The current TB multidrug therapy eliminates the majority of the M. tuberculosis (Mtb) bacteria in the first 2-3 weeks of treatment. The residual population (1%) after this period of time has become a "night mare" for TB eradication. To eliminate this 1% of drug tolerant bacteria the current multidrug treatment has to be continued for 9 month. Patient's well-being improves rapidly in the first weeks of treatment and many of them withdraw from the therapy. The latter has facilitated the emergence and expansion of multidrug-resistant strains of Mtb (MDR) and new TB cases caused by these strains are even more difficult to cure. The primary goal of this proposal is to more rapidly eradicate drug tolerant bacilli using immunotherapeutic approaches. We believe it is possible to enhance the capacity of the host (patient) to eliminate the bacilli via immune derived bactericidal mechanisms. Our preliminary studies indicate that delivery of naked small interfering RNA [siRNA] transcripts targeting the TGF?1 cytokine reduces the pulmonary bacterial load of mice chronically infected with Mtb. Moreover, this effect is enhanced in the absence of the IL-10 cytokine. Here we want to explore if we can improve this therapeutic approach by delivering the siRNA via gold nanoparticles. Thus, novel polyvalent siRNA gold nanoparticle conjugates (siRNA-GNPs) will be used to silence expression of tgf?1 or il10 transcripts in the lungs of mice with a chronic infection of Mtb. Thereafter we will test if silencing of mRNA for TGF?1 and IL-10 can enhance clearance of drug tolerant bacilli. Our long term goal is to shorten therapy for TB and to treat chronic MDR-TB infections. The outcomes will be documented using comprehensive bacteriologic, immunologic, pathologic approaches now routine in our laboratory. We are uniquely equipped with state-of-the-art BSL-III research facilities and have assembled a team of highly experienced researchers with expertise in the fields of mycobacteria infection and RNA regulation in eukaryotic cells.

Public Health Relevance

There are still no drugs or vaccine available that cure tuberculosis rapidly and effectively. The current multi- drug treatment available for tuberculosis last 4-9 mo. in the best of the cases and it frequently results in non- compliance. If we want to eradicate tuberculosis we need to find new treatments that cure patients a lot faster and more efficiently. Here we propose to develop new immune-therapy treatments to be used in combination with current standard drug-therapies that will cure patients with tuberculosis more rapidly.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI105585-01A1
Application #
8638299
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Lacourciere, Karen A
Project Start
2014-08-15
Project End
2016-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$237,777
Indirect Cost
$55,950
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523