Vitamin D Status and the Host Resistance to Infections: What It Is Currently (Not) Understood

Purpose Vitamin D is increasingly thought to play a role in regulating immunity. This comprehensive review updates the current understanding regarding ways in which we believe that vitamin D regulates responsiveness of the immune system and how serum status modulates the host defense against pathogens. Methods The literature was searched by using PubMed and Scopus with the following key words: vitamin D, immunity, innate and adaptive immunity, infectious disease, and vaccine response. Findings Vitamin D deficiency remains a major public health concern worldwide. The overall body of evidence confirms that vitamin D plays an important role in modulating the immune response to infections. Epidemiologic studies suggest a clear association between vitamin D deficiency and susceptibility to various pathogens. However, translation of vitamin D use into the clinic as a means of controlling infections is fraught with methodologic and epidemiologic challenges. The recent discovery of alternative activation pathways, different active forms of vitamin D, and possible interaction with non–vitamin D receptors provide further complications to an already complex interaction between vitamin D and the immune system. Moreover, it has become apparent that the individual responsiveness to supplementation is more dynamic than presumed from the static assessment of 25-hydroxy vitamin D status. Furthermore, the epigenetic response at the level of the individual to environmental changes and lifestyle or health conditions provides greater variation than those resulting from vitamin D receptor polymorphisms. Implications To understand the future of vitamin D with respect to clinical applications in the prevention and better control of infectious diseases, it is necessary to determine all aspects of vitamin D metabolism, as well as the mechanisms by which active forms interact with the immune system globally. For the most part, we are unable to identify tissue-specific applications of supplementation except for those subjects at high risk of osteomalacia and osteoporosis.