Active Tuberculosis Is Characterized by Highly Differentiated Effector Memory Th1 Cells
Riccardo ArrigucciKarim LakehalPooja VirDeborah HandlerAmy L. DavidowRosa María Blanca HerreraJulia Dolores Estrada-GuzmánYuri BushkinSanjay TyagiAlfred LardizabalMaria Laura Gennaro
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Despite advances in diagnosing latent Mycobacterium tuberculosis infection (LTBI), we still lack a diagnostic test that differentiates LTBI from active tuberculosis (TB) or predicts the risk of progression to active disease. One reason for the absence of such a test may be the failure of current assays to capture the dynamic complexities of the immune responses associated with various stages of TB, since these assays measure only a single parameter (release of IFNγ) and rely on prolonged (overnight) T cell stimulation. We describe a novel, semi-automated RNA flow cytometry assay to determine whether immunological differences can be identified between LTBI and active TB. We analyzed antigen-induced expression of Th1 cytokine mRNA after short (2- and 6-hr) stimulation with antigen, in the context of memory T cell immunophenotyping. IFNG and TNFA mRNA induction was detectable in CD4+ T cells after only two hours of ex vivo stimulation. Moreover, IFNG- and TNFA-expressing CD4+ T cells (Th1 cells) were more frequent in active TB than in LTBI, a difference that is undetectable with conventional, protein-based cytokine assays. We also found that active TB was associated with higher ratios of effector memory to central memory Th1 cells than LTBI. This effector memory phenotype of active TB was associated with increased T cell differentiation, as defined by loss of the CD27 marker, but not with T cell exhaustion, as determined by PD-1 abundance. These results indicate that single-cell-based, mRNA measurements may help identify time-dependent, quantitative differences in T cell functional status between latent infection and active tuberculosis.Keywords:
Immunophenotyping
Ex vivo
Immunophenotyping
Minimal Residual Disease
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Horticultural crops suffer from bacterial, fungal, and oomycete pathogens. Effectors are one of the main weapons deployed by those pathogens, especially in the early stages of infection. Pathogens secrete effectors with diverse functions to avoid recognition by plants, inhibit or manipulate plant immunity, and induce programmed cell death. Most identified effectors are proteinaceous, such as the well-studied type-III secretion system effectors (T3SEs) in bacteria, RXLR and CRN (crinkling and necrosis) motif effectors in oomycetes, and LysM (lysin motifs) domain effectors in fungi. In addition, some non-proteinaceous effectors such as toxins and sRNA also play crucial roles in infection. To cope with effectors, plants have evolved specific mechanisms to recognize them and activate effector-triggered immunity (ETI). This review summarizes the functions and mechanisms of action of typical proteinaceous and non-proteinaceous effectors secreted by important horticultural crop pathogens. The defense responses of plant hosts are also briefly introduced. Moreover, potential application of effector biology in disease management and the breeding of resistant varieties is discussed.
Oomycete
Plant Immunity
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Identification
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There is a continuous arms race between pathogens and their host plants. However, successful pathogens, such as phytopathogenic oomycetes, secrete effector proteins to manipulate host defense responses for disease development. Structural analyses of these effector proteins reveal the existence of regions that fail to fold into three-dimensional structures, intrinsically disordered regions (IDRs). Because of their flexibility, these regions are involved in important biological functions of effector proteins, such as effector-host protein interactions that perturb host immune responses. Despite their significance, the role of IDRs in phytopathogenic oomycete effector-host protein interactions is not clear. This review, therefore, searched the literature for functionally characterized oomycete intracellular effectors with known host interactors. We further classify regions that mediate effector-host protein interactions into globular or disordered binding sites in these proteins. To fully appreciate the potential role of IDRs, five effector proteins encoding potential disordered binding sites were used as case studies. We also propose a pipeline that can be used to identify, classify as well as characterize potential binding regions in effector proteins. Understanding the role of IDRs in these effector proteins can aid in the development of new disease-control strategies.
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Abstract Microbial plant pathogens use secreted effector proteins for successful infection of their host. This evolved state is rather exceptional as most microbes do not cause disease in the vast majority of plant species. An important primary activity of effectors is to interfere with a range of plant immune processes to evade and suppress pathogen detection, or to block immune signalling and downstream responses. Furthermore, effectors can enhance disease susceptibility by altering cellular processes and modulating host transcription. For most of these activities, effectors specifically target plant proteins that are central in these processes. An advanced virulence strategy is the post‐translational modification by effectors of plant targets to change their activity or stability. The knowledge gathered on the molecular mechanisms underlying effector‐triggered susceptibility of plants provides great potential for novel approaches of resistance breeding. Key Concepts Pathogens secrete and/or translocate effector proteins to promote plant disease. Besides their primary role in promoting disease, effectors or effector‐modified plant proteins can be recognised by resistance proteins to activate an effector‐triggered immune response. Many effectors block pathogen‐associated molecular pattern (PAMP)‐triggered immunity and/or effector‐triggered immunity. Other effectors rewire signalling pathways and reprogramme the plant cell to promote pathogen growth. Certain effectors can affect the activity or function of host proteins by post‐translational modifications e.g. (de)phosphorylation or targeting for proteosomal degradation.
Plant Immunity
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Human tuberculosis (TB) is caused by various members of the Mycobacterium tuberculosis (Mtb) complex. Differences in host response to infection have been reported, illustrative of a need to evaluate efficacy of novel vaccine candidates against multiple strains in preclinical studies. We previously showed that the murine lung and spleen direct mycobacterial growth inhibition assay (MGIA) can be used to assess control of ex vivo mycobacterial growth by host cells. The number of mice required for the assay is significantly lower than in vivo studies, facilitating testing of multiple strains and/or the incorporation of other cellular analyses. Here, we provide proof-of-concept that the murine MGIA can be applied to evaluate vaccine-induced protection against multiple Mtb clinical isolates. Using an ancient and modern strain of the Mtb complex, we demonstrate that ex vivo bacillus Calmette–Guérin (BCG)-mediated mycobacterial growth inhibition recapitulates protection observed in the lung and spleen following in vivo infection of mice. Further, we provide the first report of cellular and transcriptional correlates of BCG-induced growth inhibition in the lung MGIA. The ex vivo MGIA represents a promising platform to gain early insight into vaccine performance against a collection of Mtb strains and improve preclinical evaluation of TB vaccine candidates.
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Tuberculosis vaccines
BCG vaccine
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Plant diseases caused by fungal pathogens are typically initiated by molecular interactions between ‘effector’ molecules released by a pathogen and receptor molecules on or within the plant host cell. In many cases these effector-receptor interactions directly determine host resistance or susceptibility. The search for fungal effector proteins is a developing area in fungal-plant pathology, with more than 165 distinct confirmed fungal effector proteins in the public domain. For a small number of these, novel effectors can be rapidly discovered across multiple fungal species through the identification of known effector homologues. However, many have no detectable homology by standard sequence-based search methods. This study employs a novel comparison method (RemEff) that is capable of identifying protein families with greater sensitivity than traditional homology-inference methods, leveraging a growing pool of confirmed fungal effector data to enable the prediction of novel fungal effector candidates by protein family association. Resources relating to the RemEff method and data used in this study are available from https://figshare.com/projects/Effector_protein_remote_homology/87965 .
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Architecture domain
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Effectors are small, secreted molecules that mediate the establishment of interactions in nature. While some concepts of effector biology have stood the test of time, this area of study is ever-evolving as new effectors and associated characteristics are being revealed. In the present review, the different characteristics that underly effector classifications are discussed, contrasting past and present knowledge regarding these molecules to foster a more comprehensive understanding of effectors for the reader. Research gaps in effector identification and perspectives for effector application in plant disease management are also presented, with a focus on fungal effectors in the plant-microbe interaction and interactions beyond the plant host. In summary, the review provides an amenable yet thorough introduction to fungal effector biology, presenting noteworthy examples of effectors and effector studies that have shaped our present understanding of the field.
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Objective To study the relationship of immunophenotype and FAB phenotype and guide clinical analysis and treatment.Methods Cell morphology checking and immunophenotyping were performed at the same time for the 505 patients with leukemia,flow cytometry had used for immunophenotype,on the end the results had been analyzed to understand the relationship between the two phenotypes.Results ①Among the 505 cases of leukemia,there were AML(248)、ALL(200)、CML(18)、CLL(15)、HAL(14)、UAL(10) in FAB phenotype and AML(163)、Ly+AML(83)、ALL(108)、My+ALL(106)、HAL(32)、UAL(13) in immunophenotype.② In AML the accordance rate and part accordance rate of the two phenotypes was 61.3% and 30.2%.In ALL the accordance rate was and part accordance rate was 53% and 44.5%.In HAL the accordance rate was 42.9%.Conclusion Immunophenotype plays an important role to distinguish AML、ALL subtype、variants leukemia and HAL.Immunophenotyping was shaper and more accurate than FAB phenotype,and is a supplementary and correction,but it can not replace the FAB phenotype.Combination of both can improve the diagnostic accuracy.
Immunophenotyping
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