shadow_tr

Tuberculosis

photo: disease

Tuberculosis (TB) is a life threatening and debilitating disease transmitted through the air from person-to-person by breathing in bacteria called Mycobacterium tuberculosis.

  • It is estimated that ~ 2.5 billion people (one third of the world population) harbor latent TB infections, and 5- 10% of them carry a lifetime risk of reactivating their disease.
  • TB is a pandemic in sub-Saharan Africa, and a major problem in Asia, China, the pacific rim and Latin American countries, and the former Soviet Union.
  • In the U.S., tuberculosis began to disappear after several effective drugs were developed in the 1940's. Although there was a temporary increase in TB during the 1985-1992 AIDS epidemic, today about 16,000 annual cases are reported.
  • TB primarily develops in patients who have an immune system that cannot stop the growth of the bacteria. Babies and young children are at risk before their immune system is fully developed. People with HIV infection (AIDS) have very weak immune systems, as do patients with drug abuse problems, diabetes, silicosis, cancer, kidney disease, low body weight, and those undergoing systemic corticosteroid treatment or organ transplants. Similarly, the elderly, and people with Type 2 Diabetes are also at ris

Infectious Agent

TB is caused by Mycobacterium tuberculosis, a gram positive bacillus with ability to replicate within myeloid cells.

While the bacillus can infect most tissues, due to the aerogenic route of transmission, the lungs are usually affected.

Mycobacterium tuberculosis (Mtb) is the most common organism infecting humans, but Mycobacterium bovis, which infects animals, produces an indistinguishable infection in humans. Numerous closely related strains of these organisms can be distinguished by genetic tests.

A large number of people (~90%) infected with Mtb remain asymptomatic – a condition referred to as latent tuberculosis infection (LTBI). While there is immunological evidence of exposure, there are no signs of TB disease in LTBI.

Multidrug resistant tuberculosis (MDR-TB) is caused by the same organism, Mtb, but the some of the frontline drugs used against the bacterium is no longer effective. The bacterium acquires this ability through genetic mutation probably caused by inadequate or incomplete therapy; although it has been hypothesized that persister bacilli in the tissues can become phenotypically transformed to antibiotic tolerance via switches in genetic programs. Patients infected with the various MDR strains of tuberculosis cannot be cured with the standard drug regimens. Cases of Extremely Drug Resistant (XDR) and Totally Drug Resistant (TDR) – TB have also been reported.

Transmission

TB is spread through the air when a person with TB lung disease coughs or sneezes. People nearby breath in the bacteria and become infected.

TB is most likely spread to people with whom a patient has daily contact such as family members, friends, and coworkers.

People cannot get infected with TB through handshakes, sitting on public toilet seats, or by sharing dishes and utensils with a TB patient.

The Disease

TB symptoms can vary depending on where in the body TB bacteria are growing. In the lung, TB may cause a bad cough that lasts for more than two weeks, pain in the chest, coughing up blood, weakness, weight loss, no appetite, chills, fever, and night sweats.

Infection can be detected by skin test and by chest x-ray. Confirmation of TB disease is based on clinical signs, culture of the bacterium, and/or molecular testing for the bacterium.

Treatment

Effective drugs are available including isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin. Usually, multiple drugs are prescribed and taken together in a regime that lasts six months to a year.

Patients with lung infections are usually not infective to others after two weeks of treatment.

If treatment is not completed or is taken irregularly, the risk of developing a multidrug resistant strain of TB increases significantly.

In most of the world, BCG (a weakened strain of Mycobacterium bovis) is used as a vaccine to prevent TB. Because the vaccine has proven unreliable, it has never been approved for wide scale use in the United States.

Our Research

The TNPRC TB research program is funded by the National Institutes of Health (NIAID, NHLBI and NIGMS), as well as by the Bill and Melinda Gates Foundation, the Louisiana Board of Regents, the Wetmore Foundation, and other entities to study a large array of TB related questions

  1. Understanding the response of Mtb to in vivo stress. Understanding bacterial gene expression in vivo is central to unraveling mechanisms of disease caused by intracellular bacteria such as Mtb. We are specifically Interested in the intersection of the pathways governed by stress-response transcription factors SigH, DosR and ClgR and their role in potentiating the survival and persistence of Mtb in vivo. It is hypothesized that these regulatory genes play a crucial role in the process of adaptation of M. tuberculosis to the intracellular milieu, and hold the secret of this bacterium's virulence.
  2. Understanding the role of inducible bronchus associated lymphoid tissue in mediating granuloma level protection from TB. iBALT contains spatially organized T cells, B cells and macrophages and its presence is associated with better protective outcomes during TB. Additionally, a dominant feature of the granulomatous inflammation is the accumulation of neutrophils that produce inflammatory molecules such as S100A8/A9 proteins. Based on these new data, we are testing a paradigm-shifting hypothesis that a protective TB granuloma is one that contains iBALT and contributes to Mtb containment during LTBI. In contrast, progression to a more neutrophilic, inflammatory granuloma causes TB reactivation, loss of Mtb control and progression to PTB. We are addressing the function of persistent iBALT in limiting reactivation and dissemination in the NHP model of TB/SIV co-infection. Finally, we are addressing whether iBALT structures can be enhanced, or neutrophilic granulomas reversed, to decrease TB reactivation and disease severity during latency and SIV co-infection.
  3. Identifying classically activated T cell based antigen-specific responses associated with protection vs. disease. We are focusing on the mechanisms by which Mtb-specific T cell responses maintain LTBI, confer protective immunity or result in HIV-induced reactivation of LTBI. We hypothesize that co-infection with HIV depletes and/or impairs in the functional capacities of Mtb-specific CD4 and CD8 T cells to drive reactivation of LTBI and that antiretroviral therapy (ART) only partially restores these functions. We propose to test this hypothesis using mechanistic experiments in the nonhuman primate model of inhalation TB. We are also focusing on the identity of specific T cell responses that direct he control of Mtb in the LTBI state, or are responsible for reactivation. We propose to identify the immune signatures associated with control of Mtb infection as LTBI either spontaneously or upon therapy, in macaques.
  4. CD4 T cell independent mechanisms of protection from TB and HIV-induced reactivation of TB. Here we are using the macaque model of TB and of Mtb/SIV co-infection to study a variety of immune components, such as CD8 T cells, macrophages, NK cells, and innate lymphoid cells, especially ILC3 cells, and mucosal associated invariant T (MAIT) cells.
  5. Identification of biomarkers of the various stages of disease and infection. We are using transcriptomic and epigenetic approaches to define active vs. latent TB as well as reactivation of latent TB due to SIV (as a surrogate for HIV) co-infection. We are also interested in better defining the immunological mechanism of SIV-mediated reactivation of latent TB in primate lungs.
  6. Host-directed approaches to better treat TB. We are testing several host-directed approaches. Of these, one (Imatinib) has shown promising preclinical results adjunctive to chemotherapy and is now included in an NIH-supported clinical trial. Another has shown promise as a stand-alone reagent and is now being tested by Dr. Mehra adjunctive to chemotherapy. Agents targeting multiple pathways such as AMPK, NAD+ and SIRT are under investigation.
  7. Development of attenuated vaccines against TB. We are focused on the development of an extremely safe vaccine based on Stress-response attenuation. Our focus is to develop vaccines that can be mucosally delivered, elicit potent lung T and B cell responses and would be safe in the HIV+ population.

The TNPRC is a division of Tulane University (985) 871-6201 tnprc@tulane.edu