Gombart AF. The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol 4, 1151-1165

Linus Pauling Institute, Department of Biochemisty & Biophysics, Oregon State University, Corvallis, 97331-7305, USA.
Future Microbiology (Impact Factor: 4.28). 11/2009; 4(9):1151-65. DOI: 10.2217/fmb.09.87
Source: PubMed


Vitamin D deficiency has been correlated with increased rates of infection. Since the early 19th century, both environmental (i.e., sunlight) and dietary sources (cod liver) of vitamin D have been identified as treatments for TB. The recent discovery that vitamin D induces antimicrobial peptide gene expression explains, in part, the 'antibiotic' effect of vitamin D and has greatly renewed interest in the ability of vitamin D to improve immune function. Subsequent work indicates that this regulation is biologically important for the response of the innate immune system to wounds and infection and that deficiency may lead to suboptimal responses toward bacterial and viral infections. The regulation of the cathelicidin antimicrobial peptide gene is a human/primate-specific adaptation and is not conserved in other mammals. The capacity of the vitamin D receptor to act as a high-affinity receptor for vitamin D and a low-affinity receptor for secondary bile acids and potentially other novel nutritional compounds suggests that the evolutionary selection to place the cathelicidin gene under control of the vitamin D receptor allows for its regulation under both endocrine and xenobiotic response systems. Future studies in both humans and humanized mouse models will elucidate the importance of this regulation and lead to the development of potential therapeutic applications.

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    • "Vitamin D3 is a potent endogenous inducer of hCAP18 in various cell types [87–92], as the CAMP gene promoter sequence contains vitamin D response elements (VDRE) for the vitamin D receptor (VDR), a transcription factor belonging to the steroid/hormone receptor family [88]. This is an evolutionarily recent form of regulation, as it is primatespecific , and likely derives from the exaptation of an ancient Alu short interspersed element [91]. It may be particularly useful to us as diurnal and hairless apes. "
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    ABSTRACT: The human cathelicidin hCAP18/LL-37 has become a paradigm for the pleiotropic roles of peptides in host defence. It has a remarkably wide functional repertoire that includes direct antimicrobial activities against various types of microorganisms, the role of 'alarmin' that helps to orchestrate the immune response to infection, the capacity to locally modulate inflammation both enhancing it to aid in combating infection and limiting it to prevent damage to infected tissues, the promotion of angiogenesis and wound healing, and possibly also the elimination of abnormal cells. LL-37 manages to carry out all its reported activities with a small and simple, amphipathic, helical structure. In this review we consider how different aspects of its primary and secondary structure, as well as its marked tendency to form oligomers under physiological solution conditions and then bind to molecular surfaces as such, explain some of its cytotoxic and immunomodulatory effects. We consider its modes of interaction with bacterial membranes and capacity to act as a pore-forming toxin directed by our organism against bacterial cells, contrasting this with the mode of action of related peptides from other species. We also consider its different membrane-dependent effects on our own cells, which underlie many of its other activities in host defence. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.
    No preview · Article · Nov 2015 · Biochimica et Biophysica Acta
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    • ", 2013 ) . Moreover , vitamin D elicits the expression of the anti - microbial peptides cathelicidin and defensin , important for counteracting infection ( Gombart , 2009 ) . Despite the substantial amount of evidence linking VDR and the immune response , its role in the regulation of the inflammatory response in mood disorders remains to be elucidated . "
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    ABSTRACT: Major depressive disorder (MDD) is a mood disorder of multifactorial origin affecting millions of people worldwide. The alarming estimated rates of prevalence and relapse make it a global public health concern. Moreover, the current setback of available antidepressants in the clinical setting is discouraging. Therefore, efforts to eradicate depression should be directed towards understanding the pathomechanisms involved in the hope of finding cost-effective treatment alternatives. The pathophysiology of MDD comprises the breakdown of different pathways, including the hypothalamus-pituitary-adrenal (HPA) axis, the glutamatergic system, and monoaminergic neurotransmission, affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. In addition, evidence from different studies suggests that impairment of glial functions appears to be a major contributor as well. Thus, the intricate role between glia, namely microglia and astrocytes, and the central nervous system's (CNSs) immune response is briefly discussed, highlighting the kynurenine pathway as a pivotal player. Moreover, evaluations of different treatment strategies targeting the inflammatory response are considered. The immuno-modulatory properties of vitamin D receptor (VDR) suggest that vitamin D is an attractive and plausible candidate in spite of controversial findings. Further research investigating the role of VDR in mood disorders is warranted.
    Full-text · Article · Jul 2015 · Frontiers in Cellular Neuroscience
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    • "Chronic disseminated candidiasis (CDC) is typically observed during neutrophil recovery in patients with acute leukemia, and the efficacy of corticosteroid therapy supports the pathophysiological hypothesis that CDC is a fungus-related immune reconstitution inflammatory syndrome [33]. The active form of vitamin D has been proved to inhibit M. tuberculosis, virus and bacteria through the induction of the cathelicidin antimicrobial peptide and β-defensins[34], [35], or autophagy[36], while decreasing the inflammatory response to microbial infections[37], [38], [39], [40], [41]. Upon in vitro LPS, C. albicans, and M. tuberculosis stimulation, the active form of vitamin D has been observed to inhibit the production of TNF-α, IL-1β, and IL-6 by monocytes directly, or through down-regulating the expression of TLR2, TLR4 and dectin-1 on monocytes [39], [40], [41], [42], [43]. "
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    ABSTRACT: Background Vitamin D plays an important role in pulmonary resistance and immunity, and its deficiency has been linked to various respiratory infections. Little is known about the effect of vitamin D deficiency on host pulmonary defense to Aspergillus fumigatus (A. fumigatus). Methods Mice raised on vitamin D sufficient or deficient diets were infected intratracheally with A. fumigatus conidia. Mortality, fungal growth, weight loss and lung histology were monitored. Alveolar macrophages (AMs) were stimulated with A. fumigatus conidia in vitro. The kinetics of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), chemokines (CXCL1, CCL3), and pattern recognition receptors (Toll-like receptor [TLR] 2, TLR 4 and dectin-1) expression in the lungs and AMs were measured. Results Upon A. fumigatus infection, vitamin D deficient mice showed higher mortality, greater fungal load, and more weight loss than its sufficient counterparts. Vitamin D deficient mice demonstrated aggravated and prolonged histological evidence of lung inflammation as well as enhanced BAL cell counts, dominated by neutrophils after A. fumigatus inoculation. Increased basal levels of pro-inflammatory cytokines in the lungs and AMs from naïve vitamin D deficient mice were observed. Upon A. fumigatus exposure, vitamin D deficiency led to enhanced and sustained expression of TNF-α, IL-1β, IL-6, CXCL1 and CCL3 both in vivo and in vitro. Up-regulation of TLR2, TLR4 and dectin-1was observed in the lungs and AMs from vitamin D deficient mice both at baseline and after A. fumigatus exposure. Conclusions Vitamin D deficiency causes defective pulmonary resistance to A. fumigatus in mice, possibly by the enhanced basal expression of pattern recognition receptors and pro-inflammatory cytokines, which induced excessive inflammatory response in response to A. fumigatus challenge.
    Full-text · Article · Jun 2014 · PLoS ONE
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