scholarly journals Dysregulated Immunometabolism Is Associated with the Generation of Myeloid-Derived Suppressor Cells in Staphylococcus aureus Chronic Infection

2021 ◽  
pp. 1-18
Author(s):  
Oliver Dietrich ◽  
Alexander Heinz ◽  
Oliver Goldmann ◽  
Robert Geffers ◽  
Andreas Beineke ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Metabolic Profiling ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Glucose Consumption ◽  
Immature Stage ◽  
Myeloid Derived Suppressor Cells ◽  
Chronic Infections ◽  
Consumption Rates

Myeloid-derived suppressor cells (MDSCs) are a compendium of immature myeloid cells that exhibit potent T-cell suppressive capacity and expand during pathological conditions such as cancer and chronic infections. Although well-characterized in cancer, the physiology of MDSCs in the infection setting remains enigmatic. Here, we integrated single-cell RNA sequencing (scRNA-seq) and functional metabolic profiling to gain deeper insights into the factors governing the generation and maintenance of MDSCs in chronic <i>Staphylococcus aureus</i> infection. We found that MDSCs originate not only in the bone marrow but also at extramedullary sites in <i>S. aureus</i>-infected mice. scRNA-seq showed that infection-driven MDSCs encompass a spectrum of myeloid precursors in different stages of differentiation, ranging from promyelocytes to mature neutrophils. Furthermore, the scRNA-seq analysis has also uncovered valuable phenotypic markers to distinguish mature myeloid cells from immature MDSCs. Metabolic profiling indicates that MDSCs exhibit high glycolytic activity and high glucose consumption rates, which are required for undergoing terminal maturation. However, rapid glucose consumption by MDSCs added to infection-induced perturbations in the glucose supplies in infected mice hinders the terminal maturation of MDSCs and promotes their accumulation in an immature stage. In a proof-of-concept in vivo experiment, we demonstrate the beneficial effect of increasing glucose availability in promoting MDSC terminal differentiation in infected mice. Our results provide valuable information of how metabolic alterations induced by infection influence reprogramming and differentiation of MDSCs.

scholarly journals Staphylococcus aureus biofilm elicits the expansion, activation and polarization of myeloid-derived suppressor cells in vivo and in vitro

PLoS ONE ◽  
2017 ◽  
Vol 12 (8) ◽  
pp. e0183271 ◽  
Author(s):  
Kuo-Ti Peng ◽  
Ching-Chuan Hsieh ◽  
Tsung-Yu Huang ◽  
Pei-Chun Chen ◽  
Hsin-Nung Shih ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

scholarly journals Murine Staphylococcus aureus chronic infection is cured by theory-driven therapy

2020 ◽  
Author(s):  
Lito A. Papaxenopoulou ◽  
Gang Zhao ◽  
Sahamoddin Khailaie ◽  
Konstantinos Katsoulis-Dimitriou ◽  
Ingo Schmitz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Chronic Infection ◽  
Suppressor Cells ◽  
Therapeutic Strategies ◽  
Infection Model ◽  
Myeloid Derived Suppressor Cells ◽  
Recurrent Infections ◽  
Human Pathogen ◽  
Chronic Infections ◽  
Model Driven

AbstractStaphylococcus aureus (S. aureus) is a challenging human pathogen due to its ability to evade the immune system and resist multidrug antibiotics. These evasive strategies lead to chronic and recurrent infections. Many studies have documented that during chronic infections Myeloid Derived Suppressor Cells (MDSCs) exert immunosuppressive mechanisms on T cells. A mathematical model explains how the steady state of chronic infection can be disturbed and suggests therapeutic strategies to clear the infection. Model-driven suggestions were tested experimentally and confirmed complete clearance of S. aureus chronic infection.

scholarly journals Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 726
Author(s):  
Christopher Groth ◽  
Ludovica Arpinati ◽  
Merav E. Shaul ◽  
Nina Winkler ◽  
Klara Diester ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Receptor Expression ◽  
Myeloid Derived Suppressor Cells ◽  
Melanoma Progression ◽  
Relative Contribution ◽  
Immunosuppressive Tumor Microenvironment ◽  
Metastatic Sites

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.

scholarly journals Myeloid phenotypes in severe COVID-19 predict secondary infection and mortality: a pilot study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Clémence Marais ◽  
Caroline Claude ◽  
Nada Semaan ◽  
Ramy Charbel ◽  
Simon Barreault ◽  
...  
Keyword(s):  
Critically Ill ◽  
Host Response ◽  
Secondary Infection ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Human Leukocyte ◽  
Myeloid Derived Suppressor Cells ◽  
Phenotypic Characteristics ◽  
Leukocyte Antigen ◽  
Hla Dr

Abstract Background De-regulated host response to severe coronavirus disease 2019 (COVID-19), directly referring to the concept of sepsis-associated immunological dysregulation, seems to be a strong signature of severe COVID-19. Myeloid cells phenotyping is well recognized to diagnose critical illness-induced immunodepression in sepsis and has not been well characterized in COVID-19. The aim of this study is to review phenotypic characteristics of myeloid cells and evaluate their relations with the occurrence of secondary infection and mortality in patients with COVID-19 admitted in an intensive care unit. Methods Retrospective analysis of the circulating myeloid cells phenotypes of adult COVID-19 critically ill patients. Phenotyping circulating immune cells was performed by flow cytometry daily for routine analysis and twice weekly for lymphocytes and monocytes subpopulations analysis, as well as monocyte human leukocyte antigen (mHLA)-DR expression. Results Out of the 29 critically ill adult patients with severe COVID-19 analyzed, 12 (41.4%) developed secondary infection and six patients died during their stay. Monocyte HLA-DR kinetics was significantly different between patients developing secondary infection and those without, respectively, at day 5–7 and 8–10 following admission. The monocytes myeloid-derived suppressor cells to total monocytes ratio was associated with 28- and 60-day mortality. Those myeloid characteristics suggest three phenotypes: hyperactivated monocyte/macrophage is significantly associated with mortality, whereas persistent immunodepression is associated with secondary infection occurrence compared to transient immunodepression. Conclusions Myeloid phenotypes of critically ill COVID-19 patients may be associated with development of secondary infection, 28- and 60-day mortality.

Abstract 87: The Accumulation of Myeloid-derived Suppressor Cells Is a Compensatory Response to the Development of Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Xiao Z Shen ◽  
Peng Shi ◽  
Jorge Giani ◽  
Ellen Bernstein ◽  
Kenneth E Bernstein
Keyword(s):  
Blood Pressure ◽  
T Cell ◽  
Angiotensin Ii ◽  
Critical Role ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Compensatory Response ◽  
Immunosuppressive Cell ◽  
Induced Hypertension

The immune system plays a critical role in the development of hypertension. The immune response consists of pro-inflammatory cells, but also immunosuppressive cells that reduce T cell function. An important category of natural immunosuppressive cell is myeloid-derived suppressor cells (MDSC). We now show that blood and spleen CD11b+ Gr1+ myeloid cells are elevated 2-fold in both angiotensin II and L-NAME induced hypertension. These increased myeloid cells are MDSC in that they elevate IL-4R expression and suppress T cell proliferation. When hypertensive mice were depleted of MDSC, using either anti-Gr1 antibody or gemcitabine, there was a 15 mmHg rise in blood pressure and aggravation of T cells activation with increased production of IFN-γ, TNFα and IL-17 in both spleen and kidney. In contrast, adoptive transfer of MDSC reduced blood pressure in angiotensin-II induced hypertension by 25 mmHg (see Figure). These data suggest a new concept, that the accumulation of MDSC is a compensatory response to the inflammation induced by hypertension. They also indicate that MDSC play an important role in regulating blood pressure.

Liposomal microparticle injection can induce myeloid-derived suppressor cells (MDSC)-like cells in vivo

2017 ◽  
Vol 39 (3) ◽  
pp. 140-147 ◽  
Author(s):  
Hiroshi Azuma ◽  
Yoichiro Yoshida ◽  
Hironori Takahashi ◽  
Emi Ishibazawa ◽  
Hiroya Kobayashi ◽  
...  
Keyword(s):  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

scholarly journals Staphylococcus aureus biofilms release leukocidins to elicit extracellular trap formation and evade neutrophil-mediated killing

2018 ◽  
Vol 115 (28) ◽  
pp. 7416-7421 ◽  
Author(s):  
Mohini Bhattacharya ◽  
Evelien T. M. Berends ◽  
Rita Chan ◽  
Elizabeth Schwab ◽  
Sashwati Roy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
White Blood Cells ◽  
Neutrophil Extracellular Trap ◽  
Bacterial Survival ◽  
Chronic Infections ◽  
Burn Wound ◽  
Wound Model ◽  
Immune Defenses ◽  
Extracellular Trap

Bacterial biofilms efficiently evade immune defenses, greatly complicating the prognosis of chronic infections. How methicillin-resistant Staphylococcus aureus (MRSA) biofilms evade host immune defenses is largely unknown. This study describes some of the major mechanisms required for S. aureus biofilms to evade the innate immune response and provides evidence of key virulence factors required for survival and persistence of bacteria during chronic infections. Neutrophils are the most abundant white blood cells in circulation, playing crucial roles in the control and elimination of bacterial pathogens. Specifically, here we show that, unlike single-celled populations, S. aureus biofilms rapidly skew neutrophils toward neutrophil extracellular trap (NET) formation through the combined activity of leukocidins Panton–Valentine leukocidin and γ-hemolysin AB. By eliciting this response, S. aureus was able to persist, as the antimicrobial activity of released NETs was ineffective at clearing biofilm bacteria. Indeed, these studies suggest that NETs could inadvertently potentiate biofilm infections. Last, chronic infection in a porcine burn wound model clearly demonstrated that leukocidins are required for “NETosis” and facilitate bacterial survival in vivo.

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