scholarly journals Coxiella burnetii-Infected NK Cells Release Infectious Bacteria by Degranulation

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Svea Matthiesen ◽  
Luca Zaeck ◽  
Kati Franzke ◽  
Rico Jahnke ◽  
Charlie Fricke ◽  
...  
Keyword(s):  
Nk Cells ◽  
Coxiella Burnetii ◽  
Defense Mechanism ◽  
Cell Types ◽  
Chlamydia Psittaci ◽  
Content Type ◽  
Lytic Granules ◽  
Self Defense ◽  
Different Types ◽  
Ifn Γ

ABSTRACT Natural killer (NK) cells are critically involved in the early immune response against various intracellular pathogens, including Coxiella burnetii and Chlamydia psittaci. Chlamydia-infected NK cells functionally mature, induce cellular immunity, and protect themselves by killing the bacteria in secreted granules. Here, we report that infected NK cells do not allow intracellular multiday growth of Coxiella, as is usually observed in other host cell types. C. burnetii-infected NK cells display maturation and gamma interferon (IFN-γ) secretion, as well as the release of Coxiella-containing lytic granules. Thus, NK cells possess a potent program to restrain and expel different types of invading bacteria via degranulation. Strikingly, though, in contrast to Chlamydia, expulsed Coxiella organisms largely retain their infectivity and, hence, escape the cell-autonomous self-defense mechanism in NK cells.

scholarly journals Chlamydia psittaci-Infected Dendritic Cells Communicate with NK Cells via Exosomes To Activate Antibacterial Immunity

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Nadine Radomski ◽  
Axel Karger ◽  
Kati Franzke ◽  
Elisabeth Liebler-Tenorio ◽  
Rico Jahnke ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Nk Cell ◽  
Early Response ◽  
Chlamydia Psittaci ◽  
Target Cells ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Host Cell Death ◽  
Ifn Γ

ABSTRACT Dendritic cells (DCs) and natural killer (NK) cells are critically involved in the early response against various bacterial microbes. Functional activation of infected DCs and NK cell-mediated gamma interferon (IFN-γ) secretion essentially contribute to the protective immunity against Chlamydia. How DCs and NK cells cooperate during the antichlamydial response is not fully understood. Therefore, in the present study, we investigated the functional interplay between Chlamydia-infected DCs and NK cells. Our biochemical and cell biological experiments show that Chlamydia psittaci-infected DCs display enhanced exosome release. We find that such extracellular vesicles (referred to as dexosomes) do not contain infectious bacterial material but strongly induce IFN-γ production by NK cells. This directly affects C. psittaci growth in infected target cells. Furthermore, NK cell-released IFN-γ in cooperation with tumor necrosis factor alpha (TNF-α) and/or dexosomes augments apoptosis of both noninfected and infected epithelial cells. Thus, the combined effect of dexosomes and proinflammatory cytokines restricts C. psittaci growth and attenuates bacterial subversion of apoptotic host cell death. In conclusion, this provides new insights into the functional cooperation between DCs, dexosomes, and NK cells in the early steps of antichlamydial defense.

scholarly journals Exacerbated Type II Interferon Response Drives Hypervirulence and Toxic Shock by an Emergent Epidemic Strain of Streptococcus suis

2013 ◽  
Vol 81 (6) ◽  
pp. 1928-1939 ◽  
Author(s):  
Claude Lachance ◽  
Marcelo Gottschalk ◽  
Pehuén P. Gerber ◽  
Paul Lemire ◽  
Jianguo Xu ◽  
...  
Keyword(s):  
Nk Cells ◽  
North American ◽  
Streptococcus Suis ◽  
Pathogenic Strain ◽  
Interferon Response ◽  
Epidemic Strain ◽  
Toxic Shock ◽  
Chinese Strain ◽  
Content Type ◽  
Ifn Γ

ABSTRACTStreptococcus suis, a major porcine pathogen, can be transmitted to humans and cause severe symptoms. A large human outbreak associated with an unusual streptococcal toxic shock-like syndrome (STSLS) was described in China. Albeit an early burst of proinflammatory cytokines following ChineseS. suisinfection was suggested to be responsible for STSLS case severity, the mechanisms involved are still poorly understood. Using a mouse model, the host response toS. suisinfection with a North American intermediately pathogenic strain, a European highly pathogenic strain, and the Chinese epidemic strain was investigated by a whole-genome microarray approach. Proinflammatory genes were expressed at higher levels in mice infected with the Chinese strain than those infected with the European strain. The Chinese strain induced a fast and strong gamma interferon (IFN-γ) response by natural killer (NK) cells. In fact, IFN-γ-knockout mice infected with the Chinese strain showed significantly better survival than wild-type mice. Conversely, infection with the less virulent North American strain resulted in an IFN-β-subjugated, low inflammatory response that might be beneficial for the host to clear the infection. Overall, our data suggest that a highly virulent epidemic strain has evolved to massively activate IFN-γ production, mainly by NK cells, leading to a rapid and lethal STSLS.

scholarly journals Vaccinia Virus Encodes a Novel Inhibitor of Apoptosis That Associates with the Apoptosome

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
Melissa R. Ryerson ◽  
Monique M. Richards ◽  
Marc Kvansakul ◽  
Christine J. Hawkins ◽  
Joanna L. Shisler
Keyword(s):  
Vaccinia Virus ◽  
Host Defense ◽  
Mammalian Cells ◽  
Defense Mechanism ◽  
Current Model ◽  
Protein A ◽  
Cell Types ◽  
Jurkat Cells ◽  
Content Type ◽  
Inhibitory Function

ABSTRACT Apoptosis is an important antiviral host defense mechanism. Here we report the identification of a novel apoptosis inhibitor encoded by the vaccinia virus (VACV) M1L gene. M1L is absent in the attenuated modified vaccinia virus Ankara (MVA) strain of VACV, a strain that stimulates apoptosis in several types of immune cells. M1 expression increased the viability of MVA-infected THP-1 and Jurkat cells and reduced several biochemical hallmarks of apoptosis, such as PARP-1 and procaspase-3 cleavage. Furthermore, ectopic M1L expression decreased staurosporine-induced (intrinsic) apoptosis in HeLa cells. We then identified the molecular basis for M1 inhibitory function. M1 allowed mitochondrial depolarization but blocked procaspase-9 processing, suggesting that M1 targeted the apoptosome. In support of this model, we found that M1 promoted survival in Saccharomyces cerevisiae overexpressing human Apaf-1 and procaspase-9, critical components of the apoptosome, or overexpressing only conformationally active caspase-9. In mammalian cells, M1 coimmunoprecipitated with Apaf-1–procaspase-9 complexes. The current model is that M1 associates with and allows the formation of the apoptosome but prevents apoptotic functions of the apoptosome. The M1 protein features 14 predicted ankyrin (ANK) repeat domains, and M1 is the first ANK-containing protein reported to use this inhibitory strategy. Since ANK-containing proteins are encoded by many large DNA viruses and found in all domains of life, studies of M1 may lead to a better understanding of the roles of ANK proteins in virus-host interactions. IMPORTANCE Apoptosis selectively eliminates dangerous cells such as virus-infected cells. Poxviruses express apoptosis antagonists to neutralize this antiviral host defense. The vaccinia virus (VACV) M1 ankyrin (ANK) protein, a protein with no previously ascribed function, inhibits apoptosis. M1 interacts with the apoptosome and prevents procaspase-9 processing as well as downstream procaspase-3 cleavage in several cell types and under multiple conditions. M1 is the first poxviral protein reported to associate with and prevent the function of the apoptosome, giving a more detailed picture of the threats VACV encounters during infection. Dysregulation of apoptosis is associated with several human diseases. One potential treatment of apoptosis-related diseases is through the use of designed ANK repeat proteins (DARPins), similar to M1, as caspase inhibitors. Thus, the study of the novel antiapoptosis effects of M1 via apoptosome association will be helpful for understanding how to control apoptosis using either natural or synthetic molecules.

scholarly journals Mast Cell Cytonemes as a Defense Mechanism againstCoxiella burnetii

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Soraya Mezouar ◽  
Joana Vitte ◽  
Laurent Gorvel ◽  
Amira Ben Amara ◽  
Benoit Desnues ◽  
...  
Keyword(s):  
Mast Cells ◽  
Coxiella Burnetii ◽  
Actin Filaments ◽  
Defense Mechanism ◽  
Host Cells ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Microbicidal Activity ◽  
Mediators Of Inflammation

ABSTRACTMast cells (MCs) are critical mediators of inflammation; however, their microbicidal activity against invading pathogens remains largely unknown. Here, we describe a nonpreviously reported antibacterial mechanism used by MCs againstCoxiella burnetii, the agent of Q fever. We show thatC. burnetiiinteraction with MCs does not result in bacterial uptake but rather induces the formation of extracellular actin filaments named cytonemes. MC cytonemes express cathelicidin and neutrophil elastase and mediate the capture and destruction of entrapped bacteria. We provide evidence that MC cytoneme formation and microbicidal activity are dependent on the cooperation of the scavenger receptor CD36 and Toll-like receptor 4. Taken together, our results suggest that MCs use an extracellular sophisticated mechanism of defense to eliminate intracellular pathogens, such asC. burnetii, before their entry into host cells.IMPORTANCEMast cells (MCs) are found in tissues that are in close contact with external environment, such as skin, lungs, or intestinal mucosa but also in the placenta during pregnancy. If their role in mediating allergic conditions is established, several studies now highlight their importance during infection with extracellular pathogens. This study showed a new and effective antimicrobial mechanism of MCs againstCoxiella burnetii, an intracellular bacterium whose infection during pregnancy is associated with abortion, preterm labor, and stillbirth. The data reveal that in response toC. burnetii, MCs release extracellular actin filaments that contain antimicrobial agents and are capable to trap and kill bacteria. We show that this mechanism is dependent on the cooperation of two membrane receptors, CD36 and Toll-like receptor 4, and may occur in the placenta during pregnancy by usingex vivoplacental MCs. Overall, this study reports an unexpected role for MCs during infection with intracellular bacteria and suggests that MC response toC. burnetiiinfection is a protective defense mechanism during pregnancy.

scholarly journals Sheltering Effect and Indirect Pathogenesis of Carbapenem-Resistant Acinetobacter baumannii in Polymicrobial Infection

2014 ◽  
Vol 58 (7) ◽  
pp. 3983-3990 ◽  
Author(s):  
Yu-Ting Liao ◽  
Shu-Chen Kuo ◽  
Yi-Tzu Lee ◽  
Chien-Pei Chen ◽  
Shu-Wen Lin ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Defense Mechanism ◽  
Polymicrobial Infection ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Self Defense ◽  
Class D ◽  
Extracellular Release ◽  
Monomicrobial Infection ◽  
Sheltering Effect

ABSTRACTThe role of carbapenem-resistantAcinetobacter baumannii(CRAb) in polymicrobial infection remains elusive. Having observed the ability of CRAb to shelter other susceptible bacteria from carbapenem killing, we sought to determine the factors contributing to this sheltering effect by transforming different recombinant plasmids into recipientA. baumanniicells. The sheltering effects of CRAb were reproduced in recipientA. baumanniicells that highly expressed carbapenem-hydrolyzing class D β-lactamases (CHDLs) through their associated strong promoter. With the use of Western blot analysis and a bioassay, the highly expressed CHDLs were found to be extracellularly released and led to hydrolysis of carbapenem. The level of extracellular CHDLs increased after challenge with a higher concentration of CHDL substrates, such as carbapenem and ticarcillin. This increased CHDL may, in part, be attributed to cell lysis, as indicated by the presence of extracellular gyrase. In the planktonic condition, the sheltering effect for the cocultured susceptible bacteria might represent an indirect and passive effect of the CRAb self-defense mechanism, because coculture with the susceptible pathogen did not augment the amount of the extracellular CHDLs. Polymicrobial infection caused by CRAb and a susceptible counterpart exerted higher pathogenicity than monomicrobial infection caused by either pathogen alone in mice receiving carbapenem therapy. This study demonstrated that CHDL-producing CRAb appears to provide a sheltering effect for carbapenem-susceptible pathogens via the extracellular release of CHDLs and, by this mechanism, can enhance the pathogenesis of polymicrobial infection in the presence of carbapenem therapy.

scholarly journals Endotoxin-Induced Gamma Interferon Production: Contributing Cell Types and Key Regulatory Factors

2002 ◽  
Vol 9 (3) ◽  
pp. 530-543 ◽  
Author(s):  
Tushar K. Varma ◽  
Cheng Y. Lin ◽  
Tracy E. Toliver-Kinsky ◽  
Edward R. Sherwood
Keyword(s):  
Nk Cells ◽  
Cell Types ◽  
Nkt Cells ◽  
Gamma Interferon ◽  
Mouse Spleen ◽  
Interleukin 12 ◽  
Specific Cell ◽  
Regulatory Factors ◽  
Lps Challenge ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ) is an important mediator of endotoxin (lipopolysaccharide [LPS])-induced immune responses. However, the specific cell types that produce IFN-γ in response to LPS and the cellular factors that regulate LPS-induced IFN-γ production have not been fully determined. The present studies were undertaken to characterize the cell populations that produce IFN-γ after LPS challenge in the spleens of mice and to determine the regulatory factors that modulate LPS-induced production of IFN-γ. Our studies show that the levels of splenic IFN-γ mRNA and protein production peak at 6 and 8 h, respectively, after systemic LPS challenge. Approximately 60% of IFN-γ-producing cells are natural killer (NK) cells (CD3−DX5+) and 25% are NKT cells (CD3+DX5+). Most of the remaining IFN-γ-producing cells are T cells (CD3+DX5−), macrophages, and dendritic cells. Functionally, interleukin-12 (IL-12) is the major IFN-γ-stimulating factor after LPS challenge, with costimulation provided by IL-15, IL-18, and B7 proteins. IL-10 is a major inhibitor of LPS-induced IFN-γ production. Unlike intact heat-killed gram-negative and gram-positive bacteria, the class II major histocompatibility complex did not play a functional role in LPS-induced IFN-γ production. LPS is a potent stimulus for splenic IL-10, IL-12 p40, and IL-15 mRNA expression, whereas IL-12 p35 and IL-18 mRNAs, as well as B7 proteins, are constitutively expressed in the mouse spleen. Of the factors studied, IL-18 serves as the most potent costimulus with IL-12 for IFN-γ production, followed by IL-15 and B7 proteins. These data demonstrate that NK cells and NKT cells are the most abundant IFN-γ-producing cells in the mouse spleen after LPS challenge and that IL-10 and IL-12 are key functional regulators of LPS-induced IFN-γ production.

Altered oxidative stress markers in relation to T cells, NK cells & killer immunoglobulin receptors that are associated with disease activity in SLE patients

Lupus ◽  
2020 ◽  
Vol 29 (14) ◽  
pp. 1831-1844
Author(s):  
Ankit Tandon ◽  
Kumari Anupam ◽  
Jyotsana Kaushal ◽  
Preeti Gautam ◽  
Aman Sharma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nk Cells ◽  
Lupus Erythematosus ◽  
Defense Mechanism ◽  
Nk Cell ◽  
Cell Types ◽  
Stress Markers ◽  
Organ Systems ◽  
The Relationship ◽  
Immunoglobulin Receptors

Systemic Lupus Erythematosus is an autoimmune disease with symptoms pervasive to all organ systems. It affects more females as compared to males (in the ratio 9:1). Oxidative stress plays a major role in the pathogenesis of SLE and other autoimmune diseases. In order to understand the relationship between cell specific oxidative stress and the severity of SLE, this research study involving the estimation of intracellular ROS accumulation in T and NK cell was conducted on SLE patients of North Indian Population. At the same time, to estimate anti-oxidant defense, Keap1 and Nrf2 levels were estimated in these cell types. The relationship between the expression of Killer immunoglobulin receptors i.e., KIR2DL4 & KIR3DL1 and oxidative stress was also evaluated as these receptors are imperative for the function and self-tolerance of NK cells. Oxidative stress was raised along with Keap1 and Nrf2 in T and NK cell subsets in SLE patients. The expression of KIR2DL4 was raised and that of KIR3DL1 was reduced in the NK cells of patients. The intensity of change in expression and its significance varied among the subsets. Nrf2 expression was raised in these species against oxidative stress as the antioxidant defense mechanism pertaining to Keap1-Nrf2 pathway, but the adequacy of response needs to be understood in further studies. The expression of KIR2DL4 and KIR3DL1 varied among the patient and healthy controls and the expression of the latter was found to have a significant positive relationship with plasma Glutathione(reduced) concentration.

scholarly journals Super-resolution imaging of remodeled synaptic actin reveals different synergies between NK cell receptors and integrins

Blood ◽  
2012 ◽  
Vol 120 (18) ◽  
pp. 3729-3740 ◽  
Author(s):  
Alice C. N. Brown ◽  
Ian M. Dobbie ◽  
Juha-Matti Alakoskela ◽  
Ilan Davis ◽  
Daniel M. Davis
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Three Dimensional ◽  
Super Resolution ◽  
Cortical Actin ◽  
Cell Receptors ◽  
Lytic Granules ◽  
Nk Cell Receptors ◽  
Activating Receptors ◽  
Ifn Γ

Abstract Natural killer (NK) cells secrete lytic granules to directly kill virus-infected or transformed cells and secrete cytokines to communicate with other cells. Three-dimensional super-resolved images of F-actin, lytic granules, and IFN-γ in primary human NK cells stimulated through different activating receptors reveal that both IFN-γ and lytic granules accumulated in domains where the periodicity of the cortical actin mesh at the synapse opened up to be penetrable. Ligation of some activating receptors alone (eg, CD16 or NKG2D) was sufficient to increase the periodicity of the actin mesh, but surprisingly, ligation of others (eg, NKp46 or CD2) was not sufficient to induce cortical actin remodeling unless LFA-1 was coligated. Importantly, influenza virus particles that can be recognized by NK cells similarly did not open the actin mesh but could if LFA-1 was coligated. This leads us to propose that immune cells using germline-encoded receptors to directly recognize foreign proteins can use integrin recognition to differentiate between free pathogens and pathogen-infected cells that will both be present in blood. This distinction would not be required for NK cell receptors, such as NKG2D, which recognize host cell–encoded proteins that can only be found on diseased cells and not pathogens.

scholarly journals Subdiffraction-resolution fluorescence imaging of immunological synapse formation between NK cells and A. fumigatus by expansion microscopy

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nora Trinks ◽  
Sebastian Reinhard ◽  
Matthias Drobny ◽  
Linda Heilig ◽  
Jürgen Löffler ◽  
...  
Keyword(s):  
Nk Cells ◽  
Fluorescence Imaging ◽  
Synapse Formation ◽  
Immunological Synapse ◽  
Nk Cell ◽  
Super Resolution ◽  
Cell Types ◽  
Lytic Granules ◽  
Isotropic Expansion ◽  
Confocal Fluorescence Imaging

AbstractExpansion microscopy (ExM) enables super-resolution fluorescence imaging on standard microscopes by physical expansion of the sample. However, the investigation of interactions between different organisms such as mammalian and fungal cells by ExM remains challenging because different cell types require different expansion protocols to ensure identical, ideally isotropic expansion of both partners. Here, we introduce an ExM method that enables super-resolved visualization of the interaction between NK cells and Aspergillus fumigatus hyphae. 4-fold expansion in combination with confocal fluorescence imaging allows us to resolve details of cytoskeleton rearrangement as well as NK cells’ lytic granules triggered by contact with an RFP-expressing A. fumigatus strain. In particular, subdiffraction-resolution images show polarized degranulation upon contact formation and the presence of LAMP1 surrounding perforin at the NK cell-surface post degranulation. Our data demonstrate that optimized ExM protocols enable the investigation of immunological synapse formation between two different species with so far unmatched spatial resolution.

Modulation of Immune Cell Responses by Human Mesenchymal Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1288-1288 ◽  
Author(s):  
Sudeepta Aggarwal ◽  
Mark F. Pittenger
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Dendritic Cells ◽  
Cell Surface ◽  
Nk Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Human Mscs ◽  
Ifn Γ

Abstract Mesenchymal stem cells (hMSCs) are multipotent stem cells that have the capacity to differentiate into various lineages. These cells provide stromal support and can be utilized as a feeder layer for expansion of hematopoitic stem cells and embryonic stem cells. Furthermore, allo-transplanted MSCs are not rejected and have been shown to mediate immuno-modulatory functions in vitro. Also, MSCs have been found at the wound site at extended times. The mechanisms underlying MSC migration and immuno-modulation are still under investigation. Aim: To understand the factors involved in human MSC (hMSC) migration and their interaction with various immune cell types. Methods: Human MSCs were examined for the presence of cell surface receptors that may play a role in migration using quantitative RT-PCR. Next, hMSCs were co-cultured with purified immune cell types including dendritic cells (DCs), naïve T cells and NK cells. Following the co-culture, changes in the phenotype of the immune cells under activating conditions were analyzed using ELISA and functional assays. Results: Human MSCs express Toll receptors, especially TLR4, on their cell surface. The TLR4 on hMSCs is functional as seen by a several-fold increase in IL-6 and chemokine IL-8 upon incubation with TLR4 exogenous ligand lipopolysaccharide (LPS) and the endogenous ligand, soluble hyaluronic acid (sHA). When hMSCs were incubated with activated dendritic cells, there was a >50% decrease in TNF-α secretion and a >50% increase in IL-10 secretion. When hMSCs were incubated with naïve T cells, hMSCs decreased IFN-γ secretion and increased IL-4 secretion. Decreased IFN-γ was also seen when MSCs were incubated with NK cells. Conclusion: These results suggest that (i) hMSCs may respond to the signals generated by breakdown products of extracellular matrix (e.g. sHA) via TLR4 and assist in wound healing (ii) hMSCs immuno-modulatory effects are mediated by interacting with various immune cell types and altering their phenotypic response to a more tolerant and anti-inflammatory response.

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