Tuberculosis (TB) kills 1-2 million people each year, making it the second leading cause of death due to an infectious agent. Almost 9 million TB patients are newly diagnosed each year, and half had latent TB infection (LTBI) prior to becoming sick. It is well known that LTBI bacilli are difficult to detect and difficult to treat. Many fundamental questions regarding LTBI are unanswered including: Where does virulent etiological agent of TB, Mycobacterium tuberculosis (M.tb) persist in vivo? How does M.tb persist when immunity or when antibiotics are present? How does M.tb leave the LTBI niche to cause reactivation TB? This latter unsolved question is particularly important for the understanding of the mechanisms by which reactivation occurs during co-infection with HIV. This project will address these important questions focusing primarily on the protection afforded by the newly described host cell for M.tb, the CD271+ bone marrow mesenchymal stem cell (BM-MSC). BMSCs are ideal cellular hosts for LTBI because these cells harbor poorly replicative M.tuberculosis;BMSC's lack antibacterial and immune activation functions;and BMSCs have membrane efflux pumps that may prevent antibiotics from acting on M.tb. The proposals are built on our results published early this year in Science Translational Medicine and on exciting unpublished data using the Cornell model of LTBI.
The specific aims are:
Aim 1. Define the mechanisms that protect M.tb in CD271+ BMSCs from immunity.
Aim 2. Determine how M.tb in CD271+ BMSCs can be reactivated to cause active TB.
Aim 3. Identify how CD271+ BMSCs protect M.tb from antibiotics. These studies are important because they address the following specific critical knowledge gaps: 1. Understanding of reactivation of LTBI in the context of a variety of immunossupressive scenarios including co-infection with HIV. 2. TB vaccine development, by defining mechanisms that contribute to M.tb's immune evasion. 3. TB drug development, by defining mechanisms that contribute to M.tb's drug evasion.
The microbe Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB), a deadly disease, in millions of humans and infects billions of others without causing apparent clinical manifestations (latent of dormant TB infection). M.tb achieves this spectacular success despite being vigorously attacked by the immune cells. We have recently shown that M.tb escapes the host immune defense by hiding inside bone marrow mesenchymal stem cells (BM-MSCs), a resounding immune-privileged protective niche. Because the BM-MSCs have molecular drug efflux pumps that prevent internalization of foreign molecules, like drugs, these results have direct implications in anti-TB drug development and may explain why it is so difficult to treat active and latent TB. In the present application, we will use a mouse model of TB to: a) dissect the mechanisms by which M.tb can successfully reside in a latent stage inside BM-MSCs;b) to evaluate how reactivation of the latent infection may occur including under immunodeficiency conditions that mimic those caused by HIV infection in humans;and c) to evaluate how this unique host/pathogen relationship protects the microbe from therapeutic drugs.