Modulation of T-Cell Activation During Mycobacterium tuberculosis Infection
Abstract
Mycobacterium tuberculosis (Mtb) causes the most infectious disease-related deaths in the world. Over 1.5 million people are killed annually, surpassing even HIV (human immunodeficiency virus) infections. While many developed countries have very low rates of the inflammatory disease tuberculosis (TB) caused by Mtb, there are endemic areas for TB around the globe. Like many of the most contagious infections, Mtb is transmitted through aerosol droplets produced by coughing. This route of transmission makes Mtb efficient at spreading between humans. There are several other factors that contribute to the TB crisis. A minimum of 6 months of multiple antibiotic treatment is required for drug-sensitive infections. Even worse, due to high levels of antibiotic resistance, some treatment regimens can last beyond a year and now “totally drug-resistant” strains have been isolated that appear to have no effective treatment whatsoever. This highlights the urgent need to develop new therapies that can prevent Mtb infection in the first place, or reduce treatment times and target drug-resistant strains. These new treatments would protect our Armed Forces from this devastating disease when they are deployed throughout the world. The overall goal of our proposal is to identify new targets for TB therapeutics that can be used to improve treatment outcomes. Upon inhalation of an infected aerosol droplet, Mtb is taken inside a specialized cell called a macrophage. Macrophages are normally effective at killing bacteria that are taken up; however, virulence strategies allow Mtb to evade this killing and replicate all while contained within a host cell. This presents a challenge to the host immune response that is responsible for responding to and eliminating invading pathogens. By living in an intracellular niche, TB can easily evade a subset of host immune responses. Therefore, the immune cells that are best equipped to eliminate Mtb infections are called T cells. T cells are immune cells that circulate the body looking for signals of infection. When they sense these infection cues, they become activated and directly kill the cells harboring pathogens, removing the Mtb intracellular niche and controlling infection. Much of the focus in Mtb research has been to find ways to activate more T cells. However, increasing the number and functionality of the T cells has not proven an effective approach at controlling TB disease. We believe that this is due to the inability of the T cells to accurately sense the signals of infection and find the infected cells efficiently due to Mtb interference. We predict that if we reprogram infected cells to more robustly send the correct signals of infection and identify themselves as an infected cell, we could augment control of infection and prevent active disease. We recently developed a platform to reprogram cells to more readily give the signals of infection. In this proposal, we will use this innovative approach in two parallel ways. In Aim 1, we will infect reprogrammed cells with Mtb and identify cells that give more robust signals of infection. After identification, we will follow up on each candidate to better understand how reprogramming bypassed Mtb evasion strategies. In Aim 2, we will directly test our prediction that increased signals of infection produced by infected cells leads to T cells that better control TB disease. These studies will inform future research to develop therapeutic approaches to reprogram cells in humans during Mtb. Given the TB crisis is only worsening, the time is ripe to apply innovative genetic approaches and uncover ways to undo Mtb immune evasion. The overall impact of these studies is three-fold. First, these studies will identify new potential therapeutic targets that may ultimately provide better protection against TB to our troops and the general population. Second, the unique cell reprogramming platform will allow us to examine a wide ran
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010147
Entities
People
- Andrew Olive
Organizations
- Michigan State University
- United States Army