Role of Staphylococcus aureus Formate Metabolism during Prosthetic Joint Infection

Bertrand, Blake P.; Heim, Cortney E.; West, Sean; Chaudhari, Sujata S.; Ali, Hesham H.; Thomas, Vinai Chittezham; Kielian, Tammy

doi:10.1128/iai.00428-22

Cited by 18 publications

(10 citation statements)

References 65 publications

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“…S8 . Metabolic genes involved in fermentation pathways [glycerol, lactate, formate ( 31 ), and acetoin metabolism] that are important under glucose limiting and microaerobic skin conditions, and secreted proteases [metalloproteases: SepA ( 32 ), cysteine protease Ecp and serine protease Esp ( 33 ), and a sphingomyelinase [ sph ( 11 )] that play a role in microbe–microbe and host–microbe interactions were also detected. Well-characterized genes that were restricted to either S. capitis or S. hominis were rare.…”

Section: Resultsmentioning

confidence: 99%

Integrated genomic and functional analyses of human skin–associated Staphylococcus reveal extensive inter- and intra-species diversity

Joglekar,

Conlan,

Lee-Lin

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Human skin is stably colonized by a distinct microbiota that functions together with epidermal cells to maintain a protective physical barrier. Staphylococcus , a prominent genus of the skin microbiota, participates in colonization resistance, tissue repair, and host immune regulation in strain-specific manners. To unlock the potential of engineering skin microbial communities, we aim to characterize the diversity of this genus within the context of the skin environment. We reanalyzed an extant 16S rRNA amplicon dataset obtained from distinct body sites of healthy volunteers, providing a detailed biogeographic depiction of staphylococcal species that colonize our skin. S. epidermidis , S. capitis, and S. hominis were the most abundant staphylococcal species present in all volunteers and were detected at all body sites. Pan-genome analysis of isolates from these three species revealed that the genus-core was dominated by central metabolism genes. Species-restricted-core genes encoded known host colonization functions. The majority (~68%) of genes were detected only in a fraction of isolate genomes, underscoring the immense strain-specific gene diversity. Conspecific genomes grouped into phylogenetic clades, exhibiting body site preference. Each clade was enriched for distinct gene sets that are potentially involved in site tropism. Finally, we conducted gene expression studies of select isolates showing variable growth phenotypes in skin-like medium. In vitro expression revealed extensive intra- and inter-species gene expression variation, substantially expanding the functional diversification within each species. Our study provides an important resource for future ecological and translational studies to examine the role of shared and strain-specific staphylococcal genes within the skin environment.

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Section: Resultsmentioning

confidence: 99%

Integrated genomic and functional analyses of human skin–associated Staphylococcus reveal extensive inter- and intra-species diversity

Joglekar,

Conlan,

Lee-Lin

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…As previously discussed, biofilm represents a unique growth state compared to planktonic bacteria and S. aureus biofilm polarizes macrophages towards an anti-inflammatory state and leads to preferential G-MDSC recruitment [ 38 , 45 , 72 ]. Furthermore, S. aureus biofilm growth is associated with metabolites, such as lactate and formate, that interfere with innate immune responses that would typically clear planktonic infection [ 33 , 73 ]. However, most of this information originates from models of biofilm infection in the periphery; therefore, much work remains to be done to understand the mechanisms responsible for driving a maladaptive immune response during craniotomy biofilm infection, both from the host and pathogen perspectives.…”

Section: Discussionmentioning

confidence: 99%

IL-10 production by granulocytes promotes Staphylococcus aureus craniotomy infection

Kak

Roy

Heim

et al. 2023

J Neuroinflammation

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Background Treatment of brain tumors, epilepsy, or hemodynamic abnormalities requires a craniotomy to access the brain. Nearly 1 million craniotomies are performed in the US annually, which increase to ~ 14 million worldwide and despite prophylaxis, infectious complications after craniotomy range from 1 to 3%. Approximately half are caused by Staphylococcus aureus (S. aureus), which forms a biofilm on the bone flap that is recalcitrant to antibiotics and immune-mediated clearance. However, the mechanisms responsible for the persistence of craniotomy infection remain largely unknown. The current study examined the role of IL-10 in promoting bacterial survival. Methods A mouse model of S. aureus craniotomy infection was used with wild type (WT), IL-10 knockout (KO), and IL-10 conditional KO mice where IL-10 was absent in microglia and monocytes/macrophages (CX3CR1CreIL-10 fl/fl) or neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs; Mrp8CreIL-10 fl/fl), the major immune cell populations in the infected brain vs. subcutaneous galea, respectively. Mice were examined at various intervals post-infection to quantify bacterial burden, leukocyte recruitment, and inflammatory mediator production in the brain and galea to assess the role of IL-10 in craniotomy persistence. In addition, the role of G-MDSC-derived IL-10 on neutrophil activity was examined. Results Granulocytes (neutrophils and G-MDSCs) were the major producers of IL-10 during craniotomy infection. Bacterial burden was significantly reduced in IL-10 KO mice in the brain and galea at day 14 post-infection compared to WT animals, concomitant with increased CD4+ and γδ T cell recruitment and cytokine/chemokine production, indicative of a heightened proinflammatory response. S. aureus burden was reduced in Mrp8CreIL-10 fl/fl but not CX3CR1CreIL-10 fl/fl mice that was reversed following treatment with exogenous IL-10, suggesting that granulocyte-derived IL-10 was important for promoting S. aureus craniotomy infection. This was likely due, in part, to IL-10 production by G-MDSCs that inhibited neutrophil bactericidal activity and TNF production. Conclusion Collectively, these findings reveal a novel role for granulocyte-derived IL-10 in suppressing S. aureus clearance during craniotomy infection, which is one mechanism to account for biofilm persistence.

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“…In brief, to enhance the infectious effects, MDSCs commonly produce immunosuppressive metabolites via iNOS and ARG‐1, and increase the expressions of immunosuppressive molecules like IL‐10, ROS, STAT3, and so on, mainly to prevent immune cell proliferation and activation, especially T cells 71–75 . For instance, in the chronic infectious condition induced by Staphylococcus aureus ( S. aureus ), a large number of MDSCs were found in the surrounding bacterial biofilm, contributing to the persistence and low clearance of S. aureus , by secret iNOS, ARG‐1, as well as IL‐10 to inhibit the infiltration of immune cells 76 ; in turn, stimulated by MDSCs, S. aureus will upregulate formate acetyltransferase (pflB) to form a larger and more pervasive biofilm 77 . Apart from the common mediatory mechanisms, MDSC can induce high‐level ER stress to enhance its immunosuppressive activity, therefore leading to the promotion of leprosy and tuberculosis 78,79 .…”

Section: Functions Of Mdscsmentioning

confidence: 99%

The recent progress of myeloid‐derived suppressor cell and its targeted therapies in cancers

Ren

Xiong

et al. 2023

MedComm

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Myeloid‐derived suppressor cells (MDSCs) are an immature group of myeloid‐derived cells generated from myeloid cell precursors in the bone marrow. MDSCs appear almost exclusively in pathological conditions, such as tumor progression and various inflammatory diseases. The leading function of MDSCs is their immunosuppressive ability, which plays a crucial role in tumor progression and metastasis through their immunosuppressive effects. Since MDSCs have specific molecular features, and only a tiny amount exists in physiological conditions, MDSC‐targeted therapy has become a promising research direction for tumor treatment with minimal side effects. In this review, we briefly introduce the classification, generation and maturation process, and features of MDSCs, and detail their functions under various circumstances. The present review specifically demonstrates the environmental specificity of MDSCs, highlighting the differences between MDSCs from cancer and healthy individuals, as well as tumor‐infiltrating MDSCs and circulating MDSCs. Then, we further describe recent advances in MDSC‐targeted therapies. The existing and potential targeted drugs are divided into three categories, monoclonal antibodies, small‐molecular inhibitors, and peptides. Their targeting mechanisms and characteristics have been summarized respectively. We believe that a comprehensive in‐depth understanding of MDSC‐targeted therapy could provide more possibilities for the treatment of cancer.

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Role of Staphylococcus aureus Formate Metabolism during Prosthetic Joint Infection

Cited by 18 publications

References 65 publications

Integrated genomic and functional analyses of human skin–associated Staphylococcus reveal extensive inter- and intra-species diversity

Integrated genomic and functional analyses of human skin–associated Staphylococcus reveal extensive inter- and intra-species diversity

IL-10 production by granulocytes promotes Staphylococcus aureus craniotomy infection

The recent progress of myeloid‐derived suppressor cell and its targeted therapies in cancers

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