Genetic models of latent tuberculosis in mice reveal differential influence of adaptive immunity

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Hongwei Su ◽  
Kan Lin ◽  
Divya Tiwari ◽  
Claire Healy ◽  
Carolina Trujillo ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mouse Model ◽  
Adaptive Immunity ◽  
High Frequency ◽  
Latent Infection ◽  
Latent Tuberculosis ◽  
Thioredoxin Reductase ◽  
Therapeutic Strategies ◽  
Biotin Protein Ligase

Studying latent Mycobacterium tuberculosis (Mtb) infection has been limited by the lack of a suitable mouse model. We discovered that transient depletion of biotin protein ligase (BPL) and thioredoxin reductase (TrxB2) results in latent infections during which Mtb cannot be detected but that relapse in a subset of mice. The immune requirements for Mtb control during latency, and the frequency of relapse, were strikingly different depending on how latency was established. TrxB2 depletion resulted in a latent infection that required adaptive immunity for control and reactivated with high frequency, whereas latent infection after BPL depletion was independent of adaptive immunity and rarely reactivated. We identified immune signatures of T cells indicative of relapse and demonstrated that BCG vaccination failed to protect mice from TB relapse. These reproducible genetic latency models allow investigation of the host immunological determinants that control the latent state and offer opportunities to evaluate therapeutic strategies in settings that mimic aspects of latency and TB relapse in humans.

scholarly journals Genetic models of latent tuberculosis in mice reveal differential control by innate and adaptive immunity

2021 ◽  
Author(s):  
Hongwei Su ◽  
Kan Lin ◽  
Divya Tiwari ◽  
Claire Healy ◽  
Carolina Trujillo ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Adaptive Immunity ◽  
High Frequency ◽  
Latent Infection ◽  
Latent Tuberculosis ◽  
Thioredoxin Reductase ◽  
Therapeutic Strategies ◽  
Innate And Adaptive Immunity ◽  
Biotin Ligase ◽  
Differential Control

AbstractStudying latent Mycobacterium tuberculosis (Mtb) infection has been limited by the lack of a suitable mouse model. We discovered that transient depletion of protein biotin ligase (BPL) and thioredoxin reductase (TrxB2) results in latent infections during which Mtb cannot be detected but that relapse in a subset of mice. The immune requirements for Mtb control during latency, and the frequency of relapse, were strikingly different depending on how latency was established. TrxB2 depletion resulted in a latent infection that required adaptive immunity for control and reactivated with high frequency, whereas latent infection after BPL depletion was dependent on innate immunity and rarely reactivated. We identified immune signatures of T cells indicative of relapse and demonstrated that BCG vaccination failed to protect mice from TB relapse. These reproducible genetic latency models allow investigating the host immunological determinants that control the latent state and offer opportunities to evaluate therapeutic strategies in settings that mimic aspects of latency and TB relapse in humans.

scholarly journals Impaired Degranulation and Proliferative Capacity of Mycobacterium tuberculosis–Specific CD8+ T Cells in HIV-Infected Individuals With Latent Tuberculosis

2014 ◽  
Vol 211 (4) ◽  
pp. 635-640 ◽  
Author(s):  
Ameeta S. Kalokhe ◽  
Toidi Adekambi ◽  
Chris C. Ibegbu ◽  
Susan M. Ray ◽  
Cheryl L. Day ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd8 T Cells ◽  
Latent Tuberculosis ◽  
Proliferative Capacity

scholarly journals Interleukin-2 from Adaptive T Cells Enhances Natural Killer Cell Activity against Human Cytomegalovirus-Infected Macrophages

2015 ◽  
Vol 89 (12) ◽  
pp. 6435-6441 ◽  
Author(s):  
Zeguang Wu ◽  
Giada Frascaroli ◽  
Carina Bayer ◽  
Tatjana Schmal ◽  
Thomas Mertens
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Adaptive Immunity ◽  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Immune Surveillance ◽  
Interleukin 2

ABSTRACTControl of human cytomegalovirus (HCMV) requires a continuous immune surveillance, thus HCMV is the most important viral pathogen in severely immunocompromised individuals. Both innate and adaptive immunity contribute to the control of HCMV. Here, we report that peripheral blood natural killer cells (PBNKs) from HCMV-seropositive donors showed an enhanced activity toward HCMV-infected autologous macrophages. However, this enhanced response was abolished when purified NK cells were applied as effectors. We demonstrate that this enhanced PBNK activity was dependent on the interleukin-2 (IL-2) secretion of CD4+T cells when reexposed to the virus. Purified T cells enhanced the activity of purified NK cells in response to HCMV-infected macrophages. This effect could be suppressed by IL-2 blocking. Our findings not only extend the knowledge on the immune surveillance in HCMV—namely, that NK cell-mediated innate immunity can be enhanced by a preexisting T cell antiviral immunity—but also indicate a potential clinical implication for patients at risk for severe HCMV manifestations due to immunosuppressive drugs, which mainly suppress IL-2 production and T cell responsiveness.IMPORTANCEHuman cytomegalovirus (HCMV) is never cleared by the host after primary infection but instead establishes a lifelong latent infection with possible reactivations when the host′s immunity becomes suppressed. Both innate immunity and adaptive immunity are important for the control of viral infections. Natural killer (NK) cells are main innate effectors providing a rapid response to virus-infected cells. Virus-specific T cells are the main adaptive effectors that are critical for the control of the latent infection and limitation of reinfection. In this study, we found that IL-2 secreted by adaptive CD4+T cells after reexposure to HCMV enhances the activity of NK cells in response to HCMV-infected target cells. This is the first direct evidence that the adaptive T cells can help NK cells to act against HCMV infection.

T cells co-producing Mycobacterium tuberculosis-specific type 1 cytokines for the diagnosis of latent tuberculosis

2010 ◽  
Vol 21 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Johannes Nemeth ◽  
Heide-Maria Winkler ◽  
Franz Karlhofer ◽  
Nicole Selenko-Gebauer ◽  
Wolfgang Graninger ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Latent Tuberculosis

Treatment of latent tuberculosis infection induces changes in multifunctional Mycobacterium tuberculosis-specific CD4+ T cells

2015 ◽  
Vol 205 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Ilaria Sauzullo ◽  
Fabio Mengoni ◽  
Claudia Mascia ◽  
Raffaella Rossi ◽  
Miriam Lichtner ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd4 T Cells ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Tuberculosis Infection

scholarly journals Mycobacterium tuberculosis-specific CD8+T cells are functionally and phenotypically different between latent infection and active disease

2013 ◽  
Vol 43 (6) ◽  
pp. 1568-1577 ◽  
Author(s):  
Virginie Rozot ◽  
Selena Vigano ◽  
Jesica Mazza-Stalder ◽  
Elita Idrizi ◽  
Cheryl L. Day ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd8 T Cells ◽  
Latent Infection ◽  
Active Disease

scholarly journals Efficient Ex Vivo Stimulation of Mycobacterium tuberculosis-Specific T Cells by Genetically Detoxified Bordetella pertussis Adenylate Cyclase Antigen Toxoids

2005 ◽  
Vol 73 (5) ◽  
pp. 2991-2998 ◽  
Author(s):  
Katalin A. Wilkinson ◽  
Marcela Simsova ◽  
Elisabeth Schölvinck ◽  
Peter Sebo ◽  
Claude Leclerc ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Adenylate Cyclase ◽  
Bordetella Pertussis ◽  
Ex Vivo ◽  
Latent Tuberculosis ◽  
Partial Protection ◽  
Purified Protein Derivative ◽  
Histocompatibility Complex ◽  
Specificity And Sensitivity

ABSTRACT Mycobacterium tuberculosis is a significant threat to global health. Mycobacterium bovis BCG vaccine provides only partial protection, and the skin test reagent used to aid diagnosis of both active and latent tuberculosis, purified protein derivative (PPD), lacks specificity and sensitivity. The use of genetically detoxified Bordetella pertussis adenylate cyclase toxin (CyaA) as a delivery system for two immunodominant proteins of M. tuberculosis that are of greater specificity than PPD, early-secreted antigenic target 6-kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10), was therefore investigated. CyaA toxoids incorporating these antigens were able to restimulate T cells from more than 91% tuberculosis patients and healthy sensitized donors. Delivery of antigen by CyaA decreased by 10-fold the amount of ESAT-6 and CFP-10 required to restimulate T cells, and in low responders, the overall frequency of gamma interferon-producing cells detected by enzyme-linked immunospot assay was increased (P < 0.01 for both antigens). Delivery of ESAT-6 and CFP-10 by CyaA enabled the detection of both CD4+ and CD8+ T cells: these responses could be blocked by inhibition of major histocompatibility complex class II or class I, respectively. Covalent linkage of antigen to the CyaA vector was required for enhancement to occur, as a mixture of mock CyaA toxoid plus recombinant ESAT-6 did not lead to enhancement. In a simplified whole-blood model to detect tuberculosis infection, the frequency of positive responses to CFP-10 was increased by CyaA delivery, a potentially important attribute that could facilitate the identification of latent infection.

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