scholarly journals The Immune Phenotype of Three Drosophila Leukemia Models

2017 ◽  
Vol 7 (7) ◽  
pp. 2139-2149 ◽  
Author(s):  
Badrul Arefin ◽  
Martin Kunc ◽  
Robert Krautz ◽  
Ulrich Theopold
Keyword(s):  
Immune System ◽  
Tumor Suppressors ◽  
Natural Infection ◽  
Fruit Fly ◽  
Innate Immune ◽  
Infection Model ◽  
Tissue Formation ◽  
Wild Type ◽  
Behavioral Abnormalities ◽  
Drosophila Models

Abstract Many leukemia patients suffer from dysregulation of their immune system, making them more susceptible to infections and leading to general weakening (cachexia). Both adaptive and innate immunity are affected. The fruit fly Drosophila melanogaster has an innate immune system, including cells of the myeloid lineage (hemocytes). To study Drosophila immunity and physiology during leukemia, we established three models by driving expression of a dominant-active version of the Ras oncogene (RasV12) alone or combined with knockdowns of tumor suppressors in Drosophila hemocytes. Our results show that phagocytosis, hemocyte migration to wound sites, wound sealing, and survival upon bacterial infection of leukemic lines are similar to wild type. We find that in all leukemic models the two major immune pathways (Toll and Imd) are dysregulated. Toll–dependent signaling is activated to comparable extents as after wounding wild-type larvae, leading to a proinflammatory status. In contrast, Imd signaling is suppressed. Finally, we notice that adult tissue formation is blocked and degradation of cell masses during metamorphosis of leukemic lines, which is akin to the state of cancer-dependent cachexia. To further analyze the immune competence of leukemic lines, we used a natural infection model that involves insect-pathogenic nematodes. We identified two leukemic lines that were sensitive to nematode infections. Further characterization demonstrates that despite the absence of behavioral abnormalities at the larval stage, leukemic larvae show reduced locomotion in the presence of nematodes. Taken together, this work establishes new Drosophila models to study the physiological, immunological, and behavioral consequences of various forms of leukemia.

A Critical Role for Innate Immunity In Allogeneic Hematopoietic Cell Rejection Via the TLR4/TRIF Pathway

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 77-77
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Yiming Huang ◽  
Yujie Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Critical Role ◽  
Innate Immune ◽  
Wild Type

Abstract Abstract 77 Adaptive immunity, especially T cells, has long been believed to be the dominant immune barrier in allogeneic transplantation. Targeting host T cells significantly reduces conditioning for bone marrow cell (BMC) engraftment. Innate immunity has been recently shown to pose a significant barrier in solid organ transplantation, but has not been addressed in bone marrow transplantation (BMT). Using T cell deficient (TCR-β/δ−/−) or T and B cell deficient (Rag−/−) mice, we found that allogeneic BMC rejection occurred early before the time required for T cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. Therefore, we hypothesized that by controlling both innate and adaptive immunity, the donor BMC would have a window of advantage to engraft. Survival of BMC in vivo was significantly improved by depleting recipient macrophages and/or NK cells, but not neutrophils. Moreover, depletion of macrophages and NK cells in combination with co-stimulatory blockade with anti-CD154 and rapamycin as a novel form of conditioning resulted in 100% allogeneic engraftment without any irradiation and T cell depletion. Donor chimerism remained stable and durable up to 6 months. Moreover, specific Vβ5½ and Vβ11 clonal deletion was detected in host CD4+ T cells in chimeras, indicating central tolerance to donor alloantigens. Whether and how the innate immune system recognizes or responds to allogeneic BMCs remains unknown. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. The signaling function of TLR depends on intracellular adaptors. The adaptor MyD88 transmits signals emanating from all TLR, except TLR3 while TRIF specifically mediates TLR3 and TLR4 signaling via type 1 IFN. To further determine the innate signaling pathways in allogeneic BMC rejection, B6 background (H2b) MyD88−/− and TRIF−/− mice were conditioned with anti-CD154/rapamycin plus 100 cGy total body irradiation and transplanted with 15 × 106 BALB/c (H2d) BMC. Only 33.3% of MyD88−/− recipients engrafted at 1 month, resembling outcomes for wild-type B6 mice. In contrast, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month, significantly higher than in MyD88−/− and wild-type B6 controls (P < 0.005). To determine the mechanism of innate signaling in BMC rejection, we examined whether TRIF linked TLR3 or TLR4 is the key pattern recognition receptor involved in BMC recognition. To this end, TLR3−/− and TLR4−/− mice were transplanted with BALB/c BMC with same conditioning. None of the TLR3−/− mice engrafted. In contrast, engraftment was achieved in 100% of TLR4−/− mice up to 6 months follow up. Taken together, these results suggest that rejection of allogeneic BMC is uniquely dependent on the TLR4/TRIF signaling pathway. Thus, our results clearly demonstrate a previously unappreciated role for innate immunity in allogeneic BMC rejection. Our current findings are distinct from prior reports demonstrating a critical role of MyD88 in rejection of allogeneic skin grafts and lung, and may reflect unique features related to BMC. The findings of the role of innate immunity in BMC rejection would lead to revolutionary changes in our understanding and management of BMT. This would be informative in design of more specific innate immune targeted conditioning proposals in BMT to avoid the toxicity. Disclosures: Bozulic: Regenerex LLC: Employment. Ildstad:Regenerex LLC: Equity Ownership.

scholarly journals A Chemokine-Degrading Extracellular Protease Made by Group A Streptococcus Alters Pathogenesis by Enhancing Evasion of the Innate Immune Response

2008 ◽  
Vol 76 (3) ◽  
pp. 978-985 ◽  
Author(s):  
Paul Sumby ◽  
Shizhen Zhang ◽  
Adeline R. Whitney ◽  
Fabiana Falugi ◽  
Guido Grandi ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Group A Streptococcus ◽  
Cell Envelope ◽  
Innate Immune ◽  
Infection Model ◽  
Dependent Manner ◽  
Wild Type ◽  
Group A

ABSTRACT Circumvention of the host innate immune response is critical for bacterial pathogens to infect and cause disease. Here we demonstrate that the group A Streptococcus (GAS; Streptococcus pyogenes) protease SpyCEP (S. pyogenes cell envelope protease) cleaves granulocyte chemotactic protein 2 (GCP-2) and growth-related oncogene alpha (GROα), two potent chemokines made abundantly in human tonsils. Cleavage of GCP-2 and GROα by SpyCEP abrogated their abilities to prime neutrophils for activation, detrimentally altering the innate immune response. SpyCEP expression is negatively regulated by the signal transduction system CovR/S. Purified recombinant CovR bound the spyCEP gene promoter region in vitro, indicating direct regulation. Immunoreactive SpyCEP protein was present in the culture supernatants of covR/S mutant GAS strains but not in supernatants from wild-type strains. However, wild-type GAS strains do express SpyCEP, where it is localized to the cell wall. Strain MGAS2221, an organism representative of the highly virulent and globally disseminated M1T1 GAS clone, differed significantly from its isogenic spyCEP mutant derivative strain in a mouse soft tissue infection model. Interestingly, and in contrast to previous studies, the isogenic mutant strain generated lesions of larger size than those formed following infection with the parent strain. The data indicate that SpyCEP contributes to GAS virulence in a strain- and disease-dependent manner.

Streptozotocin induced oxidative stress, innate immune system responses and behavioral abnormalities in male mice

Neuroscience ◽  
2017 ◽  
Vol 340 ◽  
pp. 373-383 ◽  
Author(s):  
Shayan Amiri ◽  
Arya Haj-Mirzaian ◽  
Majid Momeny ◽  
Hossein Amini-Khoei ◽  
Maryam Rahimi-Balaei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune System ◽  
Innate Immune System ◽  
Innate Immune ◽  
Male Mice ◽  
Behavioral Abnormalities

scholarly journals β-(1,3)-Glucan Unmasking in Some Candida albicans Mutants Correlates with Increases in Cell Wall Surface Roughness and Decreases in Cell Wall Elasticity

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Sahar Hasim ◽  
David P. Allison ◽  
Scott T. Retterer ◽  
Alex Hopke ◽  
Robert T. Wheeler ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Immune System ◽  
Innate Immune System ◽  
Fungal Infections ◽  
Innate Immune ◽  
Surface Topology ◽  
Wild Type ◽  
Content Type ◽  
Cell Wall Elasticity

ABSTRACT Candida albicans is among the most common human fungal pathogens, causing a broad range of infections, including life-threatening systemic infections. The cell wall of C. albicans is the interface between the fungus and the innate immune system. The cell wall is composed of an outer layer enriched in mannosylated glycoproteins (mannan) and an inner layer enriched in β-(1,3)-glucan and chitin. Detection of C. albicans by Dectin-1, a C-type signaling lectin specific for β-(1,3)-glucan, is important for the innate immune system to recognize systemic fungal infections. Increased exposure of β-(1,3)-glucan to the immune system occurs when the mannan layer is altered or removed in a process called unmasking. Nanoscale changes to the cell wall during unmasking were explored in live cells with atomic force microscopy (AFM). Two mutants, the cho1Δ/Δ and kre5Δ/Δ mutants, were selected as representatives that exhibit modest and strong unmasking, respectively. Comparisons of the cho1Δ/Δ and kre5Δ/Δ mutants to the wild type reveal morphological changes in their cell walls that correlate with decreases in cell wall elasticity. In addition, AFM tips functionalized with Dectin-1 revealed that the forces of binding of Dectin-1 to all of the strains were similar, but the frequency of binding was highest for the kre5Δ/Δ mutant, decreased for the cho1Δ/Δ mutant, and rare for the wild type. These data show that nanoscale changes in surface topology are correlated with increased Dectin-1 adhesion and decreased cell wall elasticity. AFM, using tips functionalized with immunologically relevant molecules, can map epitopes of the cell wall and increase our understanding of pathogen recognition by the immune system.

Changes in the microbiota cause genetically modified Anopheles to spread in a population

Science ◽  
2017 ◽  
Vol 357 (6358) ◽  
pp. 1396-1399 ◽  
Author(s):  
Andrew Pike ◽  
Yuemei Dong ◽  
Nahid Borhani Dizaji ◽  
Anthony Gacita ◽  
Emmanuel F. Mongodin ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Bacterial Infections ◽  
Genetically Modified ◽  
Reproductive Organs ◽  
Innate Immune ◽  
Wild Type ◽  
Immune Genes ◽  
Cage Population ◽  
Genetically Modified Mosquitoes

The mosquito’s innate immune system controls both Plasmodium and bacterial infections. We investigated the competitiveness of mosquitoes genetically modified to alter expression of their own anti-Plasmodium immune genes in a mixed-cage population with wild-type mosquitoes. We observed that genetically modified mosquitoes with increased immune activity in the midgut tissue did not have an observed fitness disadvantage and showed reduced microbial loads in both the midgut and reproductive organs. These changes result in a mating preference of genetically modified males for wild-type females, whereas wild-type males prefer genetically modified females. These changes foster the spread of the genetic modification in a mosquito cage population.

scholarly journals Activation of the Innate Immune System by Treponema denticola Periplasmic Flagella through Toll-Like Receptor 2

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
John Ruby ◽  
Michael Martin ◽  
Michael J. Passineau ◽  
Valentina Godovikova ◽  
J. Christopher Fenno ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Innate Immune ◽  
Treponema Denticola ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Content Type ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Periplasmic Flagella

ABSTRACTTreponema denticolais an indigenous oral spirochete that inhabits the gingival sulcus or periodontal pocket. Increased numbers of oral treponemes within this environment are associated with localized periodontal inflammation, and they are also part of an anaerobic polymicrobial consortium responsible for endodontic infections. Previous studies have indicated thatT. denticolastimulates the innate immune system through Toll-like receptor 2 (TLR2); however, the pathogen-associated molecular patterns (PAMPs) responsible forT. denticolaactivation of the innate immune system are currently not well defined. In this study, we investigated the role played byT. denticolaperiplasmic flagella (PF), unique motility organelles of spirochetes, in stimulating an innate immune response. Wild-typeT. denticolastimulated the production of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-12 by monocytes from human peripheral blood mononuclear cells, while its isogenic nonmotile mutant lacking PF resulted in significantly diminished cytokine stimulation. In addition, highly purified PF were able to dose dependently stimulate cytokine TNF-α, IL-1β, IL-6, IL-10, and IL-12 production in human monocytes. Wild-typeT. denticolaand the purified PF triggered activation of NF-κB through TLR2, as determined using a variety of TLR-transfected human embryonic 293 cell lines, while the PF-deficient mutants lacked the ability to stimulate, and the complemented PF-positiveT. denticolastrain restored the activation. These findings suggest thatT. denticolastimulates the innate immune system in a TLR2-dependent fashion and that PF are a key bacterial component involved in this process.

Toll-like receptor 7 deficiency promotes survival and reduces adverse left ventricular remodelling after myocardial infarction

2019 ◽  
Vol 115 (12) ◽  
pp. 1791-1803 ◽  
Author(s):  
Dominique P V de Kleijn ◽  
Suet Yen Chong ◽  
Xiaoyuan Wang ◽  
Siti Maryam J M Yatim ◽  
Anna-Marie Fairhurst ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Immune System ◽  
Cardiac Function ◽  
Innate Immune System ◽  
Left Ventricular ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Ventricular Remodelling ◽  
Left Ventricular Remodelling

Abstract Aims The Toll-like receptor 7 (TLR7) is an intracellular innate immune receptor activated by nucleic acids shed from dying cells leading to activation of the innate immune system. Since innate immune system activation is involved in the response to myocardial infarction (MI), this study aims to identify if TLR7 is involved in post-MI ischaemic injury and adverse remodelling after MI. Methods and results TLR7 involvement in MI was investigated in human tissue from patients with ischaemic heart failure, as well as in a mouse model of permanent left anterior descending artery occlusion in C57BL/6J wild type and TLR7 deficient (TLR7−/−) mice. TLR7 expression was up-regulated in human and mouse ischaemic myocardium after MI. Compared to wild type mice, TLR7−/− mice had less acute cardiac rupture associated with blunted activation of matrix metalloproteinase 2, increased expression of tissue inhibitor of metalloproteinase 1, recruitment of more myofibroblasts, and the formation of a myocardial scar with higher collagen fibre density. Furthermore, inflammatory cell influx and inflammatory cytokine expression post-MI were reduced in the TLR7−/− heart. During a 28-day follow-up after MI, TLR7 deficiency resulted in less chronic adverse left ventricular remodelling and better cardiac function. Bone marrow (BM) transplantation experiments showed that TLR7 deficiency in BM-derived cells preserved cardiac function after MI. Conclusions In acute MI, TLR7 mediates the response to acute cardiac injury and chronic remodelling probably via modulation of post-MI scar formation and BM-derived inflammatory infiltration of the myocardium.

scholarly journals Interleukin-15 and NK1.1+ Cells Provide Innate Protection against Acute Salmonella enterica Serovar Typhimurium Infection in the Gut and in Systemic Tissues

2008 ◽  
Vol 77 (1) ◽  
pp. 214-222 ◽  
Author(s):  
Ali A. Ashkar ◽  
Sarah Reid ◽  
Elena F. Verdu ◽  
Kun Zhang ◽  
Brian K. Coombes
Keyword(s):  
Immune System ◽  
Salmonella Enterica ◽  
Bacterial Colonization ◽  
Reticuloendothelial System ◽  
Immune Defense ◽  
Innate Immune ◽  
Wild Type ◽  
Serovar Typhimurium ◽  
Interleukin 15

ABSTRACT Control of bacterial colonization at mucosal surfaces depends on rapid activation of the innate immune system. Interleukin-15 (IL-15) directs the development, maturation, and function of a population of cells positive for NK1.1, such as natural killer (NK) cells, which are critical components of the innate immune defense against several viral and bacterial pathogens. Using IL-15-deficient mice, in vivo depletion of NK1.1+ cells from wild-type mice, and in vivo overexpression of IL-15 from a recombinant adenovirus, we tested the role of IL-15 and NK1.1+ cells in innate protection of the murine gut and reticuloendothelial system from Salmonella enterica serovar Typhimurium infection. IL-15 and the NK1.1+ cell population provided innate protection from serovar Typhimurium in mice at the enteric mucosae and in the reticuloendothelial system during murine typhoid. Interestingly, serovar Typhimurium extensively colonized the gut of IL-15−/− mice and wild-type C57BL/6 mice depleted of NK1.1+ cells prior to infection, even though the animals were not pretreated with antibiotics to reduce colonization resistance and there was an absence of overt inflammation in the colon and cecum. Enhanced dissemination of Salmonella from the gut of mice depleted of NK1.1+ cells correlated with a localized disruption of IL-17 in the colon. These data suggest a relationship between the gut ecosystem and the innate mucosal immune system, which may be linked via IL-15 and NK1.1+ cells.

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