Dietary Vitamin D3 Suppresses Pulmonary Immunopathology Associated with Late-Stage Tuberculosis in C3HeB/FeJ Mice

Reeme, Allison E.; Robinson, Richard

doi:10.4049/jimmunol.1500931

Cited by 27 publications

(21 citation statements)

References 63 publications

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“…A 79 nmol L −1 (31.6 ng mL −1 ) increase in serum 25(OH)D was seen amongst participants in the intervention arm of the study, which was associated with a trend towards faster sputum culture conversion ( P = 0.14) and accelerated resolution of inflammatory responses in peripheral blood . This finding was echoed by a subsequent study conducted in mice . A subgroup analysis revealed that adjunctive vitamin D significantly hastened sputum culture conversion by more than 17 days in participants with the tt genotype of the TaqI VDR polymorphism (hazard ratio 8.09, 95% CI 1.36–48.01; P = 0.02) , indicating that immunomodulatory effects of vitamin D supplementation are dependent on VDR genotype.…”

Section: Randomized Controlled Trials Investigating the Effects Of VImentioning

confidence: 91%

Vitamin D and tuberculosis: where next?

2018

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Tuberculosis (TB) has troubled mankind for millennia, but current treatment strategies are long and complicated and the disease remains a major global health problem. The risk of Mycobacterium tuberculosis (Mtb) infection or progression of active TB disease is elevated in individuals with vitamin D deficiency. High-dose vitamin D was used to treat TB in the preantibiotic era, and in vitro experimental data show that vitamin D supports innate immune responses that restrict growth of Mtb. Several randomized controlled trials have tested whether adjunctive vitamin D supplementation enhances the clinical and microbiological response to standard antimicrobial chemotherapy for pulmonary TB. The effects have been modest at best, and attention is turning to the question of whether vitamin D supplementation might have a role in preventing acquisition or reactivation of latent Mtb infection. In this article, we describe the effects of vitamin D on host immune responses to Mtb in vitro and in vivo and review the results of clinical trials in the field. We also reflect on the findings of clinical trials of vitamin D supplementation for the prevention of acute respiratory tract infections, and discuss how these findings might influence the design of future trials to evaluate the role of vitamin D in the prevention and treatment of TB.

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Section: Randomized Controlled Trials Investigating the Effects Of VImentioning

confidence: 91%

Vitamin D and tuberculosis: where next?

2018

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“…S7 and S9) also implicated the expression of the Tlr8 pathway connected to vitamin D signaling as being strongly affected in the tlr2 mutant. Vitamin D has been shown to be an important regulatory factor during tuberculosis [72] and has been linked previously to TLR2 function in studies in cell cultures [73]. Therefore, aberrant vitamin D signaling could be a major contributing factor to the hyper-susceptibility phenotype of tlr2 mutants in Mm infection.…”

Section: Discussionmentioning

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

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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...

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“…One study demonstrated polymorphism of the vitamin D binding protein to be protective in people to blastomycosis . A recent study found that oral vitamin D supplementation in M. tuberculosis ‐infected mice did not decrease the bacterial load but rather was beneficial in decreasing TB‐associated immunopathology …”

Section: Discussionmentioning

confidence: 99%

25‐Hydroxyvitamin D concentrations in dogs with naturally acquired blastomycosis

O'Brien

McMichael

Boedec

2018

Veterinary Internal Medicne

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BackgroundHypovitaminosis D is common in humans with tuberculosis, and adequate serum 25‐hydroxyvitamin D [25(OH)D] concentrations may improve response to therapy. The pathomechanism of Blastomyces dermatitidis is similar to that of Mycobacterium tuberculosis, but the 25(OH)D status of dogs with blastomycosis has not been investigated.ObjectivesTo determine if dogs with blastomycosis have lower 25(OH)D concentrations compared with healthy controls and to explore the prognostic value of 25(OH)D concentrations in blastomycosis.Animals35 control dogs (16 client‐owned, healthy dogs and 19 healthy, random‐source hound mixes) and 22 dogs with blastomycosis.MethodsProspective study. Serum concentrations of 25(OH)D, parathyroid hormone (PTH), ionized calcium were measured, and biochemistry and hematology profiles were performed. The 25‐hydroxyvitamin D concentrations were compared between groups, and factors associated with 25(OH)D variation were investigated in dogs with blastomycosis. Dogs with blastomycosis were followed for up to 5 years after discharge and factors associated with survival were investigated.ResultsDogs with blastomycosis had significantly lower concentrations of 25(OH)D and PTH and higher concentrations of ionized calcium than did control dogs. In dogs with blastomycosis, 25(OH)D concentrations were independently associated with neutrophil count, pCO2, and with bone and skin involvement. The 25‐hydroxyvitamin D concentration was not associated with survival in dogs with blastomycosis, whereas lactate concentrations; bone, skin, and lymph node involvement; number of affected sites; and, presence of respiratory signs were associated with survival.Conclusions and Clinical ImportanceDogs with blastomycosis had lower 25(OH)D concentrations than did healthy controls. Despite no impact on survival, investigating the effect of 25(OH)D supplementation on recovery is warranted.

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Dietary Vitamin D3 Suppresses Pulmonary Immunopathology Associated with Late-Stage Tuberculosis in C3HeB/FeJ Mice

Cited by 27 publications

References 63 publications

Vitamin D and tuberculosis: where next?

Vitamin D and tuberculosis: where next?

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

25‐Hydroxyvitamin D concentrations in dogs with naturally acquired blastomycosis

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