scholarly journals Early Control of Mycobacterium tuberculosis Infection Requiresil12rb1Expression byrag1-Dependent Lineages

2012 ◽  
Vol 80 (11) ◽  
pp. 3828-3841 ◽  
Author(s):  
Halli E. Miller ◽  
Richard T. Robinson
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Low Dose ◽  
T And B Cells ◽  
Mycobacterium Tuberculosis Infection ◽  
Experimental Tuberculosis ◽  
Content Type ◽  
Aerosol Model ◽  
Dependent Lineages ◽  
Bone Marrow Chimeras

ABSTRACTIL12RB1is essential for human resistance toMycobacterium tuberculosisinfection. In the absence of a functionalIL12RB1allele, individuals exhibit susceptibility to disseminated, recurrent mycobacterial infections that are associated with defects in bothRAG1-dependent andRAG1-independent hematopoietic lineages. Despite this well-established association, a causal relationship betweenM. tuberculosissusceptibility andIL12RB1deficiency in eitherRAG1-dependent orRAG1-independent lineages has never been formally tested. Here, we use the low-dose aerosol model of experimental tuberculosis (TB) to both establish that infectedil12rb1−/−mice recapitulate important aspects of TB inIL12RB1null individuals and, more importantly, use radiation bone marrow chimeras to demonstrate that restriction ofil12rb1deficiency solely torag1-dependent lineages (i.e., T and B cells) allows for the full transfer of theil12rb1−/−phenotype. We further demonstrate that the protection afforded by adaptive lymphocyteil12rb1expression is mediated partially throughifngand that, within the same infection,il12rb1-sufficient T cells exhibit dominance overil12rb1-deficient T cells by enhancingifngexpression in the latter population. Collectively, our data establish a basic framework in which to understand howIL12RB1promotes control of this significant human disease.

scholarly journals Disparate Effects of Metformin on Mycobacterium tuberculosis Infection in Diabetic and Nondiabetic Mice

2020 ◽  
Vol 65 (1) ◽  
pp. e01422-20
Author(s):  
Harindra D. Sathkumara ◽  
Karyna Hansen ◽  
Socorro Miranda-Hernandez ◽  
Brenda Govan ◽  
Catherine M. Rush ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mycobacterium Tuberculosis ◽  
Disease Burden ◽  
Low Dose ◽  
Diabetic Mice ◽  
Antidiabetic Drug ◽  
Mycobacterium Tuberculosis Infection ◽  
Therapeutic Concentration ◽  
Content Type

ABSTRACTComorbid type 2 diabetes poses a great challenge to the global control of tuberculosis. Here, we assessed the efficacy of metformin (MET), an antidiabetic drug, in mice infected with a very low dose of Mycobacterium tuberculosis. In contrast to diabetic mice, infected nondiabetic mice that received the same therapeutic concentration of MET presented with significantly higher disease burden. This warrants further studies to investigate the disparate efficacy of MET against tuberculosis in diabetic and nondiabetic individuals.

scholarly journals Limited Pulmonary Mucosal-Associated Invariant T Cell Accumulation and Activation during Mycobacterium tuberculosis Infection in Rhesus Macaques

2018 ◽  
Vol 86 (12) ◽  
Author(s):  
Keith D. Kauffman ◽  
Michelle A. Sallin ◽  
Stella G. Hoft ◽  
Shunsuke Sakai ◽  
Rashida Moore ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd4 T Cells ◽  
Rhesus Macaques ◽  
Intracellular Cytokine Staining ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type ◽  
Mait Cells ◽  
Cd69 Expression

ABSTRACT Mucosal-associated invariant T cells (MAITs) are positioned in airways and may be important in the pulmonary cellular immune response against Mycobacterium tuberculosis infection, particularly prior to priming of peptide-specific T cells. Accordingly, there is interest in the possibility that boosting MAITs through tuberculosis (TB) vaccination may enhance protection, but MAIT responses in the lungs during tuberculosis are poorly understood. In this study, we compared pulmonary MAIT and peptide-specific CD4 T cell responses in M. tuberculosis-infected rhesus macaques using 5-OP-RU-loaded MR-1 tetramers and intracellular cytokine staining of CD4 T cells following restimulation with an M. tuberculosis-derived epitope megapool (MTB300), respectively. Two of four animals showed a detectable increase in the number of MAIT cells in airways at later time points following infection, but by ∼3 weeks postexposure, MTB300-specific CD4 T cells arrived in the airways and greatly outnumbered MAITs thereafter. In granulomas, MTB300-specific CD4 T cells were ∼20-fold more abundant than MAITs. CD69 expression on MAITs correlated with tissue residency rather than bacterial loads, and the few MAITs found in granulomas poorly expressed granzyme B and Ki67. Thus, MAIT accumulation in the airways is variable and late, and MAITs display little evidence of activation in granulomas during tuberculosis in rhesus macaques.

scholarly journals Cutting Edge: Control of Mycobacterium tuberculosis Infection by a Subset of Lung Parenchyma–Homing CD4 T Cells

2014 ◽  
Vol 192 (7) ◽  
pp. 2965-2969 ◽  
Author(s):  
Shunsuke Sakai ◽  
Keith D. Kauffman ◽  
Jason M. Schenkel ◽  
Cortez C. McBerry ◽  
Katrin D. Mayer-Barber ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd4 T Cells ◽  
Lung Parenchyma ◽  
Cutting Edge ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection

scholarly journals Characterization of T Cells Specific for CFP-10 and ESAT-6 in Mycobacterium tuberculosis-Infected Mauritian Cynomolgus Macaques

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Amy Ellis ◽  
Alexis Balgeman ◽  
Mark Rodgers ◽  
Cassaundra Updike ◽  
Jaime Tomko ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mhc Class Ii ◽  
Nonhuman Primates ◽  
Content Type ◽  
Host Immune Responses ◽  
Cell Responses ◽  
Cynomolgus Macaques ◽  
Mhc Haplotype

ABSTRACT Nonhuman primates can be used to study host immune responses to Mycobacterium tuberculosis. Mauritian cynomolgus macaques (MCMs) are a unique group of animals that have limited major histocompatibility complex (MHC) genetic diversity, such that MHC-identical animals can be infected with M. tuberculosis. Two MCMs homozygous for the relatively common M1 MHC haplotype were bronchoscopically infected with 41 CFU of the M. tuberculosis Erdman strain. Four other MCMs, which had at least one copy of the M1 MHC haplotype, were infected with a lower dose of 3 CFU M. tuberculosis. All animals mounted similar T-cell responses to CFP-10 and ESAT-6. Two epitopes in CFP-10 were characterized, and the MHC class II alleles restricting them were determined. A third epitope in CFP-10 was identified but exhibited promiscuous restriction. The CFP-10 and ESAT-6 antigenic regions targeted by T cells in MCMs were comparable to those seen in cases of human M. tuberculosis infection. Our data lay the foundation for generating tetrameric molecules to study epitope-specific CD4 T cells in M. tuberculosis-infected MCMs, which may guide future testing of tuberculosis vaccines in nonhuman primates.

scholarly journals Multifunctional CD4+ T cells correlate with active Mycobacterium tuberculosis infection

2010 ◽  
Vol 40 (8) ◽  
pp. 2211-2220 ◽  
Author(s):  
Nadia Caccamo ◽  
Giuliana Guggino ◽  
Simone A. Joosten ◽  
Giuseppe Gelsomino ◽  
Paola Di Carlo ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd4 T Cells ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection

scholarly journals Neither Primary nor Memory Immunity to Mycobacterium tuberculosis Infection Is Compromised in Mice with Chronic Enteric Helminth Infection

2015 ◽  
Vol 83 (3) ◽  
pp. 1217-1223 ◽  
Author(s):  
Wasiulla Rafi ◽  
Kamlesh Bhatt ◽  
William C. Gause ◽  
Padmini Salgame
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Regulatory Cells ◽  
Helminth Infection ◽  
Treg Cells ◽  
Helminth Species ◽  
Nippostrongylus Brasiliensis ◽  
T Regulatory Cell ◽  
Chronic Infections ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type

Previously we had reported thatNippostrongylus brasiliensis, a helminth with a lung migratory phase, affected host resistance againstMycobacterium tuberculosisinfection through the induction of alternatively activated (M2) macrophages. Several helminth species do not have an obligatory lung migratory phase but establish chronic infections in the host that include potent immune downregulatory effects, in part mediated through induction of a FoxP3+T regulatory cell (Treg) response. Treg cells exhibit duality in their functions in host defense againstM. tuberculosisinfection since their depletion leads to enhanced priming of T cells in the lymph nodes and attendant improved control ofM. tuberculosisinfection, while their presence in the lung granuloma protects against excessive inflammation.Heligmosomoides polygyrusis a strictly murine enteric nematode that induces a strong FoxP3 Treg response in the host. Therefore, in this study we investigated whether host immunity toM. tuberculosisinfection would be modulated in mice with chronicH. polygyrusinfection. We report that neither primary nor memory immunity conferred byMycobacterium bovisBCG vaccination was affected in mice with chronic enteric helminth infection, despite a systemic increase in FoxP3+T regulatory cells. The findings indicate that anti-M. tuberculosisimmunity is not similarly affected by all helminth species and highlight the need to consider this inequality in human coinfection studies.

scholarly journals Vaccine-Elicited 10-Kilodalton Culture Filtrate Protein-Specific CD8+ T Cells Are Sufficient To Mediate Protection against Mycobacterium tuberculosis Infection

2008 ◽  
Vol 76 (5) ◽  
pp. 2249-2255 ◽  
Author(s):  
Ying Wu ◽  
Joshua S. Woodworth ◽  
Daniel S. Shin ◽  
Sheldon Morris ◽  
Samuel M. Behar
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Culture Filtrate ◽  
Protective Immunity ◽  
Protective Antigen ◽  
T Cell Response ◽  
Rapid Expansion ◽  
Mycobacterium Tuberculosis Infection ◽  
Infected People ◽  
Culture Filtrate Protein

ABSTRACT The 10-kDa culture filtrate protein (CFP-10) and 6-kDa early secretory antigen of T cells (ESAT-6) are secreted in abundance by Mycobacterium tuberculosis and are frequently recognized by T cells from infected people. The genes encoding these proteins have been deleted from the genome of the vaccine strain Mycobacterium bovis bacillus Calmette-Guérin (BCG), and it is hypothesized that these proteins are important targets of protective immunity. Indeed, vaccination with ESAT-6 elicits protective CD4+ T cells in C57BL/6 mice. We have previously shown that M. tuberculosis infection of C3H mice elicits CFP-10-specific CD8+ and CD4+ T cells. Here we demonstrate that immunization with a CFP-10 DNA vaccine stimulates a specific T-cell response only to the H-2Kk-restricted epitope CFP-1032-39. These CFP-1032-39-specific CD8+ cells undergo a rapid expansion and accumulate in the lung following challenge of immunized mice with aerosolized M. tuberculosis. Protective immunity is induced by CFP-10 DNA vaccination as measured by a CFU reduction in the lung and spleen 4 and 8 weeks after challenge with M. tuberculosis. These data demonstrate that CFP-10 is a protective antigen and that CFP-1032-39-specific CD8+ T cells elicited by vaccination are sufficient to mediate protection against tuberculosis.

scholarly journals Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

2017 ◽  
Vol 24 (11) ◽  
Author(s):  
Ahreum Kim ◽  
Yun-Gyoung Hur ◽  
Sunwha Gu ◽  
Sang-Nae Cho
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Interleukin 2 ◽  
T Cell Epitopes ◽  
Content Type ◽  
Complete Form ◽  
Ifn Γ

ABSTRACT The aim of this study was to evaluate the protective efficacy of MTBK_24820, a complete form of PPE39 protein derived from a predominant Beijing/K strain of Mycobacterium tuberculosis in South Korea. Mice were immunized with MTKB_24820, M. bovis Bacilli Calmette-Guérin (BCG), or adjuvant prior to a high-dosed Beijing/K strain aerosol infection. After 4 and 9 weeks, bacterial loads were determined and histopathologic and immunologic features in the lungs and spleens of the M. tuberculosis-infected mice were analyzed. Putative immunogenic T-cell epitopes were examined using synthetic overlapping peptides. Successful immunization of MTBK_24820 in mice was confirmed by increased IgG responses (P < 0.05) and recalled gamma interferon (IFN-γ), interleukin-2 (IL-2), IL-6, and IL-17 responses (P < 0.05 or P < 0.01) to MTBK_24820. After challenge with the Beijing/K strain, an approximately 0.5 to 1.0 log10 reduction in CFU in lungs and fewer lung inflammation lesions were observed in MTBK_24820-immunized mice compared to those for control mice. Moreover, MTBK_24820 immunization elicited significantly higher numbers of CD4+ T cells producing protective cytokines, such as IFN-γ and IL-17, in lungs and spleens (P < 0.01) and CD4+ multifunctional T cells producing IFN-γ, tumor necrosis factor alpha (TNF-α), and/or IL-17 (P < 0.01) than in control mice, suggesting protection comparable to that of BCG against the hypervirulent Beijing/K strain. The dominant immunogenic T-cell epitopes that induced IFN-γ production were at the N terminus (amino acids 85 to 102 and 217 to 234). Its vaccine potential, along with protective immune responses in vivo, may be informative for vaccine development, particularly in regions where the M. tuberculosis Beijing/K-strain is frequently isolated from TB patients.

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