The emergence and spread of disease caused by drug resistant forms of Mycobacterium tuberculosis (Mtb) represents a significant global threat, creating an urgent need for development of preventive and therapeutic strategies efficient against antibiotic-resistant Mtb. We propose a novel concept for developing drugs that cooperate with low doses of IFN-? and selectively increase its beneficial effect on host resistance to infections. Essentiality of the IFN-? pathway in resistance to a broad range of pathogens, including various mycobacterial species, has been convincingly demonstrated both in experimental mouse models and clinical studies. However, pathogens have evolved diverse mechanisms to suppress it. Therefore, therapeutic interventions aimed at restoration and maintenance of the IFN-? pathway may produce significant and long lasting impact on management of chronic infections. This approach will be especially useful in treatment of those chronic infections where the IFN-? pathway plays an essential role, but is compromised, either systemically (as in HIV and chronic TB infection) or locally (as within TB lesions). Our work will provide a basis for the development of a novel class of drugs targeting the host, not the pathogen, and therefore effective against antibiotic resistant bacteria. By helping control lung damage, these drugs will reduce the development and spread of drug resistant forms of tuberculosis.

Public Health Relevance

The emergence and spread of drug resistant forms of Mycobacterium tuberculosis (Mtb) represents a significant global threat. Given the dearth of new drugs targeting the pathogen, interventions targeting host cells are urgently needed. We propose to develop a novel class of therapeutic agents to enhance a central pathway of host resistance to a number of intracellular pathogens-macrophage activation with interferon gamma (IFN-?). These studies will provide a basis for the development of a novel class of drugs targeting the host, not the pathogen, and therefore, effective against antibiotic resistant bacteri. These drugs will improve outcomes of tuberculosis therapy by controlling the lung damage and reducing the spread of drug resistant forms of tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI105944-02
Application #
8617225
Study Section
Special Emphasis Panel (ZAI1-JKB-M (J2))
Program Officer
Boyce, Jim P
Project Start
2013-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$223,112
Indirect Cost
$86,819
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118