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(), the causative agent of tuberculosis, can enter into a persistent state that confers resistance to antibacterial agents. Many observations suggest that persistent cells also evade the antimycobacterial immune mechanisms, thereby reducing the effectiveness of the current tuberculosis vaccine. Understanding the factors that contribute to persistence may enable the rational design of vaccines that stimulate effective immune killing mechanisms against persister cells. Independent mutations targeting the methionine and arginine biosynthetic pathways are bactericidal for in mice. However, in this study, we discovered that the addition of leucine and pantothenate auxotrophy altered the bactericidality of methionine auxotrophy. Whereas the leucine/pantothenate/methionine auxotrophic strain H37Rv Δ Δ Δ was eliminated in immunocompetent mice, this strain persisted in multiple organs of immunodeficient mice for at least a year. In contrast, the leucine/pantothenate/arginine auxotroph H37Rv Δ Δ Δ was eliminated in both immunocompetent and immunodeficient mice. Our results showed that leucine and pantothenate starvation metabolically blocked the sterilization mechanisms of methionine starvation but not those of arginine starvation. These triple-auxotrophic strains should be invaluable tools for unravelling the bacterial and host factors that enable persistence and for vaccine development studies to assess the efficacy of vaccines that boost immune recognition of in the persistent state. The sterilization of the Δ Δ Δ auxotroph in immunocompetent mice, but not in mice lacking an adaptive immune response, could provide a new system for studying the antimycobacterial killing mechanisms of adaptive immunity. The bacterial pathogen can enter into a persistent state in which can evade host immunity, thereby reducing the effectiveness of current tuberculosis vaccines. Understanding the factors that contribute to persistence would enable the rational design of vaccines effective against persisters. We previously generated two attenuated, triple-auxotrophic strains that are safe to use in a biosafety level 2 laboratory. Herein, we discovered that the triple-auxotrophic strain H37Rv Δ Δ Δ persisted in immunodeficient mice, which lack adaptive immunity, but not in immunocompetent mice. The conditional persistence of this auxotrophic mutant, which is susceptible to the sterilizing effect of the adaptive immune response over time, provides an important tool to dissect the mycobactericidal effector mechanisms mediated by adaptive immunity. Furthermore, because of its remarkable safety attributes, this auxotrophic mutant can potentially be used to develop a practical human challenge model to facilitate vaccine development.
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http://dx.doi.org/10.1128/mBio.02391-20 | DOI Listing |
Acta Crystallogr F Struct Biol Commun
January 2025
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), UMR 8576 CNRS and University of Lille, Villeneuve d'Ascq, France.
Monoclonal antibodies recognizing nonprotein antigens remain largely underrepresented in our understanding of the molecular repertoire of innate and adaptive immunity. One such antibody is Mannitou, a murine IgM that recognizes paucimannosidic glycans. In this work, we report the production and purification of the recombinant antigen-binding fragment (Fab) of Mannitou IgM (Mannitou Fab) and employ a combination of biochemical and biophysical approaches to obtain its initial structural characterization.
View Article and Find Full Text PDFFront Immunol
December 2024
Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Age-associated differences in the effect of repetitive vaccination, particularly on memory T-cell and B-cell responses, remain unclear. While older adults (aged ≥65 years) exhibited enhanced IgG responses following COVID-19 mRNA booster vaccination, they produced fewer spike-specific circulating follicular helper T cells-1 than younger adults. Similarly, the cytotoxic CD8 T-cell response remained diminished with reduced PD-1 expression even after booster vaccination compared with that in younger adults, suggesting impaired memory T-cell activation in older adults.
View Article and Find Full Text PDFFront Immunol
December 2024
Department of Academic Affairs, National Jewish Health, Denver, CO, United States.
Granulomas, organized aggregates of immune cells which form in response to (), are characteristic but not exclusive of tuberculosis (TB). Despite existing investigations on TB granulomas, the determinants that differentiate host-protective granulomas from granulomas that contribute to TB pathogenesis are often disputed. Thus, the goal of this narrative review is to help clarify the existing literature on such determinants.
View Article and Find Full Text PDFFront Cell Infect Microbiol
December 2024
Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity.
View Article and Find Full Text PDFJ Nutr
December 2024
Department of Nutrition, University of California, Davis, Davis, CA, United States; USDA Western Human Nutrition Research Center, University of California, Davis, Davis, CA, United States. Electronic address:
Background: Immune function is affected by vitamin D status but the optimal serum 25-hydroxy vitamin D [25(OH)D] level for immune function is not known.
Objectives: We hypothesized that 25(OH)D would be associated with markers of inflammation and immune activation.
Methods: We identified associations between 25(OH)D and immune markers from 361 healthy adults using polynomial regression.
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