti-SARS-CoV-2 function in a similar manner (Xu et al., 2023), suggesting a general lack of significance for its enzymatic activity in viral infections.

Although PLSCR1 has several previously described anti-influenza functions, including interfering with viral nuclear import (Luo et al., 2018), regulating TLR9 signaling (Talukder et al., 2012), and potentiating the expression of other ISGs (Dong et al., 2004), our studies have clarified the relative contribution of the type 3 IFN pathway to Plscr1-mediated anti-influenza immunity using Plscr1^-/-;Ifnlr1^-/- mice. We observed that Ifnlr1^-/- mice were more susceptible to IAV infection than Plscr1^-/-, suggesting that the complete loss of Ifn-λr1 results in worse protection than impaired Ifn-λr1 upregulation alone. Moreover, the previously identified anti-IAV functions of Plscr1 do not appear sufficient to compensate for the loss of Ifn-λr1 signaling in Ifnlr1^-/- mice. The absence of further disease exacerbation or increased viral titers in Plscr1^-/-;Ifnlr1^-/- mice compared to Ifnlr1^-/- mice indicates that the anti-influenza activity of Plscr1 is largely dependent on Ifn-λr1.

While scRNA-seq analysis revealed that endothelial cells express Plscr1 most abundantly in the lung, they are not the major target of IAV infection, and IAV does not efficiently replicate in them (Han et al., 2021). Instead, airway epithelial cells are the frontline defense against respiratory pathogens, with ciliated epithelial cells being the only cell type that express α2,3-linked SA, the primary influenza virus receptor in the mouse airway (Ibricevic et al., 2006). Coincidently, our scRNA-seq results showed that ciliated epithelial cells not only had the highest aggregated expression of Plscr1, but also had the most significant increase in Plscr1 expression in early IAV infection at 3 dpi. Experiments with Plscr1^floxStop;Foxj1-Cre⁺mice further supported ciliated epithelial cell-dependent protection against IAV, with improved immunity and viral clearance, and dampened immunopathology as early as 3 dpi. These findings suggest that as a result of enhanced Ifn-λr1 due to Plscr1 overexpression, type 3 interferons were able to exert their advantages being the earliest produced interferon, mounting both antiviral and anti-inflammatory responses in ciliated epithelial cells. To further establish the causal relationship between Plscr1 and Ifn-λ signaling in airway ciliated epithelial cells, future experiments should focus on specifically overexpressing Plscr1 in ciliated epithelial cells on an Ifnlr1^-/- background by breeding Plscr1^floxStop;Foxj1-Cre⁺;Ifnlr1^-/- mice. In addition, ciliated epithelial cells isolated from Ifnlr1^-/- murine airways could be transduced with a Plscr1 overexpression construct. We hypothesize that overexpression of Plscr1 in ciliated epithelial cells would not be able to rescue susceptibility in Ifnlr1^-/- mice or cells, as the Plscr1^-/-;Ifnlr1^-/- mouse model suggests that Plscr1’s Ifn-λr1-independent anti-influenza mechanisms are likely minor compared to its role in upregulating Ifn-λr1.

Taken together, our findings highlight the essential role of PLSCR1 in the regulation of IFN-λR1 transcription in nucleus and expression on plasma membrane, both in vitro and in vivo. These mechanisms are crucial for inhibiting viral spread, reducing inflammation, and enhancing overall host fitness during IAV infection. Furthermore, we found that the enzymatic activity of PLSCR1 is dispensable for its anti-influenza function. Finally, ciliated airway epithelial cells are the primary cell type in the lung for mounting PLSCR1-mediated anti-influenza responses. The potential of PLSCR1 agonists that target ciliated airway epithelial cells as therapeutic treatments for influenza holds promise for future medical interventions. Moreover, our results have the potential to impact the classical yet evolving field of IFN signaling. Not only do these findings elucidate and expand our understanding of newly discovered IFN-λ signaling, but they also shed light on the specific cell types and conditions under which IFN-λ signaling is modulated. Given the significance of IFN-λ signaling in various infectious diseases, these insights may pave the way for innovative therapeutic approaches targeting corresponding regulatory molecules in the treatment of other microbial infections in addition to influenza.

Sequencing data have been deposited in GEO under accession codes GSE307868.

1. 1. Yang AX
   2. Ramos-Rodriguez L
   3. Sorkhdini P
   4. Yang D
   5. Norbrun C
   6. Majid S
   7. Lee S
   8. Zhang Y
   9. Holtzman MJ
   10. Boyd DF
   11. Zhou Y

   (2025) NCBI Gene Expression Omnibus

   ID GSE307868. Phospholipid Scramblase 1 (PLSCR1) Regulates Interferon-Lambda Receptor 1 (IFN-λR1) and IFN-λ Signaling in Influenza A Virus (IAV) Infection.

   https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE307868

1. 1. Boyd DF
   2. Allen EK
   3. Randolph AG

   (2020) NCBI Sequence Read Archive

   ID SRX8008853. Spatial transcriptomics of mouse lung: Mouse D Section 1 at 10 days post influenza infection.

   https://www.ncbi.nlm.nih.gov/sra/?term=SRX8008853

1. 1. Amir-Moazami O
   2. Alexia C
   3. Charles N
   4. Launay P
   5. Monteiro RC
   6. Benhamou M

   (2008) Phospholipid scramblase 1 modulates a selected set of IgE receptor-mediated mast cell responses through LAT-dependent pathway

   The Journal of Biological Chemistry 283:25514–25523.

   https://doi.org/10.1074/jbc.M705320200

   • PubMed
   • Google Scholar
2. 1. Andreakos E
   2. Zanoni I
   3. Galani IE

   (2019) Lambda interferons come to light: dual function cytokines mediating antiviral immunity and damage control

   Current Opinion in Immunology 56:67–75.

   https://doi.org/10.1016/j.coi.2018.10.007

   • PubMed
   • Google Scholar
3. 1. Baldridge MT
   2. Lee S
   3. Brown JJ
   4. McAllister N
   5. Urbanek K
   6. Dermody TS
   7. Nice TJ
   8. Virgin HW

   (2017) Expression of Ifnlr1 on intestinal epithelial cells is critical to the antiviral effects of interferon lambda against norovirus and reovirus

   Journal of Virology 91:e02079-16.

   https://doi.org/10.1128/JVI.02079-16

   • PubMed
   • Google Scholar
4. 1. Bassé F
   2. Stout JG
   3. Sims PJ
   4. Wiedmer T

   (1996) Isolation of an erythrocyte membrane protein that mediates Ca2+-dependent transbilayer movement of phospholipid

   The Journal of Biological Chemistry 271:17205–17210.

   https://doi.org/10.1074/jbc.271.29.17205

   • PubMed
   • Google Scholar
5. 1. Borges KS
   2. Arboleda VA
   3. Vilain E

   (2015) Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase

   Cell Division 10:2.

   https://doi.org/10.1186/s13008-015-0008-8

   • PubMed
   • Google Scholar
6. 1. Boyd DF
   2. Allen EK
   3. Randolph AG
   4. Guo X-ZJ
   5. Weng Y
   6. Sanders CJ
   7. Bajracharya R
   8. Lee NK
   9. Guy CS
   10. Vogel P
   11. Guan W
   12. Li Y
   13. Liu X
   14. Novak T
   15. Newhams MM
   16. Fabrizio TP
   17. Wohlgemuth N
   18. Mourani PM
   19. PALISI Pediatric Intensive Care Influenza (PICFLU) Investigators
   20. Wight TN
   21. Schultz-Cherry S
   22. Cormier SA
   23. Shaw-Saliba K
   24. Pekosz A
   25. Rothman RE
   26. Chen K-F
   27. Yang Z
   28. Webby RJ
   29. Zhong N
   30. Crawford JC
   31. Thomas PG

   (2020) Exuberant fibroblast activity compromises lung function via ADAMTS4

   Nature 587:466–471.

   https://doi.org/10.1038/s41586-020-2877-5

   • PubMed
   • Google Scholar
7. 1. Brandes M
   2. Klauschen F
   3. Kuchen S
   4. Germain RN

   (2013) A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection

   Cell 154:197–212.

   https://doi.org/10.1016/j.cell.2013.06.013

   • PubMed
   • Google Scholar
8. 1. Broggi A
   2. Tan Y
   3. Granucci F
   4. Zanoni I

   (2017) IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function

   Nature Immunology 18:1084–1093.

   https://doi.org/10.1038/ni.3821

   • PubMed
   • Google Scholar
9. 1. Bult CJ
   2. Blake JA
   3. Smith CL
   4. Kadin JA
   5. Richardson JE
   6. Mouse Genome Database Group

   (2019) Mouse genome database (MGD) 2019

   Nucleic Acids Research 47:D801–D806.

   https://doi.org/10.1093/nar/gky1056

   • PubMed
   • Google Scholar
10. 1. Chen M-H
    2. Ben-Efraim I
    3. Mitrousis G
    4. Walker-Kopp N
    5. Sims PJ
    6. Cingolani G

    (2005) Phospholipid scramblase 1 contains a nonclassical nuclear localization signal with unique binding site in importin alpha

    The Journal of Biological Chemistry 280:10599–10606.

    https://doi.org/10.1074/jbc.M413194200

    • PubMed
    • Google Scholar
11. 1. Chen Y
    2. Hui H
    3. Yang H
    4. Zhao K
    5. Qin Y
    6. Gu C
    7. Wang X
    8. Lu N
    9. Guo Q

    (2013) Wogonoside induces cell cycle arrest and differentiation by affecting expression and subcellular localization of PLSCR1 in AML cells

    Blood 121:3682–3691.

    https://doi.org/10.1182/blood-2012-11-466219

    • PubMed
    • Google Scholar
12. 1. Chen X
    2. Liu S
    3. Goraya MU
    4. Maarouf M
    5. Huang S
    6. Chen J-L

    (2018) Host immune response to influenza a virus infection

    Frontiers in Immunology 9:320.

    https://doi.org/10.3389/fimmu.2018.00320

    • Google Scholar
13. 1. Coccia EM
    2. Severa M
    3. Giacomini E
    4. Monneron D
    5. Remoli ME
    6. Julkunen I
    7. Cella M
    8. Lande R
    9. Uzé G

    (2004) Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells

    European Journal of Immunology 34:796–805.

    https://doi.org/10.1002/eji.200324610

    • PubMed
    • Google Scholar
14. 1. Ding S
    2. Khoury-Hanold W
    3. Iwasaki A
    4. Robek MD

    (2014) Epigenetic reprogramming of the type III interferon response potentiates antiviral activity and suppresses tumor growth

    PLOS Biology 12:e1001758.

    https://doi.org/10.1371/journal.pbio.1001758

    • PubMed
    • Google Scholar
15. 1. Dong B
    2. Zhou Q
    3. Zhao J
    4. Zhou A
    5. Harty RN
    6. Bose S
    7. Banerjee A
    8. Slee R
    9. Guenther J
    10. Williams BRG
    11. Wiedmer T
    12. Sims PJ
    13. Silverman RH

    (2004) Phospholipid scramblase 1 potentiates the antiviral activity of interferon

    Journal of Virology 78:8983–8993.

    https://doi.org/10.1128/JVI.78.17.8983-8993.2004

    • PubMed
    • Google Scholar
16. 1. Donnelly RP
    2. Sheikh F
    3. Kotenko SV
    4. Dickensheets H

    (2004) The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain

    Journal of Leukocyte Biology 76:314–321.

    https://doi.org/10.1189/jlb.0204117

    • PubMed
    • Google Scholar
17. 1. Galani IE
    2. Triantafyllia V
    3. Eleminiadou E-E
    4. Koltsida O
    5. Stavropoulos A
    6. Manioudaki M
    7. Thanos D
    8. Doyle SE
    9. Kotenko SV
    10. Thanopoulou K
    11. Andreakos E

    (2017) Interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness

    Immunity 46:875–890.

    https://doi.org/10.1016/j.immuni.2017.04.025

    • PubMed
    • Google Scholar
18. 1. Guo J
    2. Li J
    3. Xia L
    4. Wang Y
    5. Zhu J
    6. Du J
    7. Lu Y
    8. Liu G
    9. Yao X
    10. Shen B

    (2020) Transient receptor potential canonical 5-scramblase signaling complex mediates neuronal phosphatidylserine externalization and apoptosis

    Cells 9:547.

    https://doi.org/10.3390/cells9030547

    • PubMed
    • Google Scholar
19. 1. Han T
    2. Lai Y
    3. Jiang Y
    4. Liu X
    5. Li D

    (2021) Influenza A virus infects pulmonary microvascular endothelial cells leading to microvascular leakage and release of pro-inflammatory cytokines

    PeerJ 9:e11892.

    https://doi.org/10.7717/peerj.11892

    • Google Scholar
20. 1. Hao Y
    2. Hao S
    3. Andersen-Nissen E
    4. Mauck WM
    5. Zheng S
    6. Butler A
    7. Lee MJ
    8. Wilk AJ
    9. Darby C
    10. Zager M
    11. Hoffman P
    12. Stoeckius M
    13. Papalexi E
    14. Mimitou EP
    15. Jain J
    16. Srivastava A
    17. Stuart T
    18. Fleming LM
    19. Yeung B
    20. Rogers AJ
    21. McElrath JM
    22. Blish CA
    23. Gottardo R
    24. Smibert P
    25. Satija R

    (2021) Integrated analysis of multimodal single-cell data

    Cell 184:3573–3587.

    https://doi.org/10.1016/j.cell.2021.04.048

    • PubMed
    • Google Scholar
21. 1. Hendershot LM
    2. Valentine VA
    3. Lee AS
    4. Morris SW
    5. Shapiro DN

    (1994) Localization of the gene encoding human BiP/GRP78, the endoplasmic reticulum cognate of the HSP70 family, to chromosome 9q34

    Genomics 20:281–284.

    https://doi.org/10.1006/geno.1994.1166

    • PubMed
    • Google Scholar
22. 1. Holbach M

    (2016) Burden of disease from influenza-like illness among hospital staff and effectiveness of influenza vaccination during the flu epidemic at the beginning of 2015

    MMW Fortschritte Der Medizin 158 Suppl 5:8–13.

    https://doi.org/10.1007/s15006-016-8607-0

    • PubMed
    • Google Scholar
23. 1. Huang H
    2. Lu Y
    3. Min L
    4. Jiang P
    5. Dai L

    (2015) Phospholipid scramblase 1 interacts with midkine and regulates hepatic cancer cell proliferation and migration

    Clinical Laboratory 61:1501–1508.

    https://doi.org/10.7754/clin.lab.2015.150205

    • PubMed
    • Google Scholar
24. 1. Huang P
    2. Liao R
    3. Chen X
    4. Wu X
    5. Li X
    6. Wang Y
    7. Cao Q
    8. Dong C

    (2020) Nuclear translocation of PLSCR1 activates STAT1 signaling in basal-like breast cancer

    Theranostics 10:4644–4658.

    https://doi.org/10.7150/thno.43150

    • Google Scholar
25. 1. Humphreys DT
    2. Carver JA
    3. Easterbrook-Smith SB
    4. Wilson MR

    (1999) Clusterin has chaperone-like activity similar to that of small heat shock proteins

    The Journal of Biological Chemistry 274:6875–6881.

    https://doi.org/10.1074/jbc.274.11.6875

    • PubMed
    • Google Scholar
26. 1. Ibricevic A
    2. Pekosz A
    3. Walter MJ
    4. Newby C
    5. Battaile JT
    6. Brown EG
    7. Holtzman MJ
    8. Brody SL

    (2006) Influenza virus receptor specificity and cell tropism in mouse and human airway epithelial cells

    Journal of Virology 80:7469–7480.

    https://doi.org/10.1128/JVI.02677-05

    • PubMed
    • Google Scholar
27. 1. Kametaka S
    2. Shibata M
    3. Moroe K
    4. Kanamori S
    5. Ohsawa Y
    6. Waguri S
    7. Sims PJ
    8. Emoto K
    9. Umeda M
    10. Uchiyama Y

    (2003) Identification of phospholipid scramblase 1 as a novel interacting molecule with beta -secretase (beta -site amyloid precursor protein (APP) cleaving enzyme (BACE))

    The Journal of Biological Chemistry 278:15239–15245.

    https://doi.org/10.1074/jbc.M208611200

    • PubMed
    • Google Scholar
28. 1. Karlsson M
    2. Zhang C
    3. Méar L
    4. Zhong W
    5. Digre A
    6. Katona B
    7. Sjöstedt E
    8. Butler L
    9. Odeberg J
    10. Dusart P
    11. Edfors F
    12. Oksvold P
    13. von Feilitzen K
    14. Zwahlen M
    15. Arif M
    16. Altay O
    17. Li X
    18. Ozcan M
    19. Mardinoglu A
    20. Fagerberg L
    21. Mulder J
    22. Luo Y
    23. Ponten F
    24. Uhlén M
    25. Lindskog C

    (2021) A single-cell type transcriptomics map of human tissues

    Science Advances 7:31.

    https://doi.org/10.1126/sciadv.abh2169

    • PubMed
    • Google Scholar
29. 1. Klinkhammer J
    2. Schnepf D
    3. Ye L
    4. Schwaderlapp M
    5. Gad HH
    6. Hartmann R
    7. Garcin D
    8. Mahlakõiv T
    9. Staeheli P

    (2018) IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission

    eLife 7:e33354.

    https://doi.org/10.7554/eLife.33354

    • PubMed
    • Google Scholar
30. 1. Kraja AT
    2. Liu C
    3. Fetterman JL
    4. Graff M
    5. Have CT
    6. Gu C
    7. Yanek LR
    8. Feitosa MF
    9. Arking DE
    10. Chasman DI
    11. Young K
    12. Ligthart S
    13. Hill WD
    14. Weiss S
    15. Luan J
    16. Giulianini F
    17. Li-Gao R
    18. Hartwig FP
    19. Lin SJ
    20. Wang L
    21. Richardson TG
    22. Yao J
    23. Fernandez EP
    24. Ghanbari M
    25. Wojczynski MK
    26. Lee W-J
    27. Argos M
    28. Armasu SM
    29. Barve RA
    30. Ryan KA
    31. An P
    32. Baranski TJ
    33. Bielinski SJ
    34. Bowden DW
    35. Broeckel U
    36. Christensen K
    37. Chu AY
    38. Corley J
    39. Cox SR
    40. Uitterlinden AG
    41. Rivadeneira F
    42. Cropp CD
    43. Daw EW
    44. van Heemst D
    45. de las Fuentes L
    46. Gao H
    47. Tzoulaki I
    48. Ahluwalia TS
    49. de Mutsert R
    50. Emery LS
    51. Erzurumluoglu AM
    52. Perry JA
    53. Fu M
    54. Forouhi NG
    55. Gu Z
    56. Hai Y
    57. Harris SE
    58. Hemani G
    59. Hunt SC
    60. Irvin MR
    61. Jonsson AE
    62. Justice AE
    63. Kerrison ND
    64. Larson NB
    65. Lin K-H
    66. Love-Gregory LD
    67. Mathias RA
    68. Lee JH
    69. Nauck M
    70. Noordam R
    71. Ong KK
    72. Pankow J
    73. Patki A
    74. Pattie A
    75. Petersmann A
    76. Qi Q
    77. Ribel-Madsen R
    78. Rohde R
    79. Sandow K
    80. Schnurr TM
    81. Sofer T
    82. Starr JM
    83. Taylor AM
    84. Teumer A
    85. Timpson NJ
    86. de Haan HG
    87. Wang Y
    88. Weeke PE
    89. Williams C
    90. Wu H
    91. Yang W
    92. Zeng D
    93. Witte DR
    94. Weir BS
    95. Wareham NJ
    96. Vestergaard H
    97. Turner ST
    98. Torp-Pedersen C
    99. Stergiakouli E
    100. Sheu WH-H
    101. Rosendaal FR
    102. Ikram MA
    103. Franco OH
    104. Ridker PM
    105. Perls TT
    106. Pedersen O
    107. Nohr EA
    108. Newman AB
    109. Linneberg A
    110. Langenberg C
    111. Kilpeläinen TO
    112. Kardia SLR
    113. Jørgensen ME
    114. Jørgensen T
    115. Sørensen TIA
    116. Homuth G
    117. Hansen T
    118. Goodarzi MO
    119. Deary IJ
    120. Christensen C
    121. Chen Y-DI
    122. Chakravarti A
    123. Brandslund I
    124. Bonnelykke K
    125. Taylor KD
    126. Wilson JG
    127. Rodriguez S
    128. Davies G
    129. Horta BL
    130. Thyagarajan B
    131. Rao DC
    132. Grarup N
    133. Davila-Roman VG
    134. Hudson G
    135. Guo X
    136. Arnett DK
    137. Hayward C
    138. Vaidya D
    139. Mook-Kanamori DO
    140. Tiwari HK
    141. Levy D
    142. Loos RJF
    143. Dehghan A
    144. Elliott P
    145. Malik AN
    146. Scott RA
    147. Becker DM
    148. de Andrade M
    149. Province MA
    150. Meigs JB
    151. Rotter JI
    152. North KE

    (2019) Associations of mitochondrial and nuclear mitochondrial variants and genes with seven metabolic traits

    American Journal of Human Genetics 104:112–138.

    https://doi.org/10.1016/j.ajhg.2018.12.001

    • PubMed
    • Google Scholar
31. 1. Li Y
    2. Rogulski K
    3. Zhou Q
    4. Sims PJ
    5. Prochownik EV

    (2006) The negative c-Myc target onzin affects proliferation and apoptosis via its obligate interaction with phospholipid scramblase I

    Molecular and Cellular Biology 26:3401–3413.

    https://doi.org/10.1128/MCB.26.9.3401-3413.2006

    • Google Scholar
32. 1. Liu Y
    2. Lin S
    3. Xie Y
    4. Zhao L
    5. Du H
    6. Yang S
    7. Yin B
    8. Li G
    9. Zhao Z
    10. Huang Z
    11. Xu Z
    12. Wu J

    (2022) ILDR1 promotes influenza A virus replication through binding to PLSCR1

    Scientific Reports 12:8515.

    https://doi.org/10.1038/s41598-022-12598-3

    • Google Scholar
33. 1. Lizak M
    2. Yarovinsky TO

    (2012) Phospholipid scramblase 1 mediates type i interferon-induced protection against staphylococcal α-toxin

    Cell Host & Microbe 11:70–80.

    https://doi.org/10.1016/j.chom.2011.12.004

    • PubMed
    • Google Scholar
34. 1. Lu B
    2. Sims PJ
    3. Wiedmer T
    4. Moser AH
    5. Shigenaga JK
    6. Grunfeld C
    7. Feingold KR

    (2007) Expression of the phospholipid scramblase (PLSCR) gene family during the acute phase response

    Biochimica et Biophysica Acta 1771:1177–1185.

    https://doi.org/10.1016/j.bbalip.2007.05.002

    • PubMed
    • Google Scholar
35. 1. Luo W
    2. Zhang J
    3. Liang L
    4. Wang G
    5. Li Q
    6. Zhu P
    7. Zhou Y
    8. Li J
    9. Zhao Y
    10. Sun N
    11. Huang S
    12. Zhou C
    13. Chang Y
    14. Cui P
    15. Chen P
    16. Jiang Y
    17. Deng G
    18. Bu Z
    19. Li C
    20. Jiang L
    21. Chen H

    (2018) Phospholipid scramblase 1 interacts with influenza A virus NP, impairing its nuclear import and thereby suppressing virus replication

    PLOS Pathogens 14:e1006851.

    https://doi.org/10.1371/journal.ppat.1006851

    • PubMed
    • Google Scholar
36. 1. Mattoo RUH
    2. Sharma SK
    3. Priya S
    4. Finka A
    5. Goloubinoff P

    (2013) Hsp110 is a bona fide chaperone using ATP to unfold stable misfolded polypeptides and reciprocally collaborate with Hsp70 to solubilize protein aggregates

    The Journal of Biological Chemistry 288:21399–21411.

    https://doi.org/10.1074/jbc.M113.479253

    • PubMed
    • Google Scholar
37. 1. Meixner A
    2. Karreth F
    3. Kenner L
    4. Penninger JM
    5. Wagner EF

    (2010) Jun and JunD-dependent functions in cell proliferation and stress response

    Cell Death and Differentiation 17:1409–1419.

    https://doi.org/10.1038/cdd.2010.22

    • PubMed
    • Google Scholar
38. Software

    1. R Development Core Team

    (2023) R: a language and environment for statistical computing

    R Foundation for Statistical Computing, Vienna, Austria.

    http://www.r-project.org
39. 1. Rusinova I
    2. Forster S
    3. Yu S
    4. Kannan A
    5. Masse M
    6. Cumming H
    7. Chapman R
    8. Hertzog PJ

    (2013) Interferome v2.0: an updated database of annotated interferon-regulated genes

    Nucleic Acids Research 41:D1040–D1046.

    https://doi.org/10.1093/nar/gks1215

    • PubMed
    • Google Scholar
40. 1. Schneider CA
    2. Rasband WS
    3. Eliceiri KW

    (2012) NIH Image to ImageJ: 25 years of image analysis

    Nature Methods 9:671–675.

    https://doi.org/10.1038/nmeth.2089

    • PubMed
    • Google Scholar
41. 1. Schwenk F
    2. Baron U
    3. Rajewsky K

    (1995) A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells

    Nucleic Acids Research 23:5080–5081.

    https://doi.org/10.1093/nar/23.24.5080

    • PubMed
    • Google Scholar
42. 1. Sheppard P
    2. Kindsvogel W
    3. Xu W
    4. Henderson K
    5. Schlutsmeyer S
    6. Whitmore TE
    7. Kuestner R
    8. Garrigues U
    9. Birks C
    10. Roraback J
    11. Ostrander C
    12. Dong D
    13. Shin J
    14. Presnell S
    15. Fox B
    16. Haldeman B
    17. Cooper E
    18. Taft D
    19. Gilbert T
    20. Grant FJ
    21. Tackett M
    22. Krivan W
    23. McKnight G
    24. Clegg C
    25. Foster D
    26. Klucher KM

    (2003) IL-28, IL-29 and their class II cytokine receptor IL-28R

    Nature Immunology 4:63–68.

    https://doi.org/10.1038/ni873

    • PubMed
    • Google Scholar
43. 1. Sommereyns C
    2. Paul S
    3. Staeheli P
    4. Michiels T

    (2008) IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo

    PLOS Pathogens 4:e1000017.

    https://doi.org/10.1371/journal.ppat.1000017

    • PubMed
    • Google Scholar
44. 1. Sun J
    2. Nanjundan M
    3. Pike LJ
    4. Wiedmer T
    5. Sims PJ

    (2002) Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts and interacts with the epidermal growth factor receptor

    Biochemistry 41:6338–6345.

    https://doi.org/10.1021/bi025610l

    • PubMed
    • Google Scholar
45. 1. Swiecki M
    2. Colonna M

    (2011) Type I interferons: diversity of sources, production pathways and effects on immune responses

    Current Opinion in Virology 1:463–475.

    https://doi.org/10.1016/j.coviro.2011.10.026

    • PubMed
    • Google Scholar
46. 1. Talukder AH
    2. Bao M
    3. Kim TW
    4. Facchinetti V
    5. Hanabuchi S
    6. Bover L
    7. Zal T
    8. Liu Y-J

    (2012) Phospholipid scramblase 1 regulates Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells

    Cell Research 22:1129–1139.

    https://doi.org/10.1038/cr.2012.45

    • PubMed
    • Google Scholar
47. 1. Tang D
    2. Wang Y
    3. Dong X
    4. Yuan Y
    5. Kang F
    6. Tian W
    7. Wang K
    8. Li H
    9. Qi S

    (2022) Scramblases and virus infection

    BioEssays 44:e2100261.

    https://doi.org/10.1002/bies.202100261

    • PubMed
    • Google Scholar
48. 1. The Medical Letter on Drugs and Therapeutics

    (2020)

    Antiviral drugs for influenza

    The Medical Letter on Drugs and Therapeutics 62:1–4.

    • PubMed
    • Google Scholar
49. Book

    1. Wickham H

    (2016) Ggplot2: Elegant Graphics for Data Analysis

    Springer Cham.

    https://doi.org/10.1007/978-3-319-24277-4

    • Google Scholar
50. 1. Wiedmer T
    2. Zhao J
    3. Nanjundan M
    4. Sims PJ

    (2003) Palmitoylation of phospholipid scramblase 1 controls its distribution between nucleus and plasma membrane

    Biochemistry 42:1227–1233.

    https://doi.org/10.1021/bi026679w

    • PubMed
    • Google Scholar
51. 1. Wu T
    2. Hu E
    3. Xu S
    4. Chen M
    5. Guo P
    6. Dai Z
    7. Feng T
    8. Zhou L
    9. Tang W
    10. Zhan L
    11. Fu X
    12. Liu S
    13. Bo X
    14. Yu G

    (2021) clusterProfiler 4.0: A universal enrichment tool for interpreting omics data

    Innovation 2:100141.

    https://doi.org/10.1016/j.xinn.2021.100141

    • PubMed
    • Google Scholar
52. 1. Wyles JP
    2. Wu Z
    3. Mirski SEL
    4. Cole SPC

    (2007) Nuclear interactions of topoisomerase II alpha and beta with phospholipid scramblase 1

    Nucleic Acids Research 35:4076–4085.

    https://doi.org/10.1093/nar/gkm434

    • PubMed
    • Google Scholar
53. 1. Xu D
    2. Jiang W
    3. Wu L
    4. Gaudet RG
    5. Park E-S
    6. Su M
    7. Cheppali SK
    8. Cheemarla NR
    9. Kumar P
    10. Uchil PD
    11. Grover JR
    12. Foxman EF
    13. Brown CM
    14. Stansfeld PJ
    15. Bewersdorf J
    16. Mothes W
    17. Karatekin E
    18. Wilen CB
    19. MacMicking JD

    (2023) PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection

    Nature 619:819–827.

    https://doi.org/10.1038/s41586-023-06322-y

    • Google Scholar
54. 1. Yin Z
    2. Dai J
    3. Deng J
    4. Sheikh F
    5. Natalia M
    6. Shih T
    7. Lewis-Antes A
    8. Amrute SB
    9. Garrigues U
    10. Doyle S
    11. Donnelly RP
    12. Kotenko SV
    13. Fitzgerald-Bocarsly P

    (2012) Type III IFNs are produced by and stimulate human plasmacytoid dendritic cells

    The Journal of Immunology 189:2735–2745.

    https://doi.org/10.4049/jimmunol.1102038

    • Google Scholar
55. 1. Zhao J
    2. Zhou Q
    3. Wiedmer T
    4. Sims PJ

    (1998) Level of expression of phospholipid scramblase regulates induced movement of phosphatidylserine to the cell surface

    The Journal of Biological Chemistry 273:6603–6606.

    https://doi.org/10.1074/jbc.273.12.6603

    • PubMed
    • Google Scholar
56. 1. Zhou Q
    2. Zhao J
    3. Al-Zoghaibi F
    4. Zhou A
    5. Wiedmer T
    6. Silverman RH
    7. Sims PJ

    (2000)

    Transcriptional control of the human plasma membrane phospholipid scramblase 1 gene is mediated by interferon-alpha

    Blood 95:2593–2599.

    • PubMed
    • Google Scholar
57. 1. Zhou Q
    2. Ben-Efraim I
    3. Bigcas J-L
    4. Junqueira D
    5. Wiedmer T
    6. Sims PJ

    (2005) Phospholipid scramblase 1 binds to the promoter region of the inositol 1,4,5-triphosphate receptor type 1 gene to enhance its expression

    The Journal of Biological Chemistry 280:35062–35068.

    https://doi.org/10.1074/jbc.M504821200

    • PubMed
    • Google Scholar

Author details

1. Alina Xiaoyu Yang

   Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

   Contribution

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

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1528-9129

2. Lisa Ramos-Rodriguez

   Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

3. Parand Sorkhdini

   Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

   Contribution

   Conceptualization, Writing – review and editing

   Competing interests

   No competing interests declared

4. Dongqin Yang

   Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

5. Carmelissa Norbrun

   Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

   Contribution

   Conceptualization, Writing – review and editing

   Competing interests

   No competing interests declared

6. Sonoor Majid

   Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

7. Sanghyun Lee

   Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

   Contribution

   Resources, Writing – review and editing

   Competing interests

   No competing interests declared

8. Yong Zhang

   Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine in St. Louis, St. Louis, United States

   Contribution

   Resources

   Competing interests

   No competing interests declared

9. Michael Holtzman

   Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine in St. Louis, St. Louis, United States

   Contribution

   Resources, Writing – review and editing

   Competing interests

   No competing interests declared

10. David F Boyd

    Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, United States

    Contribution

    Data curation, Formal analysis

    Competing interests

    No competing interests declared

11. Yang Zhou

    Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Project administration, Writing – review and editing

    For correspondence

    yang_zhou@brown.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6867-6443

• 657

  views

• 17

  downloads

• 0

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.