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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073539-04
Application #
8073042
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Parker, Tina M
Project Start
2008-06-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$439,451
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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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
Parvatiyar, Kislay; Zhang, Zhiqiang; Teles, Rosane M et al. (2012) The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol 13:1155-61
Modlin, Robert L (2012) Innate immunity: ignored for decades, but not forgotten. J Invest Dermatol 132:882-6

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