Date of Graduation
5-2011
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Chinnaswamy Jagannath
Committee Member
Robert L. Hunter
Committee Member
David McMurray
Committee Member
Bradley McIntyre
Committee Member
Audrey Wanger
Abstract
Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D3 (VD) on macrophages in relation to the viability of Mtb. A combination of these vitamins (RAVD) enhanced the receptors on THP-1 macrophage (Mannose receptor and DC-SIGN) that increased mycobacterial uptake but inhibited the
subsequent intracellular growth of Mtb by inducing reactive oxygen species (ROS) and autophagy. RAVD also enhanced antigen presenting and homing receptors in THPs that suggested an activated phenotype for THPs following RAVD treatment. RAVD mediated activation was also associated with a marked phenotypic change in Mtb infected THPs that fused with adjacent cells to form
multinucleate giant cells (MNGCs). Typically MNGCs occurred over 30 days of in vitro culture and contained non-replicating persisting Mtb for as long as 60 days in culture. We propose that the RAVD mediated inhibition of replicating Mtb leading to persistence of non-replicating Mtb within THPs may provide a novel human macrophage model simulating formation of MNGCs in human
lungs.
Keywords
Vitamin D, Retinoic Acid, Mycobacterium tuberculosis, multi-nucleated giant cell, THP-1 macrophages, Phorbol myristate acetate
Included in
Immunology of Infectious Disease Commons, Immunopathology Commons, Pathogenic Microbiology Commons