scholarly journals N-Formyl-Perosamine Surface Homopolysaccharides Hinder the Recognition of Brucella abortus by Mouse Neutrophils

2016 ◽  
Vol 84 (6) ◽  
pp. 1712-1721 ◽  
Author(s):  
Ricardo Mora-Cartín ◽  
Carlos Chacón-Díaz ◽  
Cristina Gutiérrez-Jiménez ◽  
Stephany Gurdián-Murillo ◽  
Bruno Lomonte ◽  
...  
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
Brucella Abortus ◽  
Normal Serum ◽  
Mouse Serum ◽  
Human Neutrophils ◽  
Content Type ◽  
Animal System ◽  
Surface Polysaccharide ◽  
Killing Action

Brucella abortusis an intracellular pathogen of monocytes, macrophages, dendritic cells, and placental trophoblasts. This bacterium causes a chronic disease in bovines and in humans. In these hosts, the bacterium also invades neutrophils; however, it fails to replicate and just resists the killing action of these leukocytes without inducing significant activation or neutrophilia. Moreover,B. abortuscauses the premature cell death of human neutrophils. In the murine model, the bacterium is found within macrophages and dendritic cells at early times of infection but seldom in neutrophils. Based on this observation, we explored the interaction of mouse neutrophils withB. abortus. In contrast to human, dog, and bovine neutrophils, naive mouse neutrophils fail to recognize smoothB. abortusbacteria at early stages of infection. Murine normal serum components do not opsonize smoothBrucellastrains, and neutrophil phagocytosis is achieved only after the appearance of antibodies. Alternatively, mouse normal serum is capable of opsonizing roughBrucellamutants. Despite this, neutrophils still fail to killBrucella, and the bacterium induces cell death of murine leukocytes. In addition, mouse serum does not opsonizeYersinia enterocoliticaO:9, a bacterium displaying the same surface polysaccharide antigen as smoothB. abortus. Therefore, the lack of murine serum opsonization and absence of murine neutrophil recognition are specific, and the molecules responsible for theBrucellacamouflage areN-formyl-perosamine surface homopolysaccharides. Although the mouse is a valuable model for understanding the immunobiology of brucellosis, direct extrapolation from one animal system to another has to be undertaken with caution.

scholarly journals Toxoplasma gondii Extends the Life Span of Infected Human Neutrophils by Inducing Cytosolic PCNA and Blocking Activation of Apoptotic Caspases

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tatiane S. Lima ◽  
Sharmila Mallya ◽  
Allen Jankeel ◽  
Ilhem Messaoudi ◽  
Melissa B. Lodoen
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Life Span ◽  
Peripheral Blood ◽  
Productive Infection ◽  
Human Neutrophils ◽  
Serum Starvation ◽  
Rna Seq ◽  
Content Type ◽  
Blood Neutrophils

ABSTRACT Toxoplasma gondii is an intracellular protozoan parasite that has the remarkable ability to infect and replicate in neutrophils, immune cells with an arsenal of antimicrobial effector mechanisms. We report that T. gondii infection extends the life span of primary human peripheral blood neutrophils by delaying spontaneous apoptosis, serum starvation-induced apoptosis, and tumor necrosis alpha (TNF-α)-mediated apoptosis. T. gondii blockade of apoptosis was associated with an inhibition of processing and activation of the apoptotic caspases caspase-8 and -3, decreased phosphatidylserine exposure on the plasma membrane, and reduced cell death. We performed a global transcriptome analysis of T. gondii-infected peripheral blood neutrophils using RNA sequencing (RNA-Seq) and identified gene expression changes associated with DNA replication and DNA repair pathways, which in mature neutrophils are indicative of changes in regulators of cell survival. Consistent with the RNA-Seq data, T. gondii infection upregulated transcript and protein expression of PCNA, which is found in the cytosol of human neutrophils, where it functions as a key inhibitor of apoptotic pro-caspases. Infection of neutrophils resulted in increased interaction of PCNA with pro-caspase-3. Inhibition of this interaction with an AlkB homologue 2 PCNA-interacting motif (APIM) peptide reversed the infection-induced delay in cell death. Taken together, these findings indicate a novel strategy by which T. gondii manipulates cell life span in primary human neutrophils, which may allow the parasite to maintain an intracellular replicative niche and avoid immune clearance. IMPORTANCE Toxoplasma gondii is an obligate intracellular parasite that can cause life-threatening disease in immunocompromised individuals and in the developing fetus. Interestingly, T. gondii has evolved strategies to successfully manipulate the host immune system to establish a productive infection and evade host defense mechanisms. Although it is well documented that neutrophils are mobilized during acute T. gondii infection and infiltrate the site of infection, these cells can also be actively infected by T. gondii and serve as a replicative niche for the parasite. However, there is a limited understanding of the molecular processes occurring within T. gondii-infected neutrophils. This study reveals that T. gondii extends the life span of human neutrophils by inducing the expression of PCNA, which prevents activation of apoptotic caspases, thus delaying apoptosis. This strategy may allow the parasite to preserve its replicative intracellular niche.

scholarly journals The Als3 Cell Wall Adhesin Plays a Critical Role in Human Serum Amyloid A1-Induced Cell Death and Aggregation in Candida albicans

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Jiao Gong ◽  
Jian Bing ◽  
Guobo Guan ◽  
Clarissa J. Nobile ◽  
Guanghua Huang
Keyword(s):  
Cell Death ◽  
Cell Wall ◽  
Candida Albicans ◽  
Critical Role ◽  
Membrane Integrity ◽  
Cell Aggregation ◽  
Serum Amyloid ◽  
Mouse Serum ◽  
Content Type ◽  
Serum Amyloid A1

ABSTRACT Antimicrobial peptides and proteins play critical roles in the host defense against invading pathogens. We recently discovered that recombinantly expressed human and mouse serum amyloid A1 (rhSAA1 and rmSAA1, respectively) proteins have potent antifungal activities against the major human fungal pathogen Candida albicans. At high concentrations, rhSAA1 disrupts C. albicans membrane integrity and induces rapid fungal cell death. In the present study, we find that rhSAA1 promotes cell aggregation and targets the C. albicans cell wall adhesin Als3. Inactivation of ALS3 in C. albicans leads to a striking decrease in cell aggregation and cell death upon rhSAA1 treatment, suggesting that Als3 plays a critical role in SAA1 sensing. We further demonstrate that deletion of the transcriptional regulators controlling the expression of ALS3, such as AHR1, BCR1, and EFG1, in C. albicans results in similar effects to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling indicates that rhSAA1 has a discernible impact on the expression of cell wall- and metabolism-related genes, suggesting that rhSAA1 treatment could lead to a nutrient starvation effect on C. albicans cells.

scholarly journals Toll-Like Receptor 6 Plays an Important Role in Host Innate Resistance to Brucella abortus Infection in Mice

2013 ◽  
Vol 81 (5) ◽  
pp. 1654-1662 ◽  
Author(s):  
Leonardo A. de Almeida ◽  
Gilson C. Macedo ◽  
Fábio A. V. Marinho ◽  
Marco T. R. Gomes ◽  
Patrícia P. Corsetti ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Brucella Abortus ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Innate Immune ◽  
Proinflammatory Cytokine Production ◽  
Toll Like Receptor ◽  
Content Type

ABSTRACTBrucella abortusis recognized by several Toll-like receptor (TLR)-associated pathways triggering proinflammatory responses that affect both the nature and intensity of the immune response. Previously, we demonstrated thatB. abortus-mediated dendritic cell (DC) maturation and control of infection are dependent on the adaptor molecule MyD88. However, the involvement of all TLRs in response toB. abortusinfection is not completely understood. Therefore, we decided to evaluate the requirement for TLR6 in host resistance toB. abortus. Here, we demonstrated that TLR6 is an important component for triggering an innate immune response againstB. abortus. Anin vitroluciferase assay indicated that TLR6 cooperates with TLR2 to senseBrucellaand further activates NF-κB signaling. However,in vivoanalysis showed that TLR6, not TLR2, is required for the efficient control ofB. abortusinfection. Additionally,B. abortus-infected dendritic cells require TLR6 to induce tumor necrosis factor alpha (TNF-α) and interleukin-12 (IL-12). Furthermore, our findings demonstrated that the mitogen-activated protein kinase (MAPK) signaling pathway is impaired in TLR2, TLR6, and TLR2/6 knockout (KO) DCs when infected withB. abortus, which may account for the lower proinflammatory cytokine production observed in TLR6 KO mouse dendritic cells. In summary, the results presented here indicate that TLR6 is required to trigger innate immune responses againstB. abortusin vivoand is required for the full activation of DCs to induce robust proinflammatory cytokine production.

scholarly journals Enzymatic Dysfunction of Mitochondrial Complex I of the Candida albicansgoa1Mutant Is Associated with Increased Reactive Oxidants and Cell Death

2011 ◽  
Vol 10 (5) ◽  
pp. 672-682 ◽  
Author(s):  
Dongmei Li ◽  
Hui Chen ◽  
Abigail Florentino ◽  
Deepu Alex ◽  
Patricia Sikorski ◽  
...  
Keyword(s):  
Cell Death ◽  
Complex I ◽  
Alternative Oxidase ◽  
Polyacrylamide Gel Electrophoresis ◽  
Potassium Cyanide ◽  
Human Neutrophils ◽  
Oxidase Gene ◽  
Content Type ◽  
Chronological Aging

ABSTRACTWe have previously shown that deletion ofGOA1(growth andoxidantadaptation) ofCandida albicansresults in a loss of mitochondrial membrane potential, ATP synthesis, increased sensitivity to oxidants and killing by human neutrophils, and avirulence in a systemic model of candidiasis. We established that translocation of Goa1p to mitochondria occurred during peroxide stress. In this report, we show that thegoa1Δ (GOA31), compared to the wild type (WT) and a gene-reconstituted (GOA32) strain, exhibits sensitivity to inhibitors of the classical respiratory chain (CRC), including especially rotenone (complex I [CI]) and salicylhydroxamic acid (SHAM), an inhibitor of the alternative oxidase pathway (AOX), while potassium cyanide (KCN; CIV) causes a partial inhibition of respiration. In the presence of SHAM, however, GOA31 has an enhanced respiration, which we attribute to the parallel respiratory (PAR) pathway and alternative NADH dehydrogenases. Interestingly, deletion ofGOA1also results in a decrease in transcription of the alternative oxidase geneAOX1in untreated cells as well as negligibleAOX1andAOX2transcription in peroxide-treated cells. To explain the rotenone sensitivity, we measured enzyme activities of complexes I to IV (CI to CIV) and observed a major loss of CI activity in GOA31 but not in control strains. Enzymatic data of CI were supported by blue native polyacrylamide gel electrophoresis (BN-PAGE) experiments which demonstrated less CI protein and reduced enzyme activity. The consequence of a defective CI in GOA31 is an increase in reactive oxidant species (ROS), loss of chronological aging, and programmed cell death ([PCD] apoptosis)in vitrocompared to control strains. The increase in PCD was indicated by an increase in caspase activity and DNA fragmentation in GOA31. Thus,GOA1is required for a functional CI and partially for the AOX pathway; loss ofGOA1compromises cell survival. Further, the loss of chronological aging is new to studies ofCandidaspecies and may offer an insight into therapies to control these pathogens. Our observation of increased ROS production associated with a defective CI and PCD is reminiscent of mitochondrial studies of patients with some types of neurodegenerative diseases where CI and/or CIII dysfunctions lead to increased ROS and apoptosis.

scholarly journals Tumor cytotoxicity and immunogenicity of a novel V-jet neon plasma source compared to the kINPen

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lea Miebach ◽  
Eric Freund ◽  
Stefan Horn ◽  
Felix Niessner ◽  
Sanjeev Kumar Sagwal ◽  
...  
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
Cancer Cells ◽  
Treatment Time ◽  
Plasma Source ◽  
In Vivo Model ◽  
Antitumor Effects ◽  
Plasma Device

AbstractRecent research indicated the potential of cold physical plasma in cancer therapy. The plethora of plasma-derived reactive oxygen and nitrogen species (ROS/RNS) mediate diverse antitumor effects after eliciting oxidative stress in cancer cells. We aimed at exploiting this principle using a newly designed dual-jet neon plasma source (Vjet) to treat colorectal cancer cells. A treatment time-dependent ROS/RNS generation induced oxidation, growth retardation, and cell death within 3D tumor spheroids were found. In TUM-CAM, a semi in vivo model, the Vjet markedly reduced vascularized tumors' growth, but an increase of tumor cell immunogenicity or uptake by dendritic cells was not observed. By comparison, the argon-driven single jet kINPen, known to mediate anticancer effects in vitro, in vivo, and in patients, generated less ROS/RNS and terminal cell death in spheroids. In the TUM-CAM model, however, the kINPen was equivalently effective and induced a stronger expression of immunogenic cancer cell death (ICD) markers, leading to increased phagocytosis of kINPen but not Vjet plasma-treated tumor cells by dendritic cells. Moreover, the Vjet was characterized according to the requirements of the DIN-SPEC 91315. Our results highlight the plasma device-specific action on cancer cells for evaluating optimal discharges for plasma cancer treatment.

scholarly journals Human Herpesvirus 6A Induces Dendritic Cell Death and HMGB1 Release without Virus Replication

Pathogens ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 57
Author(s):  
Rasmus Gustafsson
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
High Mobility ◽  
Human Herpesvirus ◽  
Human Monocyte ◽  
Hmgb1 Protein ◽  
Innate And Adaptive Immunity ◽  
Th2 Polarization ◽  
Dependent Cell ◽  
Ifn Γ

Human herpesvirus 6A (HHV-6A) is a common virus that has important immunomodulatory effects. Dendritic cells (DC) are key players in innate and adaptive immunity and are implicated in the pathogenesis of many human diseases, including infections. (1) Background: Previous studies have demonstrated suppressive effects of HHV-6A on key DC functions. (2) Methods: human monocyte derived dendritic cells were inoculated with HHV-6A and viral replication, cell viability, and release of high mobility group box 1 (HMGB1) protein from DC and of the cytokines IL-2, IL-4, IL-6, IL-10, TNF and IFN-γ after co-culture with allogenic CD4+ T cells were assessed. (3) Results: Nonproductive infection of HHV-6A in DC leads to titer-dependent cell death and the release of HMGB1 protein, and a Th2 polarization. (4) Conclusion: These immune responses aimed to clear the infection may also imply risks for inflammatory pathologies associated with HHV-6A such as multiple sclerosis.

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