scholarly journals Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase

mBio ◽  
2012 ◽  
Vol 3 (1) ◽  
Author(s):  
Yung-Chi Chang ◽  
Satoshi Uchiyama ◽  
Ajit Varki ◽  
Victor Nizet
Keyword(s):  
Sialic Acid ◽  
Mammalian Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Molecular Mimicry ◽  
Cell Surface Expression ◽  
Human Neutrophils ◽  
Content Type ◽  
Sialidase Activity

ABSTRACTCell surface expression of sialic acid has been reported to decrease during immune cell activation, but the significance and regulation of this phenomenon are still being investigated. The major human bacterial pathogenStreptococcus pneumoniaecauses pneumonia, sepsis and meningitis, often accompanied by strong inflammatory responses.S. pneumoniaeexpresses a sialidase (NanA) that contributes to mucosal colonization, platelet clearance, and blood-brain barrier penetration. Using wild-type and isogenic NanA-deficient mutant strains, we showed thatS. pneumoniaeNanA can desialylate the surface of human THP-1 monocytes, leading to increased ERK phosphorylation, NF-κB activation, and proinflammatory cytokine release.S. pneumoniaeNanA expression also stimulates interleukin-8 release and extracellular trap formation from human neutrophils. A mechanistic contribution of unmasking of inhibitory Siglec-5 fromcissialic acid interactions to the proinflammatory effect of NanA is suggested by decreased SHP-2 recruitment to the Siglec-5 intracellular domain and RNA interference studies. Finally, NanA increased production of proinflammatory cytokines in a murine intranasal challenge model ofS. pneumoniaepneumonia.IMPORTANCESialic acids decorate the surface of all mammalian cells and play important roles in physiology, development, and evolution. Siglecs are sialic acid-binding receptors on the surface of immune cells, many of which engage incisinteractions with host sialoglycan ligands and dampen inflammatory responses through transduction of inhibitory signals. Recently, certain bacterial pathogens have been shown to suppress leukocyte innate immune responses by molecular mimicry of host sialic acid structures and engagement of inhibitory Siglecs. Our present work shows that the converse can be true, i.e., that a microbial sialic acid-cleaving enzyme can induce proinflammatory responses, which are in part mediated by unmasking of an inhibitory Siglec. We conclude that host leukocytes are poised to detect and respond to microbial sialidase activity with exaggerated inflammatory responses, which could be beneficial or detrimental to the host depending on the site, stage and magnitude of infection.

scholarly journals Sialylation of Lipooligosaccharides Is Dispensable for the Virulence of Haemophilus ducreyi in Humans

2011 ◽  
Vol 80 (2) ◽  
pp. 679-687 ◽  
Author(s):  
Stanley M. Spinola ◽  
Wei Li ◽  
Kate R. Fortney ◽  
Diane M. Janowicz ◽  
Beth Zwickl ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Cell Activation ◽  
Molecular Mimicry ◽  
Etiologic Agent ◽  
Human Infection ◽  
Haemophilus Ducreyi ◽  
Dendritic Cell Activation ◽  
Content Type ◽  
Self Recognition ◽  
Serum Killing

ABSTRACTSialylated glycoconjugates on the surfaces of mammalian cells play important roles in intercellular communication and self-recognition. The sialic acid preferentially expressed in human tissues isN-acetylneuraminic acid (Neu5Ac). In a process called molecular mimicry, many bacterial pathogens decorate their cell surface glycolipids with Neu5Ac. Incorporation of Neu5Ac into bacterial glycolipids promotes bacterial interactions with host cell receptors called Siglecs. These interactions affect bacterial adherence, resistance to serum killing and phagocytosis, and innate immune responses.Haemophilus ducreyi, the etiologic agent of chancroid, expresses lipooligosaccharides (LOS) that are highly sialylated. However, anH. ducreyisialyltransferase (lst) mutant, whose LOS contain reduced levels of Neu5Ac, is fully virulent in human volunteers. Recently, a second sialyltransferase gene (Hd0053) was discovered inH. ducreyi, raising the possibility thatHd0053compensated for the loss oflstduring human infection. CMP-Neu5Ac is the obligate nucleotide sugar donor for all bacterial sialyltransferases; LOS derived from anH. ducreyiCMP-Neu5Ac synthetase (neuA) mutant has no detectable Neu5Ac. Here, we compared anH. ducreyi neuAmutant to its wild-type parent in several models of pathogenesis. In human inoculation experiments, theneuAmutant formed papules and pustules at rates that were no different than those of its parent. When grown in media with and without Neu5Ac supplementation, theneuAmutant and its parent had similar phenotypes in bactericidal, macrophage uptake, and dendritic cell activation assays. Although we cannot preclude a contribution of LOS sialylation to ulcerative disease, these data strongly suggest that sialylation of LOS is dispensable forH. ducreyipathogenesis in humans.

scholarly journals The Protozoan Parasite Toxoplasma gondii Selectively Reprograms the Host Cell Translatome

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Louis-Philippe Leroux ◽  
Julie Lorent ◽  
Tyson E. Graber ◽  
Visnu Chaparro ◽  
Laia Masvidal ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cell ◽  
Cell Activation ◽  
Immune Cell ◽  
Mrna Translation ◽  
Protozoan Parasite ◽  
Translational Efficiency ◽  
Type I ◽  
Content Type ◽  
Infection Inhibition

ABSTRACT The intracellular parasite Toxoplasma gondii promotes infection by targeting multiple host cell processes; however, whether it modulates mRNA translation is currently unknown. Here, we show that infection of primary murine macrophages with type I or II T. gondii strains causes a profound perturbation of the host cell translatome. Notably, translation of transcripts encoding proteins involved in metabolic activity and components of the translation machinery was activated upon infection. In contrast, the translational efficiency of mRNAs related to immune cell activation and cytoskeleton/cytoplasm organization was largely suppressed. Mechanistically, T. gondii bolstered mechanistic target of rapamycin (mTOR) signaling to selectively activate the translation of mTOR-sensitive mRNAs, including those with a 5′-terminal oligopyrimidine (5′ TOP) motif and those encoding mitochondrion-related proteins. Consistent with parasite modulation of host mTOR-sensitive translation to promote infection, inhibition of mTOR activity suppressed T. gondii replication. Thus, selective reprogramming of host mRNA translation represents an important subversion strategy during T. gondii infection.

scholarly journals Stimulation of Innate Immunity byIn VivoCyclic di-GMP Synthesis Using Adenovirus

2014 ◽  
Vol 21 (11) ◽  
pp. 1550-1559 ◽  
Author(s):  
Benjamin J. Koestler ◽  
Sergey S. Seregin ◽  
David P. W. Rastall ◽  
Yasser A. Aldhamen ◽  
Sarah Godbehere ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mammalian Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Host Cells ◽  
Content Type ◽  
Cytokines And Chemokines ◽  
Novel Approach

ABSTRACTThe bacterial second messenger cyclic di-GMP (c-di-GMP) stimulates inflammation by initiating innate immune cell recruitment and triggering the release of proinflammatory cytokines and chemokines. These properties make c-di-GMP a promising candidate for use as a vaccine adjuvant, and numerous studies have demonstrated that administration of purified c-di-GMP with different antigens increases protection against infection in animal models. Here, we have developed a novel approach to produce c-di-GMP inside host cells as an adjuvant to exploit a host-pathogen interaction and initiate an innate immune response. We have demonstrated that c-di-GMP can be synthesizedin vivoby transducing a diguanylate cyclase (DGC) gene into mammalian cells using an adenovirus serotype 5 (Ad5) vector. Expression of DGC led to the production of c-di-GMPin vitroandin vivo, and this was able to alter proinflammatory gene expression in murine tissues and increase the secretion of numerous cytokines and chemokines when administered to animals. Furthermore, coexpression of DGC modestly increased T-cell responses to aClostridium difficileantigen expressed from an adenovirus vaccine, although no significant differences in antibody titers were observed. This adenovirus c-di-GMP delivery system offers a novel method to administer c-di-GMP as an adjuvant to stimulate innate immunity during vaccination.

scholarly journals Giardia duodenalis Cathepsin B Proteases Degrade Intestinal Epithelial Interleukin-8 and Attenuate Interleukin-8-Induced Neutrophil Chemotaxis

2014 ◽  
Vol 82 (7) ◽  
pp. 2772-2787 ◽  
Author(s):  
James A. Cotton ◽  
Amol Bhargava ◽  
Jose G. Ferraz ◽  
Robin M. Yates ◽  
Paul L. Beck ◽  
...  
Keyword(s):  
Cathepsin B ◽  
Diarrheal Disease ◽  
Inflammatory Responses ◽  
Functional Gastrointestinal Disorders ◽  
Giardia Duodenalis ◽  
Cysteine Proteases ◽  
Interleukin 8 ◽  
Human Neutrophils ◽  
Intestinal Epithelial ◽  
Content Type

ABSTRACTGiardia duodenalis(syn.G. intestinalis,G. lamblia) infections are a leading cause of waterborne diarrheal disease that can also result in the development of postinfectious functional gastrointestinal disorders via mechanisms that remain unclear. Parasite numbers exceed 106trophozoites per centimeter of gut at the height of an infection. Yet the intestinal mucosa ofG. duodenalis-infected individuals is devoid of signs of overt inflammation.G. duodenalisinfections can also occur concurrently with infections with other proinflammatory gastrointestinal pathogens. Little is known of whether and how this parasite can attenuate host inflammatory responses induced by other proinflammatory stimuli, such as a gastrointestinal pathogen. Identifying hitherto-unrecognized parasitic immunomodulatory pathways, the present studies demonstrated thatG. duodenalistrophozoites attenuate secretion of the potent neutrophil chemoattractant interleukin-8 (CXCL8); these effects were observed in human small intestinal mucosal tissues and from intestinal epithelial monolayers, activated through administration of proinflammatory interleukin-1β orSalmonella entericaserovar Typhimurium. This attenuation is caused by the secretion ofG. duodenaliscathepsin B cysteine proteases that degrade CXCL8 posttranscriptionally. Furthermore, the degradation of CXCL8 viaG. duodenaliscathepsin B cysteine proteases attenuates CXCL8-induced chemotaxis of human neutrophils. Taken together, these data demonstrate for the first time thatG. duodenalistrophozoite cathepsins are capable of attenuating a component of their host's proinflammatory response induced by a separate proinflammatory stimulus.

scholarly journals Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

2021 ◽  
Vol 12 ◽  
Author(s):  
Juehong Li ◽  
Ziyang Sun ◽  
Gang Luo ◽  
Shuo Wang ◽  
Haomin Cui ◽  
...  
Keyword(s):  
Mast Cell ◽  
Heterotopic Ossification ◽  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Mast Cell Activation ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Dependent Manner

Heterotopic ossification (HO) is one of the most intractable disorders following musculoskeletal injury and is characterized by the ectopic presence of bone tissue in the soft tissue leading to severe loss of function in the extremities. Recent studies have indicated that immune cell infiltration and inflammation are involved in aberrant bone formation. In this study, we found increased monocyte/macrophage and mast cell accumulation during early HO progression. Macrophage depletion by clodronate liposomes and mast cell stabilization by cromolyn sodium significantly impeded HO formation. Therefore, we proposed that the dietary phytochemical quercetin could also suppress immune cell recruitment and related inflammatory responses to prevent HO. As expected, quercetin inhibited the monocyte-to-macrophage transition, macrophage polarization, and mast cell activation in vitro in a dose-dependent manner. Using a murine burn/tenotomy model, we also demonstrated that quercetin attenuated inflammatory responses and HO in vivo. Furthermore, elevated SIRT1 and decreased acetylated NFκB p65 expression were responsible for the mechanism of quercetin, and the beneficial effects of quercetin were reversed by the SIRT1 antagonist EX527 and mimicked by the SIRT agonist SRT1720. The findings in this study suggest that targeting monocyte/macrophage and mast cell activities may represent an attractive approach for therapeutic intervention of HO and that quercetin may serve as a promising therapeutic candidate for the treatment of trauma-induced HO by modulating SIRT1/NFκB signaling.

scholarly journals Serine Lipids of Porphyromonas gingivalis Are Human and Mouse Toll-Like Receptor 2 Ligands

2013 ◽  
Vol 81 (9) ◽  
pp. 3479-3489 ◽  
Author(s):  
Robert B. Clark ◽  
Jorge L. Cervantes ◽  
Mark W. Maciejewski ◽  
Vahid Farrokhi ◽  
Reza Nemati ◽  
...  
Keyword(s):  
Cell Activation ◽  
Inflammatory Responses ◽  
Periodontal Pathogen ◽  
Toll Like Receptor ◽  
Dendritic Cell Activation ◽  
Content Type ◽  
Hek Cells ◽  
Toll Like Receptor 2

ABSTRACTThe total cellular lipids ofPorphyromas gingivalis, a known periodontal pathogen, were previously shown to promote dendritic cell activation and inhibition of osteoblasts through engagement of Toll-like receptor 2 (TLR2). The purpose of the present investigation was to fractionate all lipids ofP. gingivalisand define which lipid classes account for the TLR2 engagement, based on bothin vitrohuman cell assays andin vivostudies in mice. Specific serine-containing lipids ofP. gingivalis, called lipid 654 and lipid 430, were identified in specific high-performance liquid chromatography fractions as the TLR2-activating lipids. The structures of these lipids were defined using tandem mass spectrometry and nuclear magnetic resonance methods.In vitro, both lipid 654 and lipid 430 activated TLR2-expressing HEK cells, and this activation was inhibited by anti-TLR2 antibody. In contrast, TLR4-expressing HEK cells failed to be activated by either lipid 654 or lipid 430. Wild-type (WT) or TLR2-deficient (TLR2−/−) mice were injected with either lipid 654 or lipid 430, and the effects on serum levels of the chemokine CCL2 were measured 4 h later. Administration of either lipid 654 or lipid 430 to WT mice resulted in a significant increase in serum CCL2 levels; in contrast, the administration of lipid 654 or lipid 430 to TLR2−/−mice resulted in no increase in serum CCL2. These results thus identify a new class of TLR2 ligands that are produced byP. gingivalisthat likely play a significant role in mediating inflammatory responses both at periodontal sites and, potentially, in other tissues where these lipids might accumulate.

scholarly journals Sexual dimorphism of monocyte transcriptome in individuals with chronic low-grade inflammation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jisun So ◽  
Albert K. Tai ◽  
Alice H. Lichtenstein ◽  
Dayong Wu ◽  
Stefania Lamon-Fava
Keyword(s):  
Sexual Dimorphism ◽  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Immune Defense ◽  
Low Grade ◽  
Immune Functions ◽  
Blood Monocytes ◽  
Low Grade Inflammation

AbstractSexual dimorphism in the immune system is evidenced by a higher prevalence of autoimmune diseases in women and higher susceptibility to infectious diseases in men. However, the molecular basis of these sex-based differences is not fully understood. We have characterized the transcriptome profiles of peripheral blood monocytes from males and postmenopausal females with chronic low-grade inflammation. We identified 41 sexually differentially expressed genes [adjusted p value (FDR) < 0.1], including genes involved in immune cell activation (e.g., CEACAM1, FCGR2B, and SLAMF7) and antigen presentation (e.g., AIM2, CD1E, and UBA1) with a higher expression in females than males. Moreover, signaling pathways of immune or inflammatory responses, including interferon (IFN) signaling [z-score = 2.45, -log(p) = 3.88], were found to be more upregulated in female versus male monocytes, based on a set of genes exhibiting sex-biased expression (p < 0.03). The contribution of IFN signaling to the sexual transcriptional differences was further confirmed by direct comparisons of the monocyte sex-biased genes with IFN signature genes (ISGs) that were previously curated in mouse macrophages. ISGs showed a greater overlap with female-biased genes than male-biased genes and a higher overall expression in female than male monocytes, particularly for the genes of antiviral and inflammatory responses to IFN. Given the role of IFN in immune defense and autoimmunity, our results suggest that sexual dimorphism in immune functions may be associated with more priming of innate immune pathways in female than male monocytes. These findings highlight the role of sex on the human immune transcriptome.

scholarly journals RIPK3 Facilitates Host Resistance to Oral Toxoplasma gondii Infection

2021 ◽  
Vol 89 (5) ◽  
Author(s):  
Patrick W. Cervantes ◽  
Bruno Martorelli Di Genova ◽  
Billy Joel Erazo Flores ◽  
Laura J. Knoll
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Parasite Burden ◽  
Kinase Domain ◽  
Content Type ◽  
Protection Mechanism ◽  
Cell Death Pathway ◽  
Toxoplasma Gondii Infection

ABSTRACT Toxoplasma gondii infection activates pattern recognition receptor (PRR) pathways that drive innate inflammatory responses to control infection. Necroptosis is a proinflammatory cell death pathway apart from the innate immune response that has evolved to control pathogenic infection. In this study, we further defined the role of Z-DNA binding protein 1 (ZBP1) as a PRR and assessed its contribution to necroptosis as a host protection mechanism to T. gondii infection. We found that ZBP1 does not induce proinflammatory necroptosis cell death, and ZBP1 null mice have reduced survival after oral T. gondii infection. In contrast, mice deleted in receptor-interacting serine/threonine-protein kinase 3 (RIPK3−/−), a central mediator of necroptosis, have significantly improved survival after oral T. gondii infection without a reduction in parasite burden. The physiological consequences of RIPK3 activity did not show any differences in intestine villus immunopathology, but RIPK3−/− mice showed higher immune cell infiltration and edema in the lamina propria. The contribution of necroptosis to host survival was clarified with mixed-lineage kinase domain-like pseudokinase null (MLKL−/−) mice. We found MLKL−/− mice succumbed to oral T. gondii infection the same as wild-type mice, indicating necroptosis-independent RIPK3 activity impacts host survival. These results provide new insights on the impacts of proinflammatory cell death pathways as a mechanism of host defense to oral T. gondii infection.

scholarly journals Multiscale analysis of acne connects molecular subnetworks with disease status

2019 ◽  
Author(s):  
Jacob B. Hall ◽  
Aparna A. Divaraniya ◽  
Hao-Chih Lee ◽  
Christine E. Becker ◽  
Benjamin McCauley ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Target Identification ◽  
Acne Vulgaris ◽  
Disease Status ◽  
Psychosocial Impairment ◽  
Response To Stress ◽  
Clinical Measurements

ABSTRACTAcne vulgaris affects millions of individuals and can lead to psychosocial impairment as well as permanent scarring. Previous studies investigating acne pathogenesis have either examined a targeted set of biological parameters in a modest-sized cohort or carried out high-throughput assays on a small number of samples. To develop a more comprehensive understanding of acne pathophysiology, we conducted an in-depth multi-omic study of 56 acne patients and 20 individuals without acne. We collected whole blood, skin punch biopsies, microbiota from skin follicles, and relevant clinical measurements to understand how multiple factors contribute to acne. We provide an integrative analysis of multi-omics data that results in a molecular network of acne. Comparisons of lesional and non-lesional skin highlighted multiple biological processes, including immune cell and inflammatory responses, response to stress, T cell activation, lipid biosynthesis, fatty acid metabolism, keratinocytes, antimicrobial activity, epithelial cell differentiation, and response to wounding, that are differentially altered in acne lesions compared to non-lesions. Our results suggest baseline differences in the skin that may predispose individuals to develop acne. These datasets and findings offer a framework for new target identification and reference for future studies.

scholarly journals The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity

2015 ◽  
Vol 112 (34) ◽  
pp. 10774-10779 ◽  
Author(s):  
Buvana Ravishankar ◽  
Haiyun Liu ◽  
Rahul Shinde ◽  
Kapil Chaudhary ◽  
Wei Xiao ◽  
...  
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Metabolic Stress ◽  
Tolerance Induction ◽  
Apoptotic Cells ◽  
Cell Clearance

Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic cell-driven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-β production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity.

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