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  1. Article ; Online: Forward Genetics in Apicomplexa Biology: The Host Side of the Story.

    Sánchez-Arcila, Juan C / Jensen, Kirk D C

    Frontiers in cellular and infection microbiology

    2022  Volume 12, Page(s) 878475

    Abstract: Forward genetic approaches have been widely used in parasitology and have proven their power to reveal the complexities of host-parasite interactions in an unbiased fashion. Many aspects of the parasite's biology, including the identification of ... ...

    Abstract Forward genetic approaches have been widely used in parasitology and have proven their power to reveal the complexities of host-parasite interactions in an unbiased fashion. Many aspects of the parasite's biology, including the identification of virulence factors, replication determinants, antibiotic resistance genes, and other factors required for parasitic life, have been discovered using such strategies. Forward genetic approaches have also been employed to understand host resistance mechanisms to parasitic infection. Here, we will introduce and review all forward genetic approaches that have been used to identify host factors involved with Apicomplexa infections, which include classical genetic screens and QTL mapping, GWAS, ENU mutagenesis, overexpression, RNAi and CRISPR-Cas9 library screens. Collectively, these screens have improved our understanding of host resistance mechanisms, immune regulation, vaccine and drug designs for Apicomplexa parasites. We will also discuss how recent advances in molecular genetics give present opportunities to further explore host-parasite relationships.
    MeSH term(s) Apicomplexa/genetics ; Biology ; Genetic Testing ; Host-Parasite Interactions/genetics ; Mutagenesis
    Language English
    Publishing date 2022-05-12
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 2619676-1
    ISSN 2235-2988 ; 2235-2988
    ISSN (online) 2235-2988
    ISSN 2235-2988
    DOI 10.3389/fcimb.2022.878475
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Training the Fetal Immune System Through Maternal Inflammation-A Layered Hygiene Hypothesis.

    Apostol, April C / Jensen, Kirk D C / Beaudin, Anna E

    Frontiers in immunology

    2020  Volume 11, Page(s) 123

    Abstract: Over the last century, the alarming surge in allergy and autoimmune disease has led to the hypothesis that decreasing exposure to microbes, which has accompanied industrialization and modern life in the Western world, has fundamentally altered the immune ...

    Abstract Over the last century, the alarming surge in allergy and autoimmune disease has led to the hypothesis that decreasing exposure to microbes, which has accompanied industrialization and modern life in the Western world, has fundamentally altered the immune response. In its current iteration, the "hygiene hypothesis" suggests that reduced microbial exposures during
    MeSH term(s) Adult ; Child ; Female ; Fetus/immunology ; Hematopoietic Stem Cells/immunology ; Hematopoietic Stem Cells/microbiology ; Host Microbial Interactions/immunology ; Humans ; Hygiene Hypothesis ; Hypersensitivity/immunology ; Immune System/immunology ; Infant, Newborn ; Inflammation/immunology ; Microbial Interactions/immunology ; Pregnancy ; T-Lymphocytes, Helper-Inducer/immunology
    Language English
    Publishing date 2020-02-11
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2020.00123
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Variation in CD8 T cell IFNγ differentiation to strains of

    Kongsomboonvech, Angel K / García-López, Laura / Njume, Ferdinand / Rodriguez, Felipe / Souza, Scott P / Rosenberg, Alex / Jensen, Kirk D C

    Frontiers in cellular and infection microbiology

    2023  Volume 13, Page(s) 1130965

    Abstract: Introduction: Toxoplasma gondii: Methods: Therefore, we screened F1 progeny from genetic crosses between the clonal lineage strains to identify ROCTR. Naïve antigen-specific CD8 T cells (T57) isolated from transnuclear mice, which are specific for ... ...

    Abstract Introduction: Toxoplasma gondii
    Methods: Therefore, we screened F1 progeny from genetic crosses between the clonal lineage strains to identify ROCTR. Naïve antigen-specific CD8 T cells (T57) isolated from transnuclear mice, which are specific for the endogenous and vacuolar TGD057 antigen, were measured for their ability to become activated, transcribe
    Results: Genetic mapping returned four non-interacting quantitative trait loci (QTL) with small effect on
    Discussion: Collectively, our data suggest that while CD8 T cell IFNγ production to
    MeSH term(s) Animals ; Mice ; Toxoplasma ; Quantitative Trait Loci ; Protozoan Proteins/metabolism ; Interferon-gamma/metabolism ; CD8-Positive T-Lymphocytes ; Cell Differentiation
    Chemical Substances Protozoan Proteins ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2023-05-23
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2619676-1
    ISSN 2235-2988 ; 2235-2988
    ISSN (online) 2235-2988
    ISSN 2235-2988
    DOI 10.3389/fcimb.2023.1130965
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: T cell exhaustion dynamics in systemic autoimmune disease.

    Turner, Christi N / Camilo Sanchez Arcila, Juan / Huerta, Noah / Quiguoe, Avi Rae / Jensen, Kirk D C / Hoyer, Katrina K

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Unlike in infection and cancer, T cell exhaustion in autoimmune disease has not been clearly defined. Here we set out to understand inhibitory protein (PD-1, Tim3, CTLA4, Lag3) expression in CXCR5- and CXCR5+ CD8 and CD4 T cells in systemic lupus ... ...

    Abstract Unlike in infection and cancer, T cell exhaustion in autoimmune disease has not been clearly defined. Here we set out to understand inhibitory protein (PD-1, Tim3, CTLA4, Lag3) expression in CXCR5- and CXCR5+ CD8 and CD4 T cells in systemic lupus erythematosus. CXCR5+ CD8 and CD4 T cells express PD-1 and engage B cells in germinal center reactions, leading to autoantibody formation in autoimmunity. We hypothesized that CXCR5+ CD8 T cells develop an exhausted phenotype as SLE autoimmunity expands from initial to chronic, self-perpetuating disease due to chronic self-antigen exposure. Our results indicate that there is no exhaustion frequency differences between sexes, although disease kinetics vary by sex. CXCR5+ CD8 T cells express primarily IFNγ, known to promote autoimmune disease development, whereas CXCR5-CD8 T cells express TNFα and IFNγ as disease progresses from 2-6 months. Tim3 is the highest expressed inhibitory marker for all CD4 and CD8 T cell populations demonstrating potential for terminally exhausted populations. CTLA4 expression on CD4 T cells suggests potential tolerance induction in these cells. We identified exhaustion phenotypes within autoimmune disease that progress with increasing lupus erythematosus severity and possibly provide a feedback mechanism for immunological tolerance.
    Highlights: CXCR5- and CXCR5+ CD8 T cells expand with rate of disease in SLE mouse model.CXCR5+ CD8 T cells are low contributors to TNFα disease progression unlike CXCR5-CD8 T cells but may increase disease mechanisms through high IFNγ production.Inhibitory markers upregulate in frequency with the highest amounts seen in Tim3+ populations. Tim3+Lag3+ expression may be an indicator of terminal differentiation for all populations.Inhibitory marker expression frequency was unrelated to sex.
    Language English
    Publishing date 2023-12-23
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.23.573167
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Antigen Presentation of Vacuolated Apicomplexans--Two Gateways to a Vaccine Antigen.

    Jensen, Kirk D C

    Trends in parasitology

    2015  Volume 32, Issue 2, Page(s) 88–90

    Abstract: For parasites that sequester themselves within a vacuole, new rules governing antigen presentation are coming into focus. Components of the host's autophagy machinery and the parasite's membranous nanotubular network within the parasitophorous vacuole ... ...

    Abstract For parasites that sequester themselves within a vacuole, new rules governing antigen presentation are coming into focus. Components of the host's autophagy machinery and the parasite's membranous nanotubular network within the parasitophorous vacuole play a major role in determining antigenicity of Toxoplasma proteins. As such, both parasite and vaccinologist may exploit these pathways to regulate the ever important CD8 T cell response to apicomplexan parasites.
    MeSH term(s) Animals ; Antigens/immunology ; Apicomplexa/immunology ; Autophagy ; CD8-Positive T-Lymphocytes/immunology ; Humans ; Protozoan Vaccines
    Chemical Substances Antigens ; Protozoan Vaccines
    Language English
    Publishing date 2015-12-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 2036227-4
    ISSN 1471-5007 ; 1471-4922
    ISSN (online) 1471-5007
    ISSN 1471-4922
    DOI 10.1016/j.pt.2015.12.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Antigen Presentation of Vacuolated Apicomplexans – Two Gateways to a Vaccine Antigen

    Jensen, Kirk D.C

    Trends in parasitology. 2016 Feb., v. 32, no. 2

    2016  

    Abstract: For parasites that sequester themselves within a vacuole, new rules governing antigen presentation are coming into focus. Components of the host's autophagy machinery and the parasite's membranous nanotubular network within the parasitophorous vacuole ... ...

    Abstract For parasites that sequester themselves within a vacuole, new rules governing antigen presentation are coming into focus. Components of the host's autophagy machinery and the parasite's membranous nanotubular network within the parasitophorous vacuole play a major role in determining antigenicity of Toxoplasma proteins. As such, both parasite and vaccinologist may exploit these pathways to regulate the ever important CD8 T cell response to apicomplexan parasites.
    Keywords antigen presentation ; antigens ; autophagy ; CD8-positive T-lymphocytes ; parasites ; proteins ; Toxoplasma ; vaccines ; vacuoles
    Language English
    Dates of publication 2016-02
    Size p. 88-90.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 2036227-4
    ISSN 1471-5007 ; 1471-4922
    ISSN (online) 1471-5007
    ISSN 1471-4922
    DOI 10.1016/j.pt.2015.12.011
    Database NAL-Catalogue (AGRICOLA)

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  7. Article ; Online: Author Correction: Cell-based versus corticosteroid injections for knee pain in osteoarthritis: a randomized phase 3 trial.

    Mautner, Ken / Gottschalk, Michael / Boden, Scott D / Akard, Alison / Bae, Won C / Black, Lora / Boggess, Blake / Chatterjee, Paramita / Chung, Christine B / Easley, Kirk A / Gibson, Greg / Hackel, Josh / Jensen, Katie / Kippner, Linda / Kurtenbach, Chad / Kurtzberg, Joanne / Mason, R Amadeus / Noonan, Benjamin / Roy, Krishnendu /
    Valentine, Verle / Yeago, Carolyn / Drissi, Hicham

    Nature medicine

    2023  Volume 30, Issue 3, Page(s) 905

    Language English
    Publishing date 2023-12-22
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-023-02776-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: T cell signaling and Treg dysfunction correlate to disease kinetics in IL-2Rα-KO autoimmune mice.

    Mullins, Genevieve N / Valentine, Kristen M / Al-Kuhlani, Mufadhal / Davini, Dan / Jensen, Kirk D C / Hoyer, Katrina K

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 21994

    Abstract: IL-2Rα, in part, comprises the high affinity receptor for IL-2, a cytokine important in immune proliferation, activation, and regulation. IL-2Rα deficient mice (IL-2Rα-KO) develop systemic autoimmune disease and die from severe anemia between 18 and 80 ... ...

    Abstract IL-2Rα, in part, comprises the high affinity receptor for IL-2, a cytokine important in immune proliferation, activation, and regulation. IL-2Rα deficient mice (IL-2Rα-KO) develop systemic autoimmune disease and die from severe anemia between 18 and 80 days of age. These mice develop kinetically distinct autoimmune progression, with approximately a quarter dying by 21 days of age and half dying after 30 days. This research aims to define immune parameters and cytokine signaling that distinguish cohorts of IL-2Rα-KO mice that develop early- versus late-stage autoimmune disease. To investigate these differences, we evaluated complete blood counts (CBC), antibody binding of RBCs, T cell numbers and activation, hematopoietic progenitor changes, and signaling kinetics, during autoimmune hemolytic anemia (AIHA) and bone marrow failure. We identified several alterations that, when combined, correlate to disease kinetics. Early onset disease correlates with anti-RBC antibodies, lower hematocrit, and reduced IL-7 signaling. CD8 regulatory T cells (Tregs) have enhanced apoptosis in early disease. Further, early and late end stage disease, while largely similar, had several differences suggesting distinct mechanisms drive autoimmune disease kinetics. Therefore, IL-2Rα-KO disease pathology rates, driven by T cell signaling, promote effector T cell activation and expansion and Treg dysfunction.
    MeSH term(s) Animals ; Apoptosis ; CD8-Positive T-Lymphocytes/immunology ; Cell Proliferation ; Erythrocytes/metabolism ; Immunologic Memory ; Interleukin-2/metabolism ; Interleukin-2 Receptor alpha Subunit/deficiency ; Interleukin-2 Receptor alpha Subunit/metabolism ; Kinetics ; Lymphocyte Activation/immunology ; Mice, Inbred BALB C ; Mice, Knockout ; Signal Transduction ; T-Lymphocytes, Regulatory/immunology ; Thymus Gland/growth & development
    Chemical Substances Interleukin-2 ; Interleukin-2 Receptor alpha Subunit
    Language English
    Publishing date 2020-12-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-78975-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Cell-based versus corticosteroid injections for knee pain in osteoarthritis: a randomized phase 3 trial.

    Mautner, Ken / Gottschalk, Michael / Boden, Scott D / Akard, Alison / Bae, Won C / Black, Lora / Boggess, Blake / Chatterjee, Paramita / Chung, Christine B / Easley, Kirk A / Gibson, Greg / Hackel, Josh / Jensen, Katie / Kippner, Linda / Kurtenbach, Chad / Kurtzberg, Joanne / Mason, R Amadeus / Noonan, Benjamin / Roy, Krishnendu /
    Valentine, Verle / Yeago, Carolyn / Drissi, Hicham

    Nature medicine

    2023  Volume 29, Issue 12, Page(s) 3120–3126

    Abstract: Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing relative efficacy to each other or corticosteroid injections. Here we aimed to ... ...

    Abstract Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing relative efficacy to each other or corticosteroid injections. Here we aimed to identify the safety and efficacy of cell injections from autologous bone marrow aspirate concentrate, autologous adipose stromal vascular fraction and allogeneic human umbilical cord tissue-derived mesenchymal stromal cells, in comparison to corticosteroid injection (CSI). The study was a phase 2/3, four-arm parallel, multicenter, single-blind, randomized, controlled clinical trial with 480 patients with a diagnosis of knee osteoarthritis (Kellgren-Lawrence II-IV). Participants were randomized to the three different arms with a 3:1 distribution. Arm 1: autologous bone marrow aspirate concentrate (n = 120), CSI (n = 40); arm 2: umbilical cord tissue-derived mesenchymal stromal cells (n = 120), CSI (n = 40); arm 3: stromal vascular fraction (n = 120), CSI (n = 40). The co-primary endpoints were the visual analog scale pain score and Knee injury and Osteoarthritis Outcome Score pain score at 12 months versus baseline. Analyses of our primary endpoints, with 440 patients, revealed that at 1 year post injection, none of the three orthobiologic injections was superior to another, or to the CSI control. In addition, none of the four groups showed a significant change in magnetic resonance imaging osteoarthritis score compared to baseline. No procedure-related serious adverse events were reported during the study period. In summary, this study shows that at 1 year post injection, there was no superior orthobiologic as compared to CSI for knee osteoarthritis. ClinicalTrials.gov Identifier: NCT03818737.
    MeSH term(s) Humans ; Osteoarthritis, Knee/complications ; Osteoarthritis, Knee/diagnostic imaging ; Osteoarthritis, Knee/drug therapy ; Pain/drug therapy ; Pain/etiology ; Single-Blind Method ; Treatment Outcome
    Language English
    Publishing date 2023-11-02
    Publishing country United States
    Document type Randomized Controlled Trial ; Multicenter Study ; Clinical Trial, Phase II ; Clinical Trial, Phase III ; Journal Article
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-023-02632-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Genetic mapping reveals Nfkbid as a central regulator of humoral immunity to Toxoplasma gondii.

    Souza, Scott P / Splitt, Samantha D / Sànchez-Arcila, Juan C / Alvarez, Julia A / Wilson, Jessica N / Wizzard, Safuwra / Luo, Zheng / Baumgarth, Nicole / Jensen, Kirk D C

    PLoS pathogens

    2021  Volume 17, Issue 12, Page(s) e1010081

    Abstract: Protective immunity to parasitic infections has been difficult to elicit by vaccines. Among parasites that evade vaccine-induced immunity is Toxoplasma gondii, which causes lethal secondary infections in chronically infected mice. Here we report that ... ...

    Abstract Protective immunity to parasitic infections has been difficult to elicit by vaccines. Among parasites that evade vaccine-induced immunity is Toxoplasma gondii, which causes lethal secondary infections in chronically infected mice. Here we report that unlike susceptible C57BL/6J mice, A/J mice were highly resistant to secondary infection. To identify correlates of immunity, we utilized forward genetics to identify Nfkbid, a nuclear regulator of NF-κB that is required for B cell activation and B-1 cell development. Nfkbid-null mice ("bumble") did not generate parasite-specific IgM and lacked robust parasite-specific IgG, which correlated with defects in B-2 cell maturation and class-switch recombination. Though high-affinity antibodies were B-2 derived, transfer of B-1 cells partially rescued the immunity defects observed in bumble mice and were required for 100% vaccine efficacy in bone marrow chimeric mice. Immunity in resistant mice correlated with robust isotype class-switching in both B cell lineages, which can be fine-tuned by Nfkbid gene expression. We propose a model whereby humoral immunity to T. gondii is regulated by Nfkbid and requires B-1 and B-2 cells for full protection.
    MeSH term(s) Animals ; B-Lymphocytes/immunology ; Disease Susceptibility/immunology ; I-kappa B Proteins/immunology ; Immunity, Humoral/immunology ; Mice ; Toxoplasma ; Toxoplasmosis, Animal/immunology
    Chemical Substances I-kappa B Proteins ; Nfkbid protein, mouse
    Language English
    Publishing date 2021-12-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1010081
    Database MEDical Literature Analysis and Retrieval System OnLINE

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