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.

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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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