Sepsis accounts for one in five deaths worldwide and is a common final pathway for many disease processes such as cancer, diabetes, and cardiovascular disease (Rhee et al., 2019). Sepsis is an inflammatory syndrome largely driven by the activation of immune cells by pathogen associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (van der Poll et al., 2017; Deutschman and Tracey, 2014). After recognizing these molecules via pattern recognition receptors, immune cells become activated and produce proinflammatory cytokines, notably interleukins IL-1, IL-6, interferons (IFNs), and tumor necrosis factor (TNF) that contribute to fever, vasodilation, and multiorgan dysfunction (Deutschman and Tracey, 2014; Yu et al., 2011; Huang et al., 2005; Wang et al., 2008). For patients that progress to septic shock, mortality rates remain as high as 40% (Napolitano, 2018).

Leukopenia is a feature of severe sepsis that arises from apoptosis of peripheral immune cells and is an independent risk factor for death. To counteract the adverse effects of leukopenia, investigators have used immunotherapies such as GM-CSF (Krebs et al., 2019) or granulocyte infusions in an attempt to restore leukocyte numbers and improve survival. These strategies have produced mixed results (Estcourt et al., 2016; Li et al., 2019; Mathias et al., 2015). The benefits of granulocyte infusions in cancer patients with fever and neutropenia are limited by the difficulty of obtaining sufficient cells and the short-lived nature of those cells (Hidalgo et al., 2019; Robinson and Marks, 2004).

Recent work from our group and others indicates that hematopoietic stem and progenitor cells (HSPCs) express surface receptors for cytokines, chemokines, and PAMPs (Karpova et al., 2017; Burberry et al., 2014; Nagai et al., 2006; Schürch et al., 2014; Matatall et al., 2014; Baldridge et al., 2011; Pietras et al., 2016; Takizawa et al., 2017) and respond rapidly upon direct and indirect stimulation by these signals. HSPCs, the progenitors of all blood and immune cells, are comprised of five subgroups of hematopoietic cells: hematopoietic stem cells (HSCs), which have long-term self-renewal capacity, and four types of multipotent progenitors (MPPs 1–4), which are defined by lower self-renewal capacity and myeloid or lymphoid differentiation biases (Wang et al., 2008; Morales-Mantilla and King, 2018; Chambers et al., 2007; Sun et al., 2014; Rodriguez-Fraticelli et al., 2018; Cabezas-Wallscheid et al., 2014). Immune responses induce HSPCs in the bone marrow (BM) to produce effector immune cells via a process called emergency hematopoiesis (Matatall et al., 2014; Pietras et al., 2016; Takizawa et al., 2017; Morales-Mantilla and King, 2018; MacNamara et al., 2011; Matatall et al., 2016). The capacity of HSPCs to directly detect pathogen-derived molecules, cytokines, and chemokines suggests that emergency granulopoiesis can be mobilized from even the most primitive hematopoietic progenitors and that HSPCs have an active role in fighting infections. However, the extent and mechanism by which HSPC responses contribute to immunity in the acute setting remain poorly defined.

We recently showed that chronic inflammatory stress impairs HSPC quiescence and self-renewal while promoting their activation and terminal differentiation (Matatall et al., 2016). Upon direct sensing of inflammatory cytokines such as interferon-gamma (IFNγ), HSCs are dislodged from their normal position near quiescence-enforcing CXCL12-abundant reticular cells in the niche. Inflammatory signaling induces transcription factors such as Pu.1, CEBPb, and BATF2 (Matatall et al., 2014; Pietras et al., 2016; Matatall et al., 2016; Sato et al., 2020) to promote myeloid differentiation, leading to the expansion of granulocyte and monocyte populations. Disruption of the homeostatic balance of self-renewal and differentiation eventually leads to depletion of the progenitor compartment (Pietras et al., 2016; Morales-Mantilla and King, 2018; Matatall et al., 2016). Collectively, these studies point toward a direct role for HSPCs in supplying the myeloid cells critical to the immune response against infection.

To test their contribution to immune responses during acute infection, we examined the role of HSPCs in a mouse model of Streptococcus pyogenes infection, also known as Group A Streptococcus (GAS). GAS is a common and clinically relevant pathogen that causes a plethora of diseases, from mild skin infections to life-threatening necrotizing fasciitis and sepsis (Wang et al., 2008; Efstratiou and Lamagni, 2016; Emgård et al., 2019; Walker et al., 2014). GAS infections can infiltrate the bloodstream and other organs, causing high systemic levels of inflammatory cytokines including IFNγ, TNF, IL-1, and IL-6. As HSPCs have been shown to activate and differentiate in response to these cytokines (Burberry et al., 2014; Matatall et al., 2014; Pietras et al., 2016; Takizawa et al., 2017; Morales-Mantilla and King, 2018; Gong et al., 2020; Esplin et al., 2011; Chou et al., 2012), in this study we sought to determine the role of HSPCs in immune responses against infections.

Here, we found that GAS infection significantly depletes HSPCs in the bone marrow (BM). We tested the idea of infusing HSPCs to restore the hematopoietic progenitor pool. Mice treated with HSPCs showed restored HSPC numbers in the BM, increased myeloid cell production, and significantly improved overall survival. Surprisingly, HSPC infusion did not reduce pathogen burden. Instead, HSPC infusion correlated with a significant increase in the abundance of myeloid-derived suppressor cells (MDSCs) and a dampening of overall systemic inflammation. In summary, our studies indicate that HSPCs contribute to survival from sepsis by supporting the production of immunosuppressive MDSCs.

Here, we show HSPC infusion holds therapeutic potential for bacterial sepsis. Our studies demonstrate that GAS infection induces a robust myeloid response just 24 hr after infection and significantly depletes HSPC populations in the BM. After infection, endogenous HSPCs are driven to differentiate toward the myeloid lineage. However, this response is insufficient to prevent disease progression and pathogen dissemination, resulting in mortality in 5–7 days. While sepsis has been described to cause mobilization of HSPCs (Skirecki et al., 2019), we did not find any evidence of HSC or MPP mobilization to the spleen. Strikingly, we found infusing just 10,000 HSPCs improved survival in GAS-infected mice and mice with GAS and influenza superinfection. This infusion was capable of increasing PB and BM hematopoietic populations of infected mice. Specifically, HSPC infusion restored BM HSPCs and both PB and BM MDSC populations. Importantly, HSPC infusion did not reduce pathogen burden, but contributed to survival via the generation of immunoregulatory cells that dampened maladaptive inflammatory signaling in infected mice.

The hematopoietic and immune systems are comprised of immune cells with antimicrobial killing capacity as well as various types of immunomodulatory cells such as MDSCs, regulatory B cells (Bregs), and regulatory T cells (Tregs) (Maizels and Smith, 2011; Rosser and Mauri, 2015; Schrijver et al., 2019). In the short time frame of acute sepsis, myeloid cells such as neutrophils, monocytes, and macrophages are of critical importance in rapidly recognizing and killing invading bacteria. Our data demonstrate that these cells and even the progenitors that produce them in the BM can be rapidly depleted during a severe acute infection. Furthermore, lineage tracing experiments provide the first direct evidence that terminally differentiated myeloid cells are rapidly produced from the level of the HSC during an acute infection. Initially we hypothesized that replacement of HSPCs may improve outcomes from acute bacterial infection by boosting the availability of myeloid cells to kill bacteria. While myeloid cell populations were somewhat restored after HSPC infusion, this was insufficient to reduce pathogen burden.

Dysregulated inflammation is one of the main drivers of morbidity and mortality during infections (Huang et al., 2005; Frank and Paust, 2020; Karki et al., 2021; Fajgenbaum and June, 2020). For example, excessive inflammatory responses are a common result of seasonal influenza (Yu et al., 2011; Frank and Paust, 2020) and SARS-CoV-2 infection (Karki et al., 2021). Seasonal influenza increases the susceptibility of patients to secondary bacterial infections or superinfection (Rynda-Apple et al., 2015). Superinfections exacerbate the proinflammatory environment of common viral infections and are associated with increased morbidity and mortality (Rynda-Apple et al., 2015; Paget and Trottein, 2019). To our surprise, HSPC infusion was protective in a model of influenza and GAS superinfection, suggesting that its protective effects are robust even in the setting of severe inflammation. In our mouse models, infection dramatically increased cytokine levels within just 3 days of infection. Interestingly, HSPC infusion was accompanied by an overall decrease in serum cytokine levels and a specific dampening of cytokines involved in ‘cytokine storm’ (Huang et al., 2005; Karki et al., 2021; Fajgenbaum and June, 2020). HSPCs have been described to produce cytokines, indicating that they have the capacity to direct immune function (Chen et al., 2016). However, whether the cytokines produced by HSPCs themselves contribute to the regulation of the immune response has heretofore been unknown. Our data point toward an immunomodulatory role of HSPC infusion that could prevent immune dysregulation during sepsis.

Immunoregulatory cells in the hematopoietic system include Tregs, Bregs, and MDSCs (Maizels and Smith, 2011; Schrijver et al., 2019; Uhel et al., 2017). Perhaps the most recognized immunomodulatory cell known is the Treg. While Tregs have essential roles regulating immune responses to pathogens (Maizels and Smith, 2011), we did not see differences in any lymphocyte population, including T cells, that would suggest a Treg-mediated anti-inflammatory mechanism after HSPC infusion. MDSCs are immature myeloid cells that have strong anti-inflammatory roles by suppressing the responses of T-helper cells that contribute to the development of sepsis (Schrijver et al., 2019; Köstlin et al., 2017; Delano et al., 2007). PMN-MDSCs and M-MDSCs have strong anti-inflammatory functions that can be beneficial or detrimental depending on the setting. In fact, some studies have shown that MDSCs contribute to clinical worsening during sepsis (Schrijver et al., 2019). For almost three decades, increased circulating immature myeloid cells have been a clinical marker of SIRS (Bone et al., 1992). Interestingly, increased MDSCs during sepsis have also been associated with increased development of nosocomial infections (Uhel et al., 2017). However, in our GAS model of accelerated infection, the increase in MDSC populations after HSPC infusion was accompanied by lower overall cytokine levels and increased survival, suggesting that the immunomodulatory functions of MDSCs are beneficial during the early stages of systemic inflammation and could prevent sepsis-related mortality (Chang et al., 2018).

An important limitation of our study is that the lineage fate and the tissue or organ destination of the infused HSPCs at the early stages of infusion remain unknown. The small number of cells infused makes it challenging to identify them in the pool of endogenous cells of the recipient mice. While our data suggest that infused HSPCs directly and indirectly boost MDSC production by endogenous cells, further work will be required to determine the mechanisms by which HSPCs contribute to MDSC expansion. In addition, further analysis of HSPC subpopulations will be required to determine if long-term HSCs or short-lived MPPs confer the greatest therapeutic potential. Identifying a short-lived hematopoietic progenitor that can signal endogenous cells to restore MDSC populations could represent a promising alternative therapeutic avenue (Hidalgo et al., 2019; Karpova et al., 2017; Nagai et al., 2006) to treat sepsis while avoiding concern of possible graft versus host disease complications (Batsali et al., 2020; Tijaro-Ovalle et al., 2019).

Currently, G-CSF, GM-CSF, and granulocyte transfusion (Robinson and Marks, 2004; Price et al., 2015; Klein and Castillo, 2017) are used to prevent or treat sepsis in oncology patients with chemotherapy-induced fever and neutropenia. However, the clinical efficacy of granulocyte transfusion is poor (Price et al., 2015; Klein and Castillo, 2017). Here, we have shown infusing HSPCs is a promising alternative to granulocyte transfusion. Current granulocyte doses in humans are around 1 × 10¹⁰ cells per m² body surface area given daily or every other day (Price et al., 2015; Teofili et al., 2016). Our infusion model only uses a single dose of 1.7 × 10⁷ cells per m² body surface area (or 10,000 HSPCs in a mouse). It is important to emphasize that 10,000 HSPCs is a relatively small number of cells to infuse into a mouse as it represents less than 0.01% of the nucleated BM cells in a mouse. Collectively, the single low HSPC dose compared to multiple larger granulocyte transfusions suggests that HSPCs are more effective than granulocytes, cell for cell, in the treatment of sepsis. While the path to a clinical application can be long, our findings could lead to the future development of a new therapeutic approach that could succeed where granulocyte infusions have fallen short.

All data generated or analysed during this study are included in the manuscript and supporting file.

1. 1. Baccam P
   2. Beauchemin C
   3. Macken CA
   4. Hayden FG
   5. Perelson AS

   (2006) Kinetics of influenza A virus infection in humans

   Journal of Virology 80:7590–7599.

   https://doi.org/10.1128/JVI.01623-05

   • PubMed
   • Google Scholar
2. 1. Baldridge MT
   2. King KY
   3. Boles NC
   4. Weksberg DC
   5. Goodell MA

   (2010) Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection

   Nature 465:793–797.

   https://doi.org/10.1038/nature09135

   • PubMed
   • Google Scholar
3. 1. Baldridge MT
   2. King KY
   3. Goodell MA

   (2011) Inflammatory signals regulate hematopoietic stem cells

   Trends in Immunology 32:57–65.

   https://doi.org/10.1016/j.it.2010.12.003

   • PubMed
   • Google Scholar
4. 1. Batsali AK
   2. Georgopoulou A
   3. Mavroudi I
   4. Matheakakis A
   5. Pontikoglou CG
   6. Papadaki HA

   (2020) The Role of Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles (MSC-EVs)

   In Normal and Abnormal Hematopoiesis and Their Therapeutic Potential. Journal of Clinical Medicine 9:1–14.

   https://doi.org/10.3390/jcm9030856

   • Google Scholar
5. 1. Bone RC
   2. Balk RA
   3. Cerra FB
   4. Dellinger RP
   5. Fein AM
   6. Knaus WA
   7. Schein RMH
   8. Sibbald WJ

   (1992) Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis

   Chest 101:1644–1655.

   https://doi.org/10.1378/chest.101.6.1644

   • PubMed
   • Google Scholar
6. 1. Burberry A
   2. Zeng MY
   3. Ding L
   4. Wicks I
   5. Inohara N
   6. Morrison SJ
   7. Núñez G

   (2014) Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling

   Cell Host & Microbe 15:779–791.

   https://doi.org/10.1016/j.chom.2014.05.004

   • PubMed
   • Google Scholar
7. 1. Cabezas-Wallscheid N
   2. Klimmeck D
   3. Hansson J
   4. Lipka DB
   5. Reyes A
   6. Wang Q
   7. Weichenhan D
   8. Lier A
   9. von Paleske L
   10. Renders S
   11. Wünsche P
   12. Zeisberger P
   13. Brocks D
   14. Gu L
   15. Herrmann C
   16. Haas S
   17. Essers MAG
   18. Brors B
   19. Eils R
   20. Huber W
   21. Milsom MD
   22. Plass C
   23. Krijgsveld J
   24. Trumpp A

   (2014) Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis

   Cell Stem Cell 15:507–522.

   https://doi.org/10.1016/j.stem.2014.07.005

   • PubMed
   • Google Scholar
8. 1. Chambers SM
   2. Boles NC
   3. Lin K-YK
   4. Tierney MP
   5. Bowman TV
   6. Bradfute SB
   7. Chen AJ
   8. Merchant AA
   9. Sirin O
   10. Weksberg DC
   11. Merchant MG
   12. Fisk CJ
   13. Shaw CA
   14. Goodell MA

   (2007) Hematopoietic fingerprints: an expression database of stem cells and their progeny

   Cell Stem Cell 1:578–591.

   https://doi.org/10.1016/j.stem.2007.10.003

   • PubMed
   • Google Scholar
9. 1. Chang S
   2. Kim Y-H
   3. Kim Y-J
   4. Kim Y-W
   5. Moon S
   6. Lee YY
   7. Jung JS
   8. Kim Y
   9. Jung H-E
   10. Kim T-J
   11. Cheong T-C
   12. Moon H-J
   13. Cho J-A
   14. Kim H-R
   15. Han D
   16. Na Y
   17. Seok S-H
   18. Cho N-H
   19. Lee H-C
   20. Nam E-H
   21. Cho H
   22. Choi M
   23. Minato N
   24. Seong S-Y

   (2018) Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor Cells That Ameliorate Sepsis in Mice

   Frontiers in Immunology 9:1984.

   https://doi.org/10.3389/fimmu.2018.01984

   • PubMed
   • Google Scholar
10. 1. Chapple RH
    2. Tseng Y-J
    3. Hu T
    4. Kitano A
    5. Takeichi M
    6. Hoegenauer KA
    7. Nakada D

    (2018) Lineage tracing of murine adult hematopoietic stem cells reveals active contribution to steady-state hematopoiesis

    Blood Advances 2:1220–1228.

    https://doi.org/10.1182/bloodadvances.2018016295

    • PubMed
    • Google Scholar
11. 1. Chen CI
    2. Zhang L
    3. Datta SK

    (2016) Hematopoietic stem and multipotent progenitor cells produce IL-17, IL-21 and other cytokines in response to TLR signals associated with late apoptotic products and augment memory Th17 and Tc17 cells in the bone marrow of normal and lupus mice

    Clinical Immunology (Orlando, Fla.) 162:9–26.

    https://doi.org/10.1016/j.clim.2015.10.007

    • PubMed
    • Google Scholar
12. 1. Chou DB
    2. Sworder B
    3. Bouladoux N
    4. Roy CN
    5. Uchida AM
    6. Grigg M
    7. Robey PG
    8. Belkaid Y

    (2012) Stromal-derived IL-6 alters the balance of myeloerythroid progenitors during Toxoplasma gondii infection

    Journal of Leukocyte Biology 92:123–131.

    https://doi.org/10.1189/jlb.1011527

    • PubMed
    • Google Scholar
13. 1. Delano MJ
    2. Scumpia PO
    3. Weinstein JS
    4. Coco D
    5. Nagaraj S
    6. Kelly-Scumpia KM
    7. O’Malley KA
    8. Wynn JL
    9. Antonenko S
    10. Al-Quran SZ
    11. Swan R
    12. Chung C-S
    13. Atkinson MA
    14. Ramphal R
    15. Gabrilovich DI
    16. Reeves WH
    17. Ayala A
    18. Phillips J
    19. Laface D
    20. Heyworth PG
    21. Clare-Salzler M
    22. Moldawer LL

    (2007) MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis

    The Journal of Experimental Medicine 204:1463–1474.

    https://doi.org/10.1084/jem.20062602

    • PubMed
    • Google Scholar
14. 1. Deutschman CS
    2. Tracey KJ

    (2014) Sepsis: current dogma and new perspectives

    Immunity 40:463–475.

    https://doi.org/10.1016/j.immuni.2014.04.001

    • PubMed
    • Google Scholar
15. 1. Efstratiou A
    2. Lamagni T

    (2016) In: Streptococcus pyogenes: Basic Biology to Clinical Manifestations

    Pathogens (Basel, Switzerland) 3:10060776.

    https://doi.org/10.3390/pathogens10060776

    • Google Scholar
16. 1. Emgård J
    2. Bergsten H
    3. McCormick JK
    4. Barrantes I
    5. Skrede S
    6. Sandberg JK
    7. Norrby-Teglund A

    (2019) MAIT Cells Are Major Contributors to the Cytokine Response in Group A Streptococcal Toxic Shock Syndrome

    PNAS 116:25923–25931.

    https://doi.org/10.1073/pnas.1910883116

    • PubMed
    • Google Scholar
17. 1. Esplin BL
    2. Shimazu T
    3. Welner RS
    4. Garrett KP
    5. Nie L
    6. Zhang Q
    7. Humphrey MB
    8. Yang Q
    9. Borghesi LA
    10. Kincade PW

    (2011) Chronic exposure to a TLR ligand injures hematopoietic stem cells

    Journal of Immunology (Baltimore, Md 186:5367–5375.

    https://doi.org/10.4049/jimmunol.1003438

    • PubMed
    • Google Scholar
18. 1. Estcourt LJ
    2. Stanworth SJ
    3. Hopewell S
    4. Doree C
    5. Trivella M
    6. Massey E

    (2016) Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction

    The Cochrane Database of Systematic Reviews 4:CD005339.

    https://doi.org/10.1002/14651858.CD005339.pub2

    • PubMed
    • Google Scholar
19. 1. Fajgenbaum DC
    2. June CH

    (2020) Cytokine Storm

    The New England Journal of Medicine 383:2255–2273.

    https://doi.org/10.1056/NEJMra2026131

    • PubMed
    • Google Scholar
20. 1. Frank K
    2. Paust S

    (2020) Dynamic Natural Killer Cell and T Cell Responses to Influenza Infection

    Frontiers in Cellular and Infection Microbiology 10:1–21.

    https://doi.org/10.3389/fcimb.2020.00425

    • PubMed
    • Google Scholar
21. 1. Gekas C
    2. Graf T

    (2013) CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age

    Blood 121:4463–4472.

    https://doi.org/10.1182/blood-2012-09-457929

    • PubMed
    • Google Scholar
22. 1. Gong T
    2. Liu L
    3. Jiang W
    4. Zhou R

    (2020) DAMP-sensing receptors in sterile inflammation and inflammatory diseases

    Nature Reviews. Immunology 20:95–112.

    https://doi.org/10.1038/s41577-019-0215-7

    • PubMed
    • Google Scholar
23. 1. Hidalgo A
    2. Chilvers ER
    3. Summers C
    4. Koenderman L

    (2019) The Neutrophil Life Cycle

    Trends in Immunology 40:584–597.

    https://doi.org/10.1016/j.it.2019.04.013

    • PubMed
    • Google Scholar
24. 1. Huang K-J
    2. Su I-J
    3. Theron M
    4. Wu Y-C
    5. Lai S-K
    6. Liu C-C
    7. Lei H-Y

    (2005) An interferon-gamma-related cytokine storm in SARS patients

    Journal of Medical Virology 75:185–194.

    https://doi.org/10.1002/jmv.20255

    • PubMed
    • Google Scholar
25. 1. Jaffer U
    2. Wade RG
    3. Gourlay T

    (2010)

    Cytokines in the systemic inflammatory response syndrome: a review

    HSR Proceedings 2:161–175.

    • PubMed
    • Google Scholar
26. 1. Karki R
    2. Sharma BR
    3. Tuladhar S
    4. Williams EP
    5. Zalduondo L
    6. Samir P
    7. Zheng M
    8. Sundaram B
    9. Banoth B
    10. Malireddi RKS
    11. Schreiner P
    12. Neale G
    13. Vogel P
    14. Webby R
    15. Jonsson CB
    16. Kanneganti T-D

    (2021) Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

    Cell 184:149–168.

    https://doi.org/10.1016/j.cell.2020.11.025

    • PubMed
    • Google Scholar
27. 1. Karpova D
    2. Ritchey JK
    3. Holt MS
    4. Abou-Ezzi G
    5. Monlish D
    6. Batoon L
    7. Millard S
    8. Spohn G
    9. Wiercinska E
    10. Chendamarai E
    11. Yang W
    12. Christ S
    13. Gehrs L
    14. Schuettpelz LG
    15. Dembowsky K
    16. Pettit AR
    17. Rettig MP
    18. Bonig H
    19. DiPersio JF

    (2017) Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells

    Blood 129:2939–2949.

    https://doi.org/10.1182/blood-2016-10-746909

    • PubMed
    • Google Scholar
28. 1. Klein K
    2. Castillo B

    (2017)

    Historical Perspectives, Current Status, and Ethical Issues in Granulocyte Transfusion

    Annals of Clinical and Laboratory Science 47:501–507.

    • PubMed
    • Google Scholar
29. 1. Köstlin N
    2. Vogelmann M
    3. Spring B
    4. Schwarz J
    5. Feucht J
    6. Härtel C
    7. Orlikowsky TW
    8. Poets CF
    9. Gille C

    (2017) Granulocytic myeloid-derived suppressor cells from human cord blood modulate T-helper cell response towards an anti-inflammatory phenotype

    Immunology 152:89–101.

    https://doi.org/10.1111/imm.12751

    • PubMed
    • Google Scholar
30. 1. Krebs J
    2. Hillenbrand A
    3. Tsagogiorgas C
    4. Patry C
    5. Tönshoff B
    6. Yard B
    7. Beck G
    8. Rafat N

    (2019) Intravenous delivery of granulocyte-macrophage colony stimulating factor impairs survival in lipopolysaccharide-induced sepsis

    PLOS ONE 14:e218602.

    https://doi.org/10.1371/journal.pone.0218602

    • PubMed
    • Google Scholar
31. 1. Larcombe AN
    2. Foong RE
    3. Bozanich EM
    4. Berry LJ
    5. Garratt LW
    6. Gualano RC
    7. Jones JE
    8. Dousha LF
    9. Zosky GR
    10. Sly PD

    (2011) Sexual dimorphism in lung function responses to acute influenza A infection

    Influenza and Other Respiratory Viruses 5:334–342.

    https://doi.org/10.1111/j.1750-2659.2011.00236.x

    • PubMed
    • Google Scholar
32. 1. Li Y
    2. Yang S
    3. Wang G
    4. Liu M
    5. Zhang Z
    6. Liu H
    7. Yu K
    8. Wang C

    (2019) Effects of immunotherapy on mortality in neonates with suspected or proven sepsis: a systematic review and network meta-analysis

    BMC Pediatrics 19:1–10.

    https://doi.org/10.1186/s12887-019-1609-1

    • PubMed
    • Google Scholar
33. 1. MacNamara KC
    2. Oduro K
    3. Martin O
    4. Jones DD
    5. McLaughlin M
    6. Choi K
    7. Borjesson DL
    8. Winslow GM

    (2011) Infection-induced myelopoiesis during intracellular bacterial infection is critically dependent upon IFN-γ signaling

    Journal of Immunology (Baltimore, Md 186:1032–1043.

    https://doi.org/10.4049/jimmunol.1001893

    • PubMed
    • Google Scholar
34. 1. Maizels RM
    2. Smith KA

    (2011) Regulatory T cells in infection

    Advances in Immunology 112:73–136.

    https://doi.org/10.1016/B978-0-12-387827-4.00003-6

    • PubMed
    • Google Scholar
35. 1. Matatall KA
    2. Shen CC
    3. Challen GA
    4. King KY

    (2014) Type II interferon promotes differentiation of myeloid-biased hematopoietic stem cells

    Stem Cells (Dayton, Ohio) 32:3023–3030.

    https://doi.org/10.1002/stem.1799

    • PubMed
    • Google Scholar
36. 1. Matatall KA
    2. Jeong M
    3. Chen S
    4. Sun D
    5. Chen F
    6. Mo Q
    7. Kimmel M
    8. King KY

    (2016) Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation

    Cell Reports 17:2584–2595.

    https://doi.org/10.1016/j.celrep.2016.11.031

    • PubMed
    • Google Scholar
37. 1. Mathias B
    2. Szpila BE
    3. Moore FA
    4. Efron PA
    5. Moldawer LL

    (2015) A Review of GM-CSF Therapy in Sepsis

    Medicine 94:1–10.

    https://doi.org/10.1097/MD.0000000000002044

    • PubMed
    • Google Scholar
38. 1. Metsalu T
    2. Vilo J

    (2015) ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap

    Nucleic Acids Research 43:W566–W570.

    https://doi.org/10.1093/nar/gkv468

    • PubMed
    • Google Scholar
39. 1. Morales-Mantilla DE
    2. King KY

    (2018) The Role of Interferon-Gamma in Hematopoietic Stem Cell Development, Homeostasis, and Disease

    Current Stem Cell Reports 4:264–271.

    https://doi.org/10.1007/s40778-018-0139-3

    • PubMed
    • Google Scholar
40. 1. Nagai Y
    2. Garrett KP
    3. Ohta S
    4. Bahrun U
    5. Kouro T
    6. Akira S
    7. Takatsu K
    8. Kincade PW

    (2006) Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment

    Immunity 24:801–812.

    https://doi.org/10.1016/j.immuni.2006.04.008

    • PubMed
    • Google Scholar
41. 1. Napolitano LM

    (2018) Sepsis 2018: Definitions and Guideline Changes

    Surgical Infections 19:117–125.

    https://doi.org/10.1089/sur.2017.278

    • PubMed
    • Google Scholar
42. 1. Paget C
    2. Trottein F

    (2019) Mechanisms of Bacterial Superinfection Post-influenza: A Role for Unconventional T Cells

    Frontiers in Immunology 10:1–13.

    https://doi.org/10.3389/fimmu.2019.00336

    • PubMed
    • Google Scholar
43. 1. Pietras EM
    2. Mirantes-Barbeito C
    3. Fong S
    4. Loeffler D
    5. Kovtonyuk LV
    6. Zhang S
    7. Lakshminarasimhan R
    8. Chin CP
    9. Techner J-M
    10. Will B
    11. Nerlov C
    12. Steidl U
    13. Manz MG
    14. Schroeder T
    15. Passegué E

    (2016) Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal

    Nature Cell Biology 18:607–618.

    https://doi.org/10.1038/ncb3346

    • PubMed
    • Google Scholar
44. 1. Price TH
    2. Boeckh M
    3. Harrison RW
    4. McCullough J
    5. Ness PM
    6. Strauss RG
    7. Nichols WG
    8. Hamza TH
    9. Cushing MM
    10. King KE
    11. Young J-AH
    12. Williams E
    13. McFarland J
    14. Holter Chakrabarty J
    15. Sloan SR
    16. Friedman D
    17. Parekh S
    18. Sachais BS
    19. Kiss JE
    20. Assmann SF

    (2015) Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection

    Blood 126:2153–2161.

    https://doi.org/10.1182/blood-2015-05-645986

    • PubMed
    • Google Scholar
45. 1. Rhee C
    2. Jones TM
    3. Hamad Y
    4. Pande A
    5. Varon J
    6. O’Brien C
    7. Anderson DJ
    8. Warren DK
    9. Dantes RB
    10. Epstein L
    11. Klompas M
    12. Centers for Disease Control and Prevention Prevention Epicenters Program

    (2019) Prevalence, Underlying Causes, and Preventability of Sepsis-Associated Mortality in US Acute Care Hospitals

    JAMA Network Open 2:e187571.

    https://doi.org/10.1001/jamanetworkopen.2018.7571

    • PubMed
    • Google Scholar
46. 1. Robinson SP
    2. Marks DI

    (2004) Granulocyte transfusions in the G-CSF er: Where do we stand?

    Bone Marrow Transplantation 34:839–846.

    https://doi.org/10.1038/sj.bmt.1704630

    • PubMed
    • Google Scholar
47. 1. Rodriguez-Fraticelli AE
    2. Wolock SL
    3. Weinreb CS
    4. Panero R
    5. Patel SH
    6. Jankovic M
    7. Sun J
    8. Calogero RA
    9. Klein AM
    10. Camargo FD

    (2018) Clonal analysis of lineage fate in native haematopoiesis

    Nature 553:212–216.

    https://doi.org/10.1038/nature25168

    • PubMed
    • Google Scholar
48. 1. Rosser EC
    2. Mauri C

    (2015) Regulatory B cells: origin, phenotype, and function

    Immunity 42:607–612.

    https://doi.org/10.1016/j.immuni.2015.04.005

    • PubMed
    • Google Scholar
49. 1. Rynda-Apple A
    2. Robinson KM
    3. Alcorn JF

    (2015) Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease

    Infection and Immunity 83:3764–3770.

    https://doi.org/10.1128/IAI.00298-15

    • PubMed
    • Google Scholar
50. 1. Sato A
    2. Kamio N
    3. Yokota A
    4. Hayashi Y
    5. Tamura A
    6. Miura Y
    7. Maekawa T
    8. Hirai H

    (2020) C/EBPβ isoforms sequentially regulate regenerating mouse hematopoietic stem/progenitor cells

    Blood Advances 4:3343–3356.

    https://doi.org/10.1182/bloodadvances.2018022913

    • PubMed
    • Google Scholar
51. 1. Schrijver IT
    2. Théroude C
    3. Roger T

    (2019) Myeloid-Derived Suppressor Cells in Sepsis

    Frontiers in Immunology 10:1–10.

    https://doi.org/10.3389/fimmu.2019.00327

    • PubMed
    • Google Scholar
52. 1. Schultze JL
    2. Mass E
    3. Schlitzer A

    (2019) Emerging Principles in Myelopoiesis at Homeostasis and during Infection and Inflammation

    Immunity 50:288–301.

    https://doi.org/10.1016/j.immuni.2019.01.019

    • PubMed
    • Google Scholar
53. 1. Schürch CM
    2. Riether C
    3. Ochsenbein AF

    (2014) Cytotoxic CD8+ T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells

    Cell Stem Cell 14:460–472.

    https://doi.org/10.1016/j.stem.2014.01.002

    • PubMed
    • Google Scholar
54. 1. Skirecki T
    2. Mikaszewska-Sokolewicz M
    3. Godlewska M
    4. Dołęgowska B
    5. Czubak J
    6. Hoser G
    7. Kawiak J
    8. Zielińska-Borkowska U

    (2019) Mobilization of Stem and Progenitor Cells in Septic Shock Patients

    Scientific Reports 9:3289.

    https://doi.org/10.1038/s41598-019-39772-4

    • PubMed
    • Google Scholar
55. 1. Smith AM
    2. Perelson AS

    (2011) Influenza A virus infection kinetics: quantitative data and models

    Wiley Interdisciplinary Reviews. Systems Biology and Medicine 3:429–445.

    https://doi.org/10.1002/wsbm.129

    • PubMed
    • Google Scholar
56. 1. Sun J
    2. Ramos A
    3. Chapman B
    4. Johnnidis JB
    5. Le L
    6. Ho Y-J
    7. Klein A
    8. Hofmann O
    9. Camargo FD

    (2014) Clonal dynamics of native haematopoiesis

    Nature 514:322–327.

    https://doi.org/10.1038/nature13824

    • PubMed
    • Google Scholar
57. 1. Takizawa H
    2. Fritsch K
    3. Kovtonyuk LV
    4. Saito Y
    5. Yakkala C
    6. Jacobs K
    7. Ahuja AK
    8. Lopes M
    9. Hausmann A
    10. Hardt W-D
    11. Gomariz Á
    12. Nombela-Arrieta C
    13. Manz MG

    (2017) Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness

    Cell Stem Cell 21:225–240.

    https://doi.org/10.1016/j.stem.2017.06.013

    • PubMed
    • Google Scholar
58. 1. Teofili L
    2. Valentini CG
    3. Di Blasi R
    4. Orlando N
    5. Fianchi L
    6. Zini G
    7. Sica S
    8. De Stefano V
    9. Pagano L

    (2016) Dose-Dependent Effect of Granulocyte Transfusions in Hematological Patients with Febrile Neutropenia

    PLOS ONE 11:e159569.

    https://doi.org/10.1371/journal.pone.0159569

    • PubMed
    • Google Scholar
59. 1. Tijaro-Ovalle NM
    2. Karantanos T
    3. Wang HT
    4. Boussiotis VA

    (2019) Metabolic Targets for Improvement of Allogeneic Hematopoietic Stem Cell Transplantation and Graft-vs.-Host Disease

    Frontiers in Immunology 10:1–13.

    https://doi.org/10.3389/fimmu.2019.00295

    • PubMed
    • Google Scholar
60. 1. Tsou CL
    2. Peters W
    3. Si Y
    4. Slaymaker S
    5. Aslanian AM
    6. Weisberg SP
    7. Mack M
    8. Charo IF

    (2007) Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites

    The Journal of Clinical Investigation 117:902–909.

    https://doi.org/10.1172/JCI29919

    • PubMed
    • Google Scholar
61. 1. Uhel F
    2. Azzaoui I
    3. Grégoire M
    4. Pangault C
    5. Dulong J
    6. Tadié J-M
    7. Gacouin A
    8. Camus C
    9. Cynober L
    10. Fest T
    11. Le Tulzo Y
    12. Roussel M
    13. Tarte K

    (2017) Early Expansion of Circulating Granulocytic Myeloid-derived Suppressor Cells Predicts Development of Nosocomial Infections in Patients with Sepsis

    American Journal of Respiratory and Critical Care Medicine 196:315–327.

    https://doi.org/10.1164/rccm.201606-1143OC

    • PubMed
    • Google Scholar
62. 1. van der Poll T
    2. van de Veerdonk FL
    3. Scicluna BP
    4. Netea MG

    (2017) The immunopathology of sepsis and potential therapeutic targets

    Nature Reviews. Immunology 17:407–420.

    https://doi.org/10.1038/nri.2017.36

    • PubMed
    • Google Scholar
63. 1. Walker MJ
    2. Barnett TC
    3. McArthur JD
    4. Cole JN
    5. Gillen CM
    6. Henningham A
    7. Sriprakash KS
    8. Sanderson-Smith ML
    9. Nizet V

    (2014) Disease manifestations and pathogenic mechanisms of Group A Streptococcus

    Clinical Microbiology Reviews 27:264–301.

    https://doi.org/10.1128/CMR.00101-13

    • PubMed
    • Google Scholar
64. 1. Wang S-M
    2. Lu I-H
    3. Lin Y-L
    4. Lin Y-S
    5. Wu J-J
    6. Chuang W-J
    7. Lin MT
    8. Liu C-C

    (2008) The severity of Streptococcus pyogenes infections in children is significantly associated with plasma levels of inflammatory cytokines

    Diagnostic Microbiology and Infectious Disease 61:165–169.

    https://doi.org/10.1016/j.diagmicrobio.2008.01.008

    • PubMed
    • Google Scholar
65. 1. Yang X
    2. Chen D
    3. Long H
    4. Zhu B

    (2020) The mechanisms of pathological extramedullary hematopoiesis in diseases

    Cellular and Molecular Life Sciences 77:2723–2738.

    https://doi.org/10.1007/s00018-020-03450-w

    • PubMed
    • Google Scholar
66. 1. Yu X
    2. Zhang X
    3. Zhao B
    4. Wang J
    5. Zhu Z
    6. Teng Z
    7. Shao J
    8. Shen J
    9. Gao Y
    10. Yuan Z
    11. Wu F

    (2011) Intensive cytokine induction in pandemic H1N1 influenza virus infection accompanied by robust production of IL-10 and IL-6

    PLOS ONE 6:e28680.

    https://doi.org/10.1371/journal.pone.0028680

    • PubMed
    • Google Scholar

Author details

1. Daniel E Morales-Mantilla

   1. Graduate Program in Immunology, Baylor College of Medicine, Houston, United States
   2. Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3459-6231

2. Bailee Kain

   1. Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, United States
   2. Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, United States

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

3. Duy Le

   1. Graduate Program in Immunology, Baylor College of Medicine, Houston, United States
   2. Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, United States

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

4. Anthony R Flores

   Division of Infectious Diseases, Department of Pediatrics, UTHSC/McGovern Medical School, Houston, United States

   Contribution

   Conceptualization, Resources

   Competing interests

   No competing interests declared

5. Silke Paust

   The Scripps Research Institute, Department of Immunology and Microbiology, La Jolla, United States

   Contribution

   Conceptualization, Resources

   Competing interests

   No competing interests declared

6. Katherine Y King

   1. Graduate Program in Immunology, Baylor College of Medicine, Houston, United States
   2. Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, United States
   3. Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, United States

   Contribution

   Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review and editing

   For correspondence

   kyk@bcm.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5093-6005

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