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The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Gombart AF. Future Microbiol. 2009 Nov;4:1151-65. PMID: 19895218 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

"Cathelicidin antimicrobial peptide is a family of polypeptides found in lysosomes in polymorphonuclear leukocytes (PMNs).[1] Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain. Cathelicidin peptides have been isolated from many different species of mammals. Cathelicidins were originally found in neutrophils but have since been found in many other cells including epithelial cells and macrophages activated by bacteria, viruses, fungi, or the hormone 1,25-D"

Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3.\nGombart AF, Borregaard N, Koeffler HP.\nFASEB J. 2005 Jul;19(9):1067-77.\nPMID: 15985530

"Numerous studies link Vitamin D and influenza, as well as Vitamin D and respiratory infections more generally. This vitamin up-regulates genetic expression of various endogenous antimicrobial peptides (AMP), which exhibit broad-spectrum microbicidal activity against bacteria, fungi, and viruses. Reports discussed below indicate that susceptibility to influenza is reduced with higher levels of sun exposure or vitamin D supplementation. Seasonal variation of vitamin D levels in humans can help explain the seasonality of flu epidemics."

The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Gombart AF. Future Microbiol. 2009 Nov;4:1151-65. PMID: 19895218 doi:10.2217/fmb.09.87

Vitamin D may suppress infections which lead to development of Multiple Sclerosis Steven R Brenner, None (16 August 2007) J Neurol Neurosurg Psychiatry 2008 I read the article with reference to the inverse relationship between multiple sclerosis clinical activity and deficiency of vitamin D by Soilu-Hannienen (1) with interest, and was considering what mechanism could be in play to cause such a relationship. 25-hydroxylated metabolites of vitamin D act as intracellular regulators of the synthesis and action of defensin (2) molecules against bacterial antigens, defensin being an endogenously synthesized antimicrobial substance (2). Human cathelicidin antimicrobial peptide gene is a target of vitamin D receptor and is strongly up-regulated by 1,25-dihydroxyvitamin D3, indicating vitamin D receptor and the 1,25-dihydroxyvitaminD3 regulate primate innate immunity (3)

"Defensins are small cysteine-rich cationic proteins found in both vertebrates and invertebrates. They are active against bacteria, fungi and many enveloped and nonenveloped viruses. They consist of 18-45 amino acids including six (in vertebrates) to 8 conserved cysteine residues. Cells of the immune system contain these peptides to assist in killing phagocytized bacteria, for example in neutrophil granulocytes and almost all epithelial cells. Most defensins function by binding to microbial cell membrane, and once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients

"Hi! This is Amy Proal. I wrote the article referenced at the start of the thread about vitamin D. Dr. Marshall is not concerned with vitamin D toxicity. Rather his molecular modeling research has clarified the actions of the two vitamin D metabolites 25-D and 1,25-D. The Vitamin D Receptor (VDR) is a fundamental receptor of the body - it controls the expression thousands of genes, as well as the activity of the innate immune system and the antimicrobial peptides. If you think of the VDR as a switch, 25-D (which is a corticosteroid) turns it off (inactivates it) and 1,25-D turn it on (activates it). What is commonly believed among vitamin D researchers is that if people supplement with extra vitamin D it will be converted into 1,25-D and activate the VDR. Unfortunately, Marshall's work revealed that the type of vitamin D derived from supplements and sun remains, for the most part, in it's precursor form 25-D. This means that the extra vitamin D we get from fortified food products and supplements is turning the VDR off, not on. That causes a decrease in immune function and gene transcription."

"If you're running low on vitamin D - as an estimated 70 percent of the U.S. population is - your immune system may not be functioning as well as it should. As a result, you may be more vulnerable to infectious diseases than you would if your vitamin D levels were optimal. Worse, you could be at higher than normal risk of a long list of diseases including heart disease and several kinds of cancer. A report recently published journal, Future Microbiology, highlighted research at the Linus Pauling Institute at Oregon State University, which has shown that vitamin D induces expression of an antimicrobial peptide gene called cathelicidin that is the "first line of defense" in the immune system's response to minor wounds, cuts and bacterial and viral infections. The regulation of cathelicidin by vitamin D could help explain its vital role in immune function. The report noted that vitamin D is a key cofactor in reducing inflammation, in blood pressure control and helping to protect against heart disease. Author Adrian Gombart explains that there is still much to explore about D's mechanisms of action, the potential use of synthetic analogs of it in new treatments, and its duty in fighting infection."

Vitamin D, respiratory infections, and asthma. Ginde AA, Mansbach JM, Camargo CA Jr. Curr Allergy Asthma Rep. 2009 Jan;9(1):81-7. Review. PMID: 19063829

Conclusion We demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs and remained under purifying selection for the last 55-60 million years. We present convincing evidence of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. Evolutionary selection to place the primate CAMP gene under regulation of the vitamin D pathway potentiates the innate immune response and may counter the anti-inflammatory properties of vitamin D. Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates. Gombart AF, Saito T, Koeffler HP. BMC Genomics. 2009 Jul 16;10:321. PMID: 19607716 doi:10.1186/1471-2164-10-321

A new study has concluded that one key part of the immune system, the ability of vitamin D to regulate anti-bactericidal proteins, is so important that is has been conserved through almost 60 million years of evolution and is shared only by primates, including humans - but no other known animal species.

Plasma 25-hydroxyvitamin D levels in young children undergoing placement of tympanostomy tubes.\nLinday LA, Shindledecker RD, Dolitsky JN, Chen TC, Holick MF.\nAnn Otol Rhinol Laryngol. 2008 Oct;117(10):740-4.\nPMID: 18998501