The long-term objective of this proposal is to gain insight into mechanisms of innate immunity to infectious agents in humans, with particular emphasis on the role of vitamin D in host defense. We recently reported that 25-hydroxyvitamin D (25D) is required for the Toll like receptor-induced antimicrobial response to Mycobacterium tuberculosis (M. tb.) in human macrophages including the induction of the antimicrobial peptide cathelicidin. Furthermore, African-Americans, known to have increased susceptibility to tuberculosis, had low serum 25D and their sera were inefficient in supporting cathelicidin mRNA induction unless supplemented with 25D in vitro. Our central hypothesis is that adequate host 25D primes a vigorous innate immune response to M. tb. Here, we propose to define the mechanism(s) by which TLR activation of human monocytes leads to antimicrobial activity, the role of the adaptive immune response in modulating this pathway and whether an in vivo supplementation intervention of 25D-deficient individuals with a standard regimen of oral vitamin D can restore TLR-induced antimicrobial activity in vitro. The proposed studies should provide new information about the human innate immune response with specific relevance to tuberculosis but of general interest to other microbial infections. It is hoped that the proposed studies will provide new insight into the role of 25D in innate immunity in humans and the potential use of vitamin D as an adjunct to therapy or preventative agent for infectious disease.

Public Health Relevance

We have chosen to study tuberculosis (TB), because it is a disease of global proportions that poses a major infectious disease risk, with the pathogen killing a human being every 15 seconds. Our preliminary data suggests a role for a form of vitamin D, 25-hydroxyvitamin D (25D3), in human host defense against the TB bacillus, in particular in 25D3-deficient African Americans, who are more susceptible to TB infection. The newly identified vitamin D antimicrobial pathway allows us to determine whether therapeutic intervention with vitamin D, costing a few dollars, could augment host defense and eventually be used as chemoprevention or as an adjuvant to chemotherapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Parker, Tina M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Adams, John S; Rafison, Brandon; Witzel, Sten et al. (2014) Regulation of the extrarenal CYP27B1-hydroxylase. J Steroid Biochem Mol Biol 144 Pt A:22-7
Teles, Rosane M B; Graeber, Thomas G; Krutzik, Stephan R et al. (2013) Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses. Science 339:1448-53
Liu, Philip T; Wheelwright, Matthew; Teles, Rosane et al. (2012) MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy. Nat Med 18:267-73
Adams, J S; Hewison, M (2012) Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase. Arch Biochem Biophys 523:95-102
Modlin, Robert L (2012) Innate immunity: ignored for decades, but not forgotten. J Invest Dermatol 132:882-6
Chun, Rene F; Adams, John S; Hewison, Martin (2011) Immunomodulation by vitamin D: implications for TB. Expert Rev Clin Pharmacol 4:583-91
Fabri, Mario; Realegeno, Susan E; Jo, Eun-Kyeong et al. (2011) Role of autophagy in the host response to microbial infection and potential for therapy. Curr Opin Immunol 23:65-70
Fabri, Mario; Stenger, Steffen; Shin, Dong-Min et al. (2011) Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci Transl Med 3:104ra102
Chun, Rene F; Lauridsen, Anna L; Suon, Lizabeth et al. (2010) Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab 95:3368-76
Modlin, Robert L (2010) The innate immune response in leprosy. Curr Opin Immunol 22:48-54

Showing the most recent 10 out of 13 publications