Immunopathogenesis of Craniotomy Infection and Niche-Specific Immune Responses to Biofilm

Bacterial infections in the central nervous system (CNS) can be life threatening and often impair neurological function. Biofilm infection is a complication following craniotomy, a neurosurgical procedure that involves the removal and replacement of a skull fragment (bone flap) to access the brain for surgical intervention. The incidence of infection following craniotomy ranges from 1% to 3% with approximately half caused by Staphylococcus aureus (S. aureus). These infections present a significant therapeutic challenge due to the antibiotic tolerance of biofilm and unique immune properties of the CNS. Previous studies have revealed a critical role for innate immune responses during S. aureus craniotomy infection. Experiments using knockout mouse models have highlighted the importance of the pattern recognition receptor Toll-like receptor 2 (TLR2) and its adaptor protein MyD88 for preventing S. aureus outgrowth during craniotomy biofilm infection. However, neither molecule affected bacterial burden in a mouse model of S. aureus brain abscess highlighting the distinctions between immune regulation of biofilm vs. planktonic infection in the CNS. Furthermore, the immune responses elicited during S. aureus craniotomy infection are distinct from biofilm infection in the periphery, emphasizing the critical role for niche-specific factors in dictating S. aureus biofilm-leukocyte crosstalk. In this review, we discuss the current knowledge concerning innate immunity to S. aureus craniotomy biofilm infection, compare this to S. aureus biofilm infection in the periphery, and discuss the importance of anatomical location in dictating how biofilm influences inflammatory responses and its impact on bacterial clearance.

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Eosinophils and Bacteria, the Beginning of a Story

International Journal of Molecular Sciences ◽

10.3390/ijms22158004 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8004

Author(s):

Edna Ondari ◽

Esther Calvino-Sanles ◽

Nicholas J. First ◽

Monica C. Gestal

Keyword(s):

Immune Responses ◽

Respiratory Tract ◽

Bacterial Infections ◽

Viral Infections ◽

Inflammatory Responses ◽

Current Knowledge ◽

Parasitic Infections ◽

Th2 Responses ◽

A Cell ◽

Anti Inflammatory

Eosinophils are granulocytes primarily associated with TH2 responses to parasites or immune hyper-reactive states, such as asthma, allergies, or eosinophilic esophagitis. However, it does not make sense from an evolutionary standpoint to maintain a cell type that is only specific for parasitic infections and that otherwise is somehow harmful to the host. In recent years, there has been a shift in the perception of these cells. Eosinophils have recently been recognized as regulators of immune homeostasis and suppressors of over-reactive pro-inflammatory responses by secreting specific molecules that dampen the immune response. Their role during parasitic infections has been well investigated, and their versatility during immune responses to helminths includes antigen presentation as well as modulation of T cell responses. Although it is known that eosinophils can present antigens during viral infections, there are still many mechanistic aspects of the involvement of eosinophils during viral infections that remain to be elucidated. However, are eosinophils able to respond to bacterial infections? Recent literature indicates that Helicobacter pylori triggers TH2 responses mediated by eosinophils; this promotes anti-inflammatory responses that might be involved in the long-term persistent infection caused by this pathogen. Apparently and on the contrary, in the respiratory tract, eosinophils promote TH17 pro-inflammatory responses during Bordetella bronchiseptica infection, and they are, in fact, critical for early clearance of bacteria from the respiratory tract. However, eosinophils are also intertwined with microbiota, and up to now, it is not clear if microbiota regulates eosinophils or vice versa, or how this connection influences immune responses. In this review, we highlight the current knowledge of eosinophils as regulators of pro and anti-inflammatory responses in the context of both infection and naïve conditions. We propose questions and future directions that might open novel research avenues in the future.

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Abstract 19409: β2-Adrenergic Receptor Regulation of Innate Immune Responses Following Acute Myocardial Injury

Circulation ◽

10.1161/circ.132.suppl_3.19409 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Laurel A Grisanti ◽

Anna Gumpert ◽

Joshua Gorsky ◽

Ashley A Repas ◽

Erhe Gao ◽

...

Keyword(s):

Immune Responses ◽

Adrenergic Receptor ◽

Inflammatory Responses ◽

Critical Role ◽

Cellular Migration ◽

Chimeric Mouse ◽

Ccr2 Expression ◽

Β2 Adrenergic Receptor ◽

The Impact

Inflammatory responses are important for cardiac remodeling and tissue repair after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune responses, in large part through the β2-adrenergic receptor (β2AR), however the influence of β2AR in regulating the inflammatory response following MI is unknown. Thus, to examine the contribution of β2AR on immune cells following MI, wild-type (WT) mice were irradiated and then received β2ARKO or WT control bone marrow (BM) transplants to create immune cell-specific knockout (KO) animals. Lack of β2AR expression in BM resulted in 100% mortality from cardiac rupture within two weeks of receiving MI, in contrast to their WT counterparts that had ∼20% death. Granulocyte populations were sequestered in the spleen of β2ARKO chimeric mice resulting in reductions in post-MI infiltration of monocyte/macrophage, neutrophil and mast cell populations into the heart. Additionally, alterations in chemokine receptor levels, particularly CCR2, on BM resulted in decreased cellular migration, and use of a CCR2 antagonist in vivo recapitulated the β2ARKO chimeric mouse phenotype following MI. Administration of β2AR agonists in vitro and in vivo increased CCR2 expression and BM migration while β2AR antagonists decreased CCR2 expression and increased splenic leukocyte retention in vivo . Use of pepducins as allosteric modulators of β2AR signaling demonstrated the importance of β-arrestin-mediated signaling in increasing CCR2 expression and responses. The impact of β2AR deletion on BM cell CCR2 expression and migration, splenic retention of leukocytes and reciprocal cardiac leukocyte infiltration following MI could be reversed via lentivirus-mediated β2AR rescue in the β2ARKO BM prior to transplantation. These results demonstrate the critical role of β2AR in the regulation of CCR2 expression on hematopoietic cells and its importance in mounting an immune response to promote healing following acute cardiac injury.

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Immunization with 3-oxododecanoyl-l-homoserine lactone–protein conjugate protects mice from lethal Pseudomonas aeruginosa lung infection

Journal of Medical Microbiology ◽

10.1099/jmm.0.46658-0 ◽

2006 ◽

Vol 55 (10) ◽

pp. 1381-1387 ◽

Cited By ~ 68

Author(s):

Shinichi Miyairi ◽

Kazuhiro Tateda ◽

Etsu T. Fuse ◽

Chihiro Ueda ◽

Hiroaki Saito ◽

...

Keyword(s):

Quorum Sensing ◽

Specific Antibody ◽

Bacterial Infections ◽

Inflammatory Responses ◽

Critical Role ◽

Lung Infection ◽

Homoserine Lactone ◽

Vaccine Strategy ◽

Protein Conjugate

Quorum-sensing systems have been reported to play a critical role in the pathogenesis of several bacterial infections. Recent data have demonstrated that Pseudomonas N-3-oxododecanoyl-l-homoserine lactone (3-oxo-C12-homoserine lactone, 3-oxo-C12-HSL), but not N-butanoyl-l-homoserine lactone (C4-HSL), induces apoptosis in macrophages and neutrophils. In the present study, the effects of active immunization with 3-oxo-C12-HSL–carrier protein conjugate on acute P. aeruginosa lung infection in mice were investigated. Immunization with 3-oxo-C12-HSL–BSA conjugate (subcutaneous, four times, at 2-week intervals) elaborated significant amounts of specific antibody in serum. Control and immunized mice were intranasally challenged with approximately 3×106 c.f.u. P. aeruginosa PAO1, and survival was then compared. All control mice died by day 2 post bacterial challenge, while 36 % of immunized mice survived to day 4 (P<0.05). Interestingly, bacterial numbers in the lungs did not differ between control and immunized groups, whereas the levels of pulmonary tumour necrosis factor (TNF)-α in the immunized mice were significantly lower than those of control mice (P<0.05). Furthermore, the extractable 3-oxo-C12-HSL levels in serum and lung homogenate were also significantly diminished in the immunized mice. Immune serum completely rescued reduction of cell viability by 3-oxo-C12-HSL-mediated apoptosis in macrophages in vitro. These results demonstrated that specific antibody to 3-oxo-C12-HSL plays a protective role in acute P. aeruginosa infection, probably through blocking of host inflammatory responses, without altering lung bacterial burden. The present data identify a promising potential vaccine strategy targeting bacterial quorum-sensing molecules, including autoinducers.

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Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes

Thrombosis and Haemostasis ◽

10.1160/th14-11-0943 ◽

2015 ◽

Vol 114 (09) ◽

pp. 478-789 ◽

Cited By ~ 59

Author(s):

Waltraud Schrottmaier ◽

Julia Kral ◽

Sigrun Badrnya ◽

Alice Assinger

Keyword(s):

Immune Responses ◽

Antiplatelet Therapy ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cardiovascular Complications ◽

P2y12 Inhibitors ◽

Beneficial Effects ◽

Cox Inhibitor ◽

The Impact

SummaryPlatelets are key players in haemostasis and represent a pivotal link between inflammation, immunity and atherogenesis. Depending on the (patho)physiological environment platelets modulate various leukocyte functions via release of inflammatory mediators and direct cell-cell interactions. Elevated levels of circulating platelet-leukocyte aggregates are found in patients suffering from several thrombotic or inflammatory conditions. Platelet-monocyte and platelet-neutrophil interaction can trigger pro- and anti-inflammatory responses and modulate effector functions of all leukocyte subpopulations. These platelet-mediated immune responses have implications for the progression of cardiovascular diseases and also play a crucial role during infections, cancer, transplantations and other inflammatory diseases of several organs. Antiplatelet therapy including the COX inhibitor aspirin and/or ADP receptor P2Y12 inhibitors such as clopidogrel, prasugrel and ticagrelor are the therapy of choice for various cardiovascular complications. Both aspirin and P2Y12 inhibitors attenuate platelet-leukocyte interactions, thereby also modulating immune responses. This may have beneficial effects in some pathological conditions, while it might be detrimental in others. This review aims to summarise the current knowledge on platelet-leukocyte interactions and the impact of aspirin and P2Y12 inhibition on platelet-mediated immune responses and to give an overview on the effects of antiplatelet therapy on platelet-leukocyte interplay in various diseases.

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Impact of STING Inflammatory Signaling during Intracellular Bacterial Infections

Cells ◽

10.3390/cells11010074 ◽

2021 ◽

Vol 11 (1) ◽

pp. 74

Author(s):

Erika S. Guimarães ◽

Fabio V. Marinho ◽

Nina M. G. P. de Queiroz ◽

Maísa M. Antunes ◽

Sergio C. Oliveira

Keyword(s):

Immune Responses ◽

Bacterial Infections ◽

Inflammatory Responses ◽

Metabolic Reprogramming ◽

Host Cells ◽

Type I Interferons ◽

Type I ◽

Bacterial Survival ◽

Inflammatory Profile ◽

The Impact

The early detection of bacterial pathogens through immune sensors is an essential step in innate immunity. STING (Stimulator of Interferon Genes) has emerged as a key mediator of inflammation in the setting of infection by connecting pathogen cytosolic recognition with immune responses. STING detects bacteria by directly recognizing cyclic dinucleotides or indirectly by bacterial genomic DNA sensing through the cyclic GMP-AMP synthase (cGAS). Upon activation, STING triggers a plethora of powerful signaling pathways, including the production of type I interferons and proinflammatory cytokines. STING activation has also been associated with the induction of endoplasmic reticulum (ER) stress and the associated inflammatory responses. Recent reports indicate that STING-dependent pathways participate in the metabolic reprogramming of macrophages and contribute to the establishment and maintenance of a robust inflammatory profile. The induction of this inflammatory state is typically antimicrobial and related to pathogen clearance. However, depending on the infection, STING-mediated immune responses can be detrimental to the host, facilitating bacterial survival, indicating an intricate balance between immune signaling and inflammation during bacterial infections. In this paper, we review recent insights regarding the role of STING in inducing an inflammatory profile upon intracellular bacterial entry in host cells and discuss the impact of STING signaling on the outcome of infection. Unraveling the STING-mediated inflammatory responses can enable a better understanding of the pathogenesis of certain bacterial diseases and reveal the potential of new antimicrobial therapy.

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Inflammation and Immune Response in COPD: Where Do We Stand?

Mediators of Inflammation ◽

10.1155/2013/413735 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 73

Author(s):

Nikoletta Rovina ◽

Antonia Koutsoukou ◽

Nikolaos G. Koulouris

Keyword(s):

Immune Responses ◽

Bacterial Infections ◽

Severe Disease ◽

Critical Role ◽

Specific Pattern ◽

Innate Immune ◽

Danger Signal ◽

Cd4 Cells ◽

Adaptive Immune ◽

Molecular Patterns

Increasing evidence indicates that chronic inflammatory and immune responses play key roles in the development and progression of COPD. Recent data provide evidence for a role in the NLRP3 inflammasome in the airway inflammation observed in COPD. Cigarette smoke activates innate immune cells by triggering pattern recognition receptors (PRRs) to release “danger signal”. These signals act as ligands to Toll-like receptors (TLRs), triggering the production of cytokines and inducing innate inflammation. In smokers who develop COPD there appears to be a specific pattern of inflammation in the airways and parenchyma as a result of both innate and adaptive immune responses, with the predominance of CD8+ and CD4+ cells, and in the more severe disease, with the presence of lymphoid follicles containing B lymphocytes and T cells. Furthermore, viral and bacterial infections interfere with the chronic inflammation seen in stable COPD and exacerbations via pathogen-associated molecular patterns (PAMPs). Finally, autoimmunity is another novel aspect that may play a critical role in the pathogenesis of COPD. This review is un update of the currently discussed roles of inflammatory and immune responses in the pathogenesis of COPD.

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Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo

Scientific Reports ◽

10.1038/s41598-020-79201-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shady Estfanous ◽

Kathrin Krause ◽

Midhun N. K. Anne ◽

Mostafa Eltobgy ◽

Kyle Caution ◽

...

Keyword(s):

Bacterial Infections ◽

Critical Role ◽

In Vitro Study ◽

Burkholderia Cenocepacia ◽

Inflammasome Activation ◽

Bacterial Survival ◽

Life Threatening ◽

Systemic Infections

AbstractBurkholderia cenocepacia (B. cenocepacia) is an opportunistic bacterium; causing severe life threatening systemic infections in immunocompromised individuals including cystic fibrosis patients. The lack of gasdermin D (GSDMD) protects mice against endotoxin lipopolysaccharide (LPS) shock. On the other hand, GSDMD promotes mice survival in response to certain bacterial infections. However, the role of GSDMD during B. cenocepacia infection is not yet determined. Our in vitro study shows that GSDMD restricts B. cenocepacia replication within macrophages independent of its role in cell death through promoting mitochondrial reactive oxygen species (mROS) production. mROS is known to stimulate autophagy, hence, the inhibition of mROS or the absence of GSDMD during B. cenocepacia infections reduces autophagy which plays a critical role in the restriction of the pathogen. GSDMD promotes inflammation in response to B. cenocepacia through mediating the release of inflammasome dependent cytokine (IL-1β) and an independent one (CXCL1) (KC). Additionally, different B. cenocepacia secretory systems (T3SS, T4SS, and T6SS) contribute to inflammasome activation together with bacterial survival within macrophages. In vivo study confirmed the in vitro findings and showed that GSDMD restricts B. cenocepacia infection and dissemination and stimulates autophagy in response to B. cenocepacia. Nevertheless, GSDMD promotes lung inflammation and necrosis in response to B. cenocepacia without altering mice survival. This study describes the double-edged functions of GSDMD in response to B. cenocepacia infection and shows the importance of GSDMD-mediated mROS in restriction of B. cenocepacia.

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Acinetobacter baumannii LOS Regulate the Expression of Inflammatory Cytokine Genes and Proteins in Human Mast Cells

Pathogens ◽

10.3390/pathogens10030290 ◽

2021 ◽

Vol 10 (3) ◽

pp. 290

Author(s):

Takane Kikuchi-Ueda ◽

Tsuneyuki Ubagai ◽

Go Kamoshida ◽

Ryuichi Nakano ◽

Akiyo Nakano ◽

...

Keyword(s):

Mast Cells ◽

Acinetobacter Baumannii ◽

Bacterial Infections ◽

Inflammatory Responses ◽

Critical Role ◽

Bacterial Invasion ◽

Inflammatory Genes ◽

Human Mast Cells ◽

Expression Of Genes ◽

Tnf Α

Herein, we investigated the effect of bacterial lipooligosaccharides (LOS), from Acinetobacter baumannii, on the expression of pro-inflammatory genes that play an essential role in bacterial clearance. LAD2 human mast cells were stimulated with LOS derived from two strains of A. baumannii—ATCC 19606 and MDRA T14. LOS exposure induced the expression of genes for pro-inflammatory mediators, including TNF-α, IL-8, LTC4S, CCL4, and TLR4. The mRNA expression levels of a majority of the pro-inflammatory genes, except TLR4, in A. baumannii-LOS stimulated mast cells were increased. Moreover, co-culture of neutrophils with the supernatant obtained from LOS (ATCC 19606 and MDRA T14)-induced LAD2 cells increased the transmigration of neutrophils, which plays a critical role in the early protection against bacterial infections. The results of the present study suggest that LOS could be involved in the pathogenicity of A. baumannii by inducing inflammatory responses via mast cells and that IL-8 is involved in recruiting neutrophils in response to bacterial invasion.

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γδ T Lymphocytes in Asthma: a Complicated Picture

Archivum Immunologiae et Therapiae Experimentalis ◽

10.1007/s00005-021-00608-7 ◽

2021 ◽

Vol 69 (1) ◽

Author(s):

Michał K. Zarobkiewicz ◽

Ewelina Wawryk-Gawda ◽

Wioleta Kowalska ◽

Mariola Janiszewska ◽

Agnieszka Bojarska-Junak

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Bacterial Infections ◽

Current Knowledge ◽

Human Subjects ◽

Γδ T Cells ◽

Mice Model ◽

Health Related ◽

Life Threatening ◽

A Minor

AbstractA minor subset (approximately 5%) of peripheral T cells has their TCR build up from γ and δ chains instead of α and β—those are the γδ T lymphocytes. They can be functionally divided into subsets, e.g., Th1-, Th2-, Th9-, Th17-, Tfh-, and Treg-like γδ T cells. They share some specifics of both innate and adaptive immunity, and are capable of rapid response to a range of stimuli, including some viral and bacterial infections. Atopic diseases, including asthma, are one of major health-related problems of modern western societies. Asthma is one of the most common airway diseases, affecting people of all ages and having potential life-threatening consequences. In this paper, we review the current knowledge about the involvement of γδ T cells in the pathogenesis of asthma and its exacerbations. We summarize both the studies performed on human subjects as well as on the murine model of asthma. γδ T cells seem to be involved in the pathogenesis of asthma, different subsets probably perform opposite functions, e.g., symptom-exacerbating Vγ1 and symptom-suppressing Vγ4 in mice model of asthma.

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MicroRNAs and Multiple Sclerosis

Autoimmune Diseases ◽

10.4061/2011/807426 ◽

2011 ◽

Vol 2011 ◽

pp. 1-27 ◽

Cited By ~ 16

Author(s):

Kemal Ugur Tufekci ◽

Meryem Gulfem Oner ◽

Sermin Genc ◽

Kursad Genc

Keyword(s):

Multiple Sclerosis ◽

Immune Responses ◽

Inflammatory Responses ◽

Current Knowledge ◽

Expression Patterns ◽

Mirna Biogenesis ◽

Disease Marker ◽

Organ Specific ◽

And Function

MicroRNAs (miRNAs) have recently emerged as a new class of modulators of gene expression. miRNAs control protein synthesis by targeting mRNAs for translational repression or degradation at the posttranscriptional level. These noncoding RNAs are endogenous, single-stranded molecules approximately 22 nucleotides in length and have roles in multiple facets of immunity, from regulation of development of key cellular players to activation and function in immune responses. Recent studies have shown that dysregulation of miRNAs involved in immune responses leads to autoimmunity. Multiple sclerosis (MS) serves as an example of a chronic and organ-specific autoimmune disease in which miRNAs modulate immune responses in the peripheral immune compartment and the neuroinflammatory process in the brain. For MS, miRNAs have the potential to serve as modifying drugs. In this review, we summarize current knowledge of miRNA biogenesis and mode of action and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We also review the role of miRNAs in autoimmunity, focusing on emerging data regarding miRNA expression patterns in MS. Finally, we discuss the potential of miRNAs as a disease marker and a novel therapeutic target in MS. Better understanding of the role of miRNAs in MS will improve our knowledge of the pathogenesis of this disease.

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