October 30, 2024
National Institute of Allergy and Infectious Diseases (NIAID)
Mycobacterium tuberculosis (Mtb) produces a spectrum of clinical states and disease in humans during both active disease and latent infection. For treatment outcomes, clinicians typically consider treatment to have either succeeded or failed based primarily on microbiological outcomes defined by sputum culture. However, the long-term clinical outcome of tuberculosis (TB) treatment is more complex, with some cured patients afflicted with irreversible lung damage and debilitating chronic lung function impairment that has come to be known as Post-TB Lung Disease (PTLD). Thirty to 50% of TB treatment survivors have chronic cardiac and pulmonary impairment. While some data have indicated that HIV co-infection may limit the risk of developing PTLD, extensive studies of the effect of HIV have not been conducted to determine whether antiretroviral therapy (ART), the level of viral suppression, and/or immune reconstitution have roles in PTLD development. To prevent the long-term impact of active TB on lung health, a better understanding of the mechanisms involved in the development of PTLD occurring before, during, and after TB treatment are needed.
Compromised lung function starting before and progressing through treatment has been observed and may drive the development of chronic lung impairment after treatment. The lung is unlike most other organs in that it has limited capacity for regenerative repair. In response to extensive damage, the lung heals by a non-regenerative process resulting in fibrous scar tissue, which can cause serious loss of lung function. During intense inflammation, proteases and other effectors disrupt the basement membrane underlying the alveolar epithelium. When this essential structural pulmonary component is damaged, regenerative repair is not possible and fibrotic repair dominates. Improving control of the inflammatory necrotic process during early TB therapy may be the most feasible way to limit lung/basement membrane damage and preserve lung function. A greater mechanistic understanding of lung injury prior to and through TB treatment will improve insight into the development of PTLD and may lead to identification of interventions to mitigate long-term lung pathology.
Most of our understanding of PTLD comes from long-term human cohorts. NIAID has had ongoing clinical and epidemiological efforts in long-term cardiopulmonary disease sequelae following treatment for TB (https://www.niaid.nih.gov/grants-contracts/characterize-post-tuberculosis-lung-disease); however, animal models for the development of PTLD seen in humans could help address the mechanistic questions that are difficult to answer when relying solely on human studies. These questions include whether specific mechanisms during TB treatment can be identified that can augment or minimize PTLD, whether the immune response can be targeted during TB therapy to preserve lung health, and whether Mtb strain differences affect lung impairment induction.
The purpose of this Notice of Special Interest (NOSI) is to invite applications for basic and translational research establishing and utilizing animals to model the development of post-TB lung disease (PTLD). This NOSI will support the establishment and utilization of pre-clinical animal models that strive to (1) better understand the pathophysiology of long-term lung damage resulting from pulmonary TB or (2) better understand the role of the immune response during TB treatment in long-term lung damage. Validating results with animal models using clinical samples is allowable, but clinical trials and clinical research will not be supported under this NOSI.
Research topics of interest that the establishment and utilization of a preclinical animal model of PTLD development could support include but are not limited to:
The areas below will NOT be supported through this NOSI:
Application and Submission Information
This notice applies to due dates on or after February 5, 2025 and subsequent receipt dates through January 7, 2028.
Submit applications for this initiative using one of the following notices of funding opportunity (NOFOs) or any reissues of these announcements through the expiration date of this notice.
All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:
Scientific/Research Contact(s)
Robert Mahon, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5427
Email: Robert.mahon@nih.gov
Financial/Grants Management Contact(s)
Robert Kirker
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-451-3176
Email: robert.kirker2@nih.gov