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 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 A murine Staphylococcus aureus fracture-related infection model characterised by fracture non-union, staphylococcal abscess communities and myeloid-derived suppressor cells

2021 ◽  
Vol 41 ◽  
pp. 774-792
Author(s):  
MI Hofstee ◽  
◽  
M Riool ◽  
F Gieling ◽  
V Stenger ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bone Marrow ◽  
T Cells ◽  
Cellular Response ◽  
Bone Fractures ◽  
Suppressor Cells ◽  
Infection Model ◽  
Myeloid Derived Suppressor Cells ◽  
Post Surgery ◽  
Over Time

A fracture-related infection (FRI) is a serious complication that can occur after surgical fixation of bone fractures. Affected patients may encounter delayed healing and functional limitations. Although it is well established that Staphylococcus aureus (S. aureus) is the main causative pathogen of an FRI, the pathophysiology of an S. aureus-induced FRI is not well characterised over time. Therefore, an experimental study in mice comparing S. aureus-inoculated and non-inoculated groups was performed that particularly focused on staphylococcal abscess communities (SACs) and host cellular response. C57Bl/6N female mice received a double osteotomy of the femur, which was stabilised using a titanium 6-hole MouseFix locking plate and four screws. Animals were either S. aureus-inoculated or non-inoculated and euthanised between 1 and 28 d post-surgery. Histopathological evaluation showed normal bone healing for non-inoculated mice, whereas inoculated mice had no fracture consolidation and severe osteolysis. Within the bone marrow of inoculated mice, SACs were observed from 7 d, which increased in size and number over time. A fibrin pseudocapsule enclosed the SACs, which were surrounded by many Ly6G+ neutrophils with some Ly6C+ monocytes and F4/80+ macrophages, the majority of which were viable. The abscesses were encapsulated by fibrin(ogen), collagen and myofibroblasts, with regulatory T cells and M2 macrophages at the periphery. Only bone marrow monocytes and neutrophils of inoculated mice displayed functional suppression of T cells, indicative of myeloid-derived suppressor cells. The present study revealed that an FRI in mice is persistent over time and associated with osteolysis, SAC formation and an immunosuppressive environment.

Myeloid-derived suppressor cells (MDSCs) in brain cancer: challenges and therapeutic strategies

2021 ◽  
Author(s):  
Mohammad Salemizadeh Parizi ◽  
Fatemeh Salemizadeh Parizi ◽  
Saeed Abdolhosseini ◽  
Shohreh Vanaei ◽  
Ali Manzouri ◽  
...  
Keyword(s):  
Brain Cancer ◽  
Suppressor Cells ◽  
Therapeutic Strategies ◽  
Myeloid Derived Suppressor Cells

scholarly journals Immunoregulation byTaenia crassicepsand Its Antigens

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Alberto N. Peón ◽  
Arlett Espinoza-Jiménez ◽  
Luis I. Terrazas
Keyword(s):  
Immune Response ◽  
Adult Stage ◽  
Parasitic Infection ◽  
Suppressor Cells ◽  
Infection Model ◽  
Myeloid Derived Suppressor Cells ◽  
Alternatively Activated Macrophages ◽  
Cestode Parasite ◽  
Alternatively Activated ◽  
Strong Capacity

Taenia crassicepsis a cestode parasite of rodents (in its larval stage) and canids (in its adult stage) that can also parasitize immunocompromised humans. We have studied the immune response elicited by this helminth and its antigens in mice and human cells, and have discovered that they have a strong capacity to induce chronic Th2-type responses that are primarily characterized by high levels of Th2 cytokines, low proliferative responses in lymphocytes, an immature and LPS-tolerogenic profile in dendritic cells, the recruitment of myeloid-derived suppressor cells and, specially, alternatively activated macrophages. We also have utilized the immunoregulatory capabilities of this helminth to successfully modulate autoimmune responses and the outcome of other infectious diseases. In the present paper, we review the work of others and ourselves with regard to the immune response induced byT. crassicepsand its antigens, and we compare the advances in our understanding of this parasitic infection model with the knowledge that has been obtained from other selected models.

scholarly journals A Modified Chronic Infection Model for Testing Treatment of Staphylococcus aureus Biofilms on Implants

PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e103688 ◽  
Author(s):  
Nis Pedersen Jørgensen ◽  
Rikke Meyer ◽  
Frederik Dagnæs-Hansen ◽  
Kurt Fuursted ◽  
Eskild Petersen
Keyword(s):  
Staphylococcus Aureus ◽  
Chronic Infection ◽  
Infection Model

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 Oleate Hydratase (OhyA) Is a Virulence Determinant in Staphylococcus aureus

2021 ◽  
Author(s):  
Christopher D. Radka ◽  
Justin L. Batte ◽  
Matthew W. Frank ◽  
Jason W. Rosch ◽  
Charles O. Rock
Keyword(s):  
Fatty Acids ◽  
Staphylococcus Aureus ◽  
Unsaturated Fatty Acids ◽  
Commensal Bacteria ◽  
Hydroxy Fatty Acids ◽  
Infection Model ◽  
Infection Site ◽  
Human Pathogen ◽  
Content Type ◽  
Oleate Hydratase

The oleate hydratase protein family was discovered in commensal bacteria that utilize host unsaturated fatty acids as the substrates to produce a spectrum of hydroxylated products. These hydroxy fatty acids are thought to act as signaling molecules that suppress the inflammatory response to create a more tolerant environment for the microbiome. S. aureus is a significant human pathogen, and defining the mechanisms used to evade the immune response is critical to understanding pathogenesis. S. aureus expresses an OhyA that produces at least three 10-hydroxy fatty acids from host unsaturated fatty acids at the infection site, and an S. aureus strain lacking the ohyA gene has compromised virulence in an immunocompetent infection model.

Plasmacytoid dendritic cells-derived IFN-α is involved in Helicobacter pylori infection-induced differentiation of Schlafen 4–expressing myeloid-derived suppressor cells

2021 ◽  
Author(s):  
Xiaodan Xiang ◽  
Yaping Wu ◽  
Hongwei Li ◽  
Cun Li ◽  
Lu Yan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Helicobacter Pylori ◽  
Dendritic Cells ◽  
Chronic Infection ◽  
Suppressor Cells ◽  
Neoplastic Transformation ◽  
Plasmacytoid Dendritic Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Wild Type ◽  
H Pylori

During chronic infection with Helicobacter pylori , Schlafen 4-expressing myeloid-derived suppressor cells (SLFN4 + MDSCs) create a microenvironment favoring intestinal metaplasia and neoplastic transformation. SLFN4 can be induced by IFN-α, which is mainly secreted from plasmacytoid dendritic cells (pDCs). This study tested the hypothesis that Helicobacter pylori infection promotes SLFN4 + MDSC differentiation by inducing pDCs to secrete IFN-α. C57BL/6 mice were gavaged with H. pylori and infection lasted 2, 4, or 6 months. The mouse pDCs were isolated from the bone marrow from wild type C57BL/6J mice. The results showed that H. pylori infection increased the number of SLFN4 + MDSCs by inducing IFN-α expression in mice. Further mechanistic experiments unraveled that IFN-α induced SLFN4 transcription by binding to the SLFN4 promoter. Furthermore, H. pylori infection stimulated pDCs to secrete IFN-α by activating the TLR9-MyD88-IRF7 pathway. Collectively, Helicobacter pylori infection promotes SLFN4 + MDSC differentiation by inducing secretion of IFN-α from pDCs.

Sign in / Sign up

Export Citation Format

Share Document