The Zebrafish Guide to Tuberculosis Immunity and Treatment

Ramakrishnan, Lalita

doi:10.1101/sqb.2013.78.023283

Cited by 64 publications

(56 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Zebrafish have also provided insights into human TB and raised questions that will be important to examine in human vaccine trials going forward [129]. In particular, a susceptibility factor involved in regulating TNF production (lta4h) was identified in a forward genetic screen in zebrafish, and a polymorphism of this gene was subsequently shown to confer susceptibility to TB in human populations [130, 131].…”

Section: The Path Forwardmentioning

confidence: 99%

Understanding and overcoming the barriers to T cell-mediated immunity against tuberculosis

Urdahl

2014

Seminars in Immunology

View full text Add to dashboard Cite

Despite the overwhelming success of immunization in reducing, and even eliminating, the global threats posed by a wide spectrum of infectious diseases, attempts to do the same for tuberculosis (TB) have failed to date. While most effective vaccines act by eliciting neutralizing antibodies, T cells are the primary mediators of adaptive immunity against TB. Unfortunately, the onset of the T cell response after aerosol infection with Mycobacterium tuberculosis (Mtb), the bacterium that causes TB, is exceedingly slow, and systemically administered vaccines only modestly accelerate the recruitment of effector T cells to the lungs. This delay seems to be orchestrated by Mtb itself to prolong the period of unrestricted bacterial replication in the lung that characterizes the innate phase of the response. When T cells finally arrive at the site of infection, multiple layers of regulation have been established that limit the ability of T cells to control or eradicate Mtb. From this understanding, emerges a strategy for achieving immunity. Lung resident memory T cells may recognize Mtb-infected cells shortly after infection and confer protection before regulatory networks are allowed to develop. Early studies using vaccines that elicit lung resident T cells by targeting the lung mucosa have been promising, but many questions remain. Due to the fundamental nature of these questions, and the need to understand and manipulate the early events in the lung after aerosol infection, only coordinated approaches that utilize tractable animal models to inform human TB vaccine trials will move the field towards its goal.

show abstract

Section: The Path Forwardmentioning

confidence: 99%

Understanding and overcoming the barriers to T cell-mediated immunity against tuberculosis

Urdahl

2014

Seminars in Immunology

View full text Add to dashboard Cite

show abstract

“…Third, the transparent larvae are ideal for imaging the early steps of the infection process in real time. Hence, zebrafish has earned its place of being a versatile tuberculosis model [1, 38, 39].…”

Section: Introductionmentioning

confidence: 99%

RNA-seq analysis of a zebrafish tlr2 mutant shows a broad function of this Toll-like receptor in transcriptional and metabolic control and defense to Mycobacterium marinum infection

Yang

Münch

et al. 2019

Preprint

View full text Add to dashboard Cite

RNA-seq analysis of a zebrafish tlr2 mutant shows a broad function of this Toll-like 1 receptor in transcriptional and metabolic control and defense to Mycobacterium 2 marinum infection 3 4 Abstract 23Background 24The function of Toll-like receptor 2 (TLR2) in host defense against pathogens, especially 25Mycobacterium tuberculosis (Mtb) is poorly understood. To investigate the role of TLR2 26 during mycobacterial infection, we analyzed the response of tlr2 zebrafish mutant larvae to 27 infection with Mycobacterium marinum (Mm), a close relative to Mtb, as a model for 28 tuberculosis. We measured infection burdens and transcriptome responses using RNA deep 29 sequencing in mutant and control larvae. 30Results 31 tlr2 mutant embryos at 2 dpf do not show morphological alterations or differences in the 32 number of macrophages and neutrophils when compared to control embryos. However, we 33 found substantial changes in gene expression in these mutants, particularly in developmental 34 and metabolic pathways, when compared with the heterozygote tlr2 +/control. After Mm 35 infection, bacterial burden was six to ten fold higher in tlr2 -/larvae than in tlr2 +/-, or tlr2 +/+ 36 larvae, indicating that Tlr2 acts as a protective factor in zebrafish host defense. RNAseq 37 analysis of infected tlr2 -/versus tlr2 +/shows that the number of up-regulated and down-38 regulated genes in response to infection was greatly diminished in tlr2 mutants by at least 2 39 fold and 10 fold, respectively. Analysis of the transcriptome data and qPCR validation shows 40 that Mm infection of tlr2 mutants leads to decreased mRNA levels of genes involved in 41 inflammation and immune responses, including il1b, tnfb, cxcl11aa/ac, fosl1a, and cebpb. 42 Furthermore, RNAseq analyses revealed that the expression of genes for Maf family 43 transcription factors, vitamin D receptors, and Dicps proteins is significantly altered in tlr2 44 mutants with or without infection. In addition, the data indicate a function of Tlr2 in the 45 4 control of induction of cytokines and chemokines, such as the CXCR3-CXCL11 signaling 46 axis. 47 Conclusion 48The transcriptome and infection burden analyses give support for a function of TLR2 in host 49 defense against mycobacteria. Transcriptome analysis revealed tlr2-specific pathways 50 involved in Mm infection, which are related to responses to Mtb infection in human 51 macrophages. Considering its dominant function in control of transcriptional processes that 52 govern defense responses and metabolism, the TLR2 protein can be expected to be also of 53 importance for other infectious diseases and interactions with the microbiome. 54 55 5 Background 56Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), which infects 57 nearly 23% of the world's population, and kills about 1.6 million people annually (WHO 58 Global Tuberculosis Report 2018). TB is characterized by the formation of granulomas, 59 aggregates of infected macrophages and other immune cells, not only in the lung but also in...

show abstract

“…Furthermore, the protective effects of 2-DG were validated in vivo using M. marinum -zebrafish infection model, which is widely used to study the role of host immunity in mycobacterial pathogenesis [11,12,13]. Specifically, previous studies have revealed the crucial role of aerobic glycolysis in cytokines production [14,15,16].…”

Section: Introductionmentioning

confidence: 99%

Temporal modulation of host aerobic glycolysis determines the outcome of M. marinum infection

Meng

Xie

Kan

et al. 2018

Preprint

View full text Add to dashboard Cite

24Macrophages are the first-line host defense where the invading Mycobacterium 25 tuberculosis (Mtb) encounters. It has been recently reported that host aerobic glycolysis 26 was elevated post the infection by a couple of virulent mycobacterial species. However, 27 whether this metabolic transition is required for host defense against intracellular 28 pathogens and the underlying mechanisms remain to be further investigated. By 29 analyzing carbon metabolism, we found that macrophages infected by M. marinum, a 30 surrogate mycobacterial specie to Mtb, showed a strong elevation of glycolysis. Next, 31 three glycolysis inhibitors were examined for their ability to inhibit mycobacterial 32 proliferation inside RAW264.7, a murine macrophage-like cell line. Among them, a 33 glucose analog, 2-deoxyglucose (2-DG) displayed a protective effect on assisting host 34 to resist mycobacterial infection, which was further validated in zebrafish-infection 35 model. The phagocytosis of M. marinum was significantly decreased in macrophages 36 pre-treated with 2-DG at concentrations of 0.5 and 1 mM, at which no inhibitory effect 37 was posed on M. marinum growth in vitro. Moreover, 2-DG pre-treatment exerted a 38 significant protective effect on zebrafish larvae to limit the proliferation of M. marinum, 39 and such effect was correlated to tumor necrosis factor alpha (TNF-α). On the contrary, 40 the 2-DG treatment post infection did not restrain proliferation of M. marinum in WT 41 zebrafish, and even accelerated bacterial replication in TNF-α -/zebrafish. Together, 42 modulation of glycolysis prior to infection boosts host immunity against M. marinum 43 infection, indicating a potential intervention strategy to control mycobacterial infection.44 3 45 46 Author Summary 47As an intracellular pathogen, Mtb exploits multiple strategies to invade and hijack 48 macrophages for its own advantages. Accordingly, recent investigations have shown 49 that Mtb infection is accompanied with an alteration of host glucose metabolism. 50Macrophage and zebrafish infection models of M. marinum, facilitating our 51 understanding towards mycobacterial pathogenesis, were applied in this study. We 52 found that the pre-treatment of macrophages with a glucose analog, 2-DG, inhibited 53 aerobic glycolysis and made host cells more inert to phagocytose the bud. In infected 54 zebrafish larvae, bacterial load inside host pretreated with 2-DG remains at a 55 significantly lower level compared to the untreated group. These findings imply that 56 the modulation of host glycolysis regulates the fate of M. marinum infection, and 57 indicate a promising metabolic target in TB intervention. 4 58 Introduction 59 Tuberculosis (TB), a serious chronic infectious disease caused by Mycobacterium 60 tuberculosis (Mtb), is still a major threaten to public health worldwide. The interaction 61 between Mtb and macrophages was initiated with phagocytosis [1]. Downstream cell 62 defense events will then be switched on, including phagosome maturation, acidification, 63 th...

show abstract

The Zebrafish Guide to Tuberculosis Immunity and Treatment

Cited by 64 publications

References 80 publications

Understanding and overcoming the barriers to T cell-mediated immunity against tuberculosis

Understanding and overcoming the barriers to T cell-mediated immunity against tuberculosis

RNA-seq analysis of a zebrafish tlr2 mutant shows a broad function of this Toll-like receptor in transcriptional and metabolic control and defense to Mycobacterium marinum infection

Temporal modulation of host aerobic glycolysis determines the outcome of M. marinum infection

Contact Info

Product

Resources

About