Browsing by Subject "Interferon-gamma"

Now showing 1 - 11 of 11
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    Cell type- and species-specific host responses to Toxoplasma gondii and its near relatives.
    (International journal for parasitology, 2020-05-11) Wong, Zhee S; Borrelli, Sarah L Sokol; Coyne, Carolyn C; Boyle, Jon P
    Toxoplasma gondii is remarkably unique in its ability to successfully infect vertebrate hosts from multiple phyla and can successfully infect most cells within these organisms. The infection outcome in each of these species is determined by the complex interaction between parasite and host genotype. As techniques to quantify global changes in cell function become more readily available and precise, new data are coming to light about how (i) different host cell types respond to parasitic infection and (ii) different parasite species impact the host. Here we focus on recent studies comparing the response to intracellular parasitism by different cell types and insights into understanding host-parasite interactions from comparative studies on T. gondii and its close extant relatives.
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    Chiropteran types I and II interferon genes inferred from genome sequencing traces by a statistical gene-family assembler.
    (BMC Genomics, 2010-07-21) Kepler, Thomas B; Sample, Christopher; Hudak, Kathryn; Roach, Jeffrey; Haines, Albert; Walsh, Allyson; Ramsburg, Elizabeth A
    BACKGROUND: The rate of emergence of human pathogens is steadily increasing; most of these novel agents originate in wildlife. Bats, remarkably, are the natural reservoirs of many of the most pathogenic viruses in humans. There are two bat genome projects currently underway, a circumstance that promises to speed the discovery host factors important in the coevolution of bats with their viruses. These genomes, however, are not yet assembled and one of them will provide only low coverage, making the inference of most genes of immunological interest error-prone. Many more wildlife genome projects are underway and intend to provide only shallow coverage. RESULTS: We have developed a statistical method for the assembly of gene families from partial genomes. The method takes full advantage of the quality scores generated by base-calling software, incorporating them into a complete probabilistic error model, to overcome the limitation inherent in the inference of gene family members from partial sequence information. We validated the method by inferring the human IFNA genes from the genome trace archives, and used it to infer 61 type-I interferon genes, and single type-II interferon genes in the bats Pteropus vampyrus and Myotis lucifugus. We confirmed our inferences by direct cloning and sequencing of IFNA, IFNB, IFND, and IFNK in P. vampyrus, and by demonstrating transcription of some of the inferred genes by known interferon-inducing stimuli. CONCLUSION: The statistical trace assembler described here provides a reliable method for extracting information from the many available and forthcoming partial or shallow genome sequencing projects, thereby facilitating the study of a wider variety of organisms with ecological and biomedical significance to humans than would otherwise be possible.
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    Chlamydia trachomatis-infected cells and uninfected-bystander cells exhibit diametrically opposed responses to interferon gamma.
    (Scientific reports, 2018-05) Ibana, Joyce A; Sherchand, Shardulendra P; Fontanilla, Francis L; Nagamatsu, Takeshi; Schust, Danny J; Quayle, Alison J; Aiyar, Ashok
    The intracellular bacterial pathogen, Chlamydia trachomatis, is a tryptophan auxotroph. Therefore, induction of the host tryptophan catabolizing enzyme, indoleamine-2,3-dioxgenase-1 (IDO1), by interferon gamma (IFNγ) is one of the primary protective responses against chlamydial infection. However, despite the presence of a robust IFNγ response, active and replicating C. trachomatis can be detected in cervical secretions of women. We hypothesized that a primary C. trachomatis infection may evade the IFNγ response, and that the protective effect of this cytokine results from its activation of tryptophan catabolism in bystander cells. To test this hypothesis, we developed a novel method to separate a pool of cells exposed to C. trachomatis into pure populations of live infected and bystander cells and applied this technique to distinguish between the effects of IFNγ on infected and bystander cells. Our findings revealed that the protective induction of IDO1 is suppressed specifically within primary infected cells because Chlamydia attenuates the nuclear import of activated STAT1 following IFNγ exposure, without affecting STAT1 levels or phosphorylation. Critically, the IFNγ-mediated induction of IDO1 activity is unhindered in bystander cells. Therefore, the IDO1-mediated tryptophan catabolism is functional in these cells, transforming these bystander cells into inhospitable hosts for a secondary C. trachomatis infection.
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    Cryopreserved Mesenchymal Stromal Cells Are Susceptible to T-Cell Mediated Apoptosis Which Is Partly Rescued by IFNγ Licensing.
    (Stem cells (Dayton, Ohio), 2016-09) Chinnadurai, Raghavan; Copland, Ian B; Garcia, Marco A; Petersen, Christopher T; Lewis, Christopher N; Waller, Edmund K; Kirk, Allan D; Galipeau, Jacques
    We have previously demonstrated that cryopreservation and thawing lead to altered Mesenchymal stromal cells (MSC) functionalities. Here, we further analyzed MSC's fitness post freeze-thaw. We have observed that thawed MSC can suppress T-cell proliferation when separated from them by transwell membrane and the effect is lost in a MSC:T-cell coculture system. Unlike actively growing MSCs, thawed MSCs were lysed upon coculture with activated autologous Peripheral Blood Mononuclear Cells (PBMCs) and the lysing effect was further enhanced with allogeneic PBMCs. The use of DMSO-free cryoprotectants or substitution of Human Serum Albumin (HSA) with human platelet lysate in freezing media and use of autophagy or caspase inhibitors did not prevent thaw defects. We tested the hypothesis that IFNγ prelicensing before cryobanking can enhance MSC fitness post thaw. Post thawing, IFNγ licensed MSCs inhibit T cell proliferation as well as fresh MSCs and this effect can be blocked by 1-methyl Tryptophan, an Indoleamine 2,3-dioxygenase (IDO) inhibitor. In addition, IFNγ prelicensed thawed MSCs inhibit the degranulation of cytotoxic T cells while IFNγ unlicensed thawed MSCs failed to do so. However, IFNγ prelicensed thawed MSCs do not deploy lung tropism in vivo following intravenous injection as well as fresh MSCs suggesting that IFNγ prelicensing does not fully rescue thaw-induced lung homing defect. We identified reversible and irreversible cryoinjury mechanisms that result in susceptibility to host T-cell cytolysis and affect MSC's cell survival and tissue distribution. The susceptibility of MSC to negative effects of cryopreservation and the potential to mitigate the effects with IFNγ prelicensing may inform strategies to enhance the therapeutic efficacy of MSC in clinical use. Stem Cells 2016;34:2429-2442.
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    Cytokine profiles of preterm neonates with fungal and bacterial sepsis.
    (Pediatr Res, 2012-08) Sood, Beena G; Shankaran, Seetha; Schelonka, Robert L; Saha, Shampa; Benjamin, Danny K; Sánchez, Pablo J; Adams-Chapman, Ira; Stoll, Barbara J; Thorsen, Poul; Skogstrand, Kristin; Ehrenkranz, Richard A; Hougaard, David M; Goldberg, Ronald N; Tyson, Jon E; Das, Abhik; Higgins, Rosemary D; Carlo, Waldemar A; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
    BACKGROUND: Information on cytokine profiles in fungal sepsis (FS), an important cause of mortality in extremely low birthweight (ELBW) infants, is lacking. We hypothesized that cytokine profiles in the first 21 d of life in ELBW infants with FS differ from those with bacterial sepsis (BS) or no sepsis (NS). METHODS: In a secondary analysis of the National Institute of Child Health and Human Development Cytokine study, three groups were defined-FS (≥1 episode of FS), BS (≥1 episode of BS without FS), and NS. Association between 11 cytokines assayed in dried blood spots obtained on days 0-1, 3 ± 1, 7 ± 2, 14 ± 3, and 21 ± 3 and sepsis group was explored. RESULTS: Of 1,066 infants, 89 had FS and 368 had BS. As compared with BS, FS was more likely to be associated with lower birthweight, vaginal delivery, patent ductus arteriosus, postnatal steroids, multiple central lines, longer respiratory support and hospital stay, and higher mortality (P < 0.05). Analyses controlling for covariates showed significant group differences over time for interferon-γ (IFN-γ), interleukin (IL)-10, IL-18, transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) (P < 0.05). CONCLUSION: Significant differences in profiles for IFN-γ, IL-10, IL-18, TGF-β, and TNF-α in FS, BS, or NS in this hypothesis-generating secondary study require validation in rigorously designed prospective studies and may have implications for diagnosis and treatment.
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    Differential inhibition of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and TZM-bl cells by endotoxin-mediated chemokine and gamma interferon production.
    (AIDS Res Hum Retroviruses, 2010-03) Geonnotti, Anthony R; Bilska, Miroslawa; Yuan, Xing; Ochsenbauer, Christina; Edmonds, Tara G; Kappes, John C; Liao, Hua-Xin; Haynes, Barton F; Montefiori, David C
    Bacterial lipopolysaccharide (endotoxin) is a frequent contaminant of biological specimens and is also known to be a potent inducer of beta-chemokines and other soluble factors that inhibit HIV-1 infection in vitro. Though lipopolysaccharide (LPS) has been shown to stimulate the production of soluble HIV-1 inhibitors in cultures of monocyte-derived macrophages, the ability of LPS to induce similar inhibitors in other cell types is poorly characterized. Here we show that LPS exhibits potent anti-HIV activity in phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMCs) but has no detectable anti-HIV-1 activity in TZM-bl cells. The anti-HIV-1 activity of LPS in PBMCs was strongly associated with the production of beta-chemokines from CD14-positive monocytes. Culture supernatants from LPS-stimulated PBMCs exhibited potent anti-HIV-1 activity when added to TZM-bl cells but, in this case, the antiviral activity appeared to be related to IFN-gamma rather than to beta-chemokines. These observations indicate that LPS stimulates PBMCs to produce a complex array of soluble HIV-1 inhibitors, including beta-chemokines and IFN-gamma, that differentially inhibit HIV-1 depending on the target cell type. The results also highlight the need to use endotoxin-free specimens to avoid artifacts when assessing HIV-1-specific neutralizing antibodies in PBMC-based assays.
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    Interleukin 21 (IL-21) regulates chronic allograft vasculopathy (CAV) in murine heart allograft rejection.
    (PloS one, 2019-01) Khattar, Mithun; Baum, Caitlin E; Schroder, Paul; Breidenbach, Joshua D; Haller, Steven T; Chen, Wenhao; Stepkowski, Stanislaw
    IL-21 is the most recently discovered common gamma-chain cytokine that promotes persistent T-cell responses in chronic infections, autoimmunity and cancer. However, the therapeutic potential of inhibiting the IL-21-BATF signaling axis, particularly in transplant rejection, remains unclear. We used heart transplant models to examine the effects of IL-21 blockade in prevention of chronic cardiac allograft vasculopathy (CAV) using genetic knock-out and therapeutic approaches. Both wild-type C57BL/6 and IL-21-/- strains acutely rejected Balb/c skin grafts and once immunized with this skin graft, rejected Balb/c heart allografts in an accelerated fashion. However, when transplanted with heart grafts from the class-II major histocompatibility complex mutant, B6bm12 mice; wild-type recipients developed CAV, while IL-21-/- recipients were protected, even at day 100 post-transplant. Similarly, BATF-/- recipients, lacking the transcription factor BATF responsible for IL-21 production, did not develop CAV in B6-bm12 heart allografts. Strikingly, in a transient treatment protocol, the development of CAV in wild-type recipients of B6-bm12 hearts allografts was blocked by the administration of IL-21 receptor fusion protein (R-Fc). Thus, we demonstrate that CAV is regulated at least in part by IL-21 signaling and its blockade by genetic approaches or therapy with IL-21R-Fc prevents CAV in mice.
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    Interleukin-17 synergizes with IFNγ or TNFα to promote inflammatory mediator release and intercellular adhesion molecule-1 (ICAM-1) expression in human intervertebral disc cells.
    (Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2011-01) Gabr, Mostafa A; Jing, Liufang; Helbling, Antonia R; Sinclair, S Michael; Allen, Kyle D; Shamji, Mohammed F; Richardson, William J; Fitch, Robert D; Setton, Lori A; Chen, Jun
    Interleukin-17 (IL-17) is a cytokine recently shown to be elevated, along with interferon-γ (IFNγ) and tumor necrosis factor (TNFα), in degenerated and herniated intervertebral disc (IVD) tissues, suggesting a role for these cytokines in intervertebral disc disease. The objective of our study was to investigate the involvement of IL-17 and costimulants IFNγ and TNFα in intervertebral disc pathology. Cells were isolated from anulus fibrosus and nucleus pulposus tissues of patients undergoing surgery for intervertebral disc degeneration or scoliosis. The production of inflammatory mediators, nitric oxide (NOx), prostaglandin E2 (PGE2) and interleukin-6 (IL-6), as well as intercellular adhesion molecule (ICAM-1) expression, were quantified for cultured cells following exposure to IL-17, IFNγ, and TNFα. Intervertebral disc cells exposed to IL-17, IFNγ, or TNFα showed a remarkable increase in inflammatory mediator release and ICAM-1 expression (GLM and ANOVA, p < 0.05). Addition of IFNγ or TNFα to IL-17 demonstrated a synergistic increase in inflammatory mediator release, and a marked increase in ICAM-1 expression. These findings suggest that IVD cells not only respond with a catabolic phenotype to IL-17 and costimulants IFNγ and TNFα, but also express surface ligands with consequent potential to recruit additional lymphocytes and immune cells to the IVD microenvironment. IL-17 may be an important regulator of inflammation in the IVD pathologies.
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    Pairing QuantiFERON gold in-tube with opt-out HIV testing in a tuberculosis contact investigation in the Southeastern United States.
    (AIDS Patient Care STDS, 2010-09) Person, Anna K; Goswami, Neela D; Bissette, Deborah J; Turner, Debra S; Baker, Ann V; Gadkowski, L Beth; Naggie, Susanna; Erlandson, Kirby; Chen, Luke; Lalani, Tahaniyat; Cox, Gary M; Stout, Jason E
    Knowing one's HIV status is particularly important in the setting of recent tuberculosis (TB) exposure. Blood tests for assessment of tuberculosis infection, such as the QuantiFERON Gold in-tube test (QFT; Cellestis Limited, Carnegie, Victoria, Australia), offer the possibility of simultaneous screening for TB and HIV with a single blood draw. We performed a cross-sectional analysis of all contacts to a highly infectious TB case in a large meatpacking factory. Twenty-two percent were foreign-born and 73% were black. Contacts were tested with both tuberculin skin testing (TST) and QFT. HIV testing was offered on an opt-out basis. Persons with TST >or=10 mm, positive QFT, and/or positive HIV test were offered latent TB treatment. Three hundred twenty-six contacts were screened: TST results were available for 266 people and an additional 24 reported a prior positive TST for a total of 290 persons with any TST result (89.0%). Adequate QFT specimens were obtained for 312 (95.7%) of persons. Thirty-two persons had QFT results but did not return for TST reading. Twenty-two percent met the criteria for latent TB infection. Eighty-eight percent accepted HIV testing. Two (0.7%) were HIV seropositive; both individuals were already aware of their HIV status, but one had stopped care a year previously. None of the HIV-seropositive persons had latent TB, but all were offered latent TB treatment per standard guidelines. This demonstrates that opt-out HIV testing combined with QFT in a large TB contact investigation was feasible and useful. HIV testing was also widely accepted. Pairing QFT with opt-out HIV testing should be strongly considered when possible.
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    Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens.
    (J Virol, 2016-04) Asbach, Benedikt; Kliche, Alexander; Köstler, Josef; Perdiguero, Beatriz; Esteban, Mariano; Jacobs, Bertram L; Montefiori, David C; LaBranche, Celia C; Yates, Nicole L; Tomaras, Georgia D; Ferrari, Guido; Foulds, Kathryn E; Roederer, Mario; Landucci, Gary; Forthal, Donald N; Seaman, Michael S; Hawkins, Natalie; Self, Steven G; Sato, Alicia; Gottardo, Raphael; Phogat, Sanjay; Tartaglia, James; Barnett, Susan W; Burke, Brian; Cristillo, Anthony D; Weiss, Deborah E; Francis, Jesse; Galmin, Lindsey; Ding, Song; Heeney, Jonathan L; Pantaleo, Giuseppe; Wagner, Ralf
    UNLABELLED: In a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C+ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8(+)and CD4(+)T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings. IMPORTANCE: Within the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.
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    The impact of caspase-12 on susceptibility to candidemia.
    (European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2012-03) Rosentul, DC; Plantinga, TS; Scott, WK; Alexander, BD; van de Geer, NMD; Perfect, JR; Kullberg, BJ; Johnson, MD; Netea, MG
    Candida is one of the leading causes of sepsis, and an effective host immune response to Candida critically depends on the cytokines IL-1β and IL-18, which need caspase-1 cleavage to become bioactive. Caspase-12 has been suggested to inhibit caspase-1 activation and has been implicated as a susceptibility factor for bacterial sepsis. In populations of African descent, CASPASE-12 is either functional or non-functional. Here, we have assessed the frequencies of both CASPASE-12 alleles in an African-American Candida sepsis patients cohort compared to uninfected patients with similar predisposing factors. African-American Candida sepsis patients (n = 93) and non-infected African-American patients (n = 88) were genotyped for the CASPASE-12 genotype. Serum cytokine concentrations of IL-6, IL-8, and IFNγ were measured in the serum of infected patients. Statistical comparisons were performed in order to assess the effect of the CASPASE-12 genotype on susceptibility to candidemia and on serum cytokine concentrations. Our findings demonstrate that CASPASE-12 does not influence the susceptibility to Candida sepsis, nor has any effect on the serum cytokine concentrations in Candida sepsis patients during the course of infection. Although the functional CASPASE-12 allele has been suggested to increase susceptibility to bacterial sepsis, this could not be confirmed in our larger cohort of fungal sepsis patients.