Current TB chemotherapy is incapable of rapidly eliminating one hundred percent of the Mycobacterium tuberculosis bacilli. Although 99% of the bacteria are eliminated within three weeks of commencing treatment, a small population (~ 1%) of drug-tolerant bacilli requires an additional 6-8 months of multidrug treatment to be eliminated. This treatment regimen results in a dramatic improvement in patient health early on and many patients therefore fail to complete the full long-term treatment. This limitation has facilitated te continued emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains which have spread globally. 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 host's own bactericidal response by using immunotherapy to combat pulmonary immunosuppression. Our preliminary studies indicate that delivery of small interfering RNA [siRNA] transcripts targeting the TGF?1 cytokine reduces the pulmonary bacterial load of mice chronically infected with Mycobacterium tuberculosis. Moreover, this effect is enhanced in the absence of the IL-10 cytokine. Here we will test whether siRNA targeting of TGF?1 and IL-10 can enhance clearance of drug tolerant bacilli and whether this approach is efficacious in 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. Thus, this application uses innovative, cutting- edge research to develop anti-bacterial products directed against NIAID Category C Priority Pathogens.

Public Health Relevance

Tuberculosis represents an enormous challenge to global health because of the inadequacy of currently available drugs and vaccines. The lengthy treatment for tuberculosis is the primary cause for the emergence of multidrug resistant tuberculosis, as it frequently results in non-compliance. Eradication of tuberculosis depends on the development of shorter and more effective treatment regimens, including novel treatment alternatives combined with classical tuberculosis therapies. Here we propose to develop new immune-based therapies that increase the capacity of the infected host to eliminate the bacteria.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZAI1-RRS-M (M4))
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Lacourciere, Karen A
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Colorado State University-Fort Collins
Schools of Veterinary Medicine
Fort Collins
United States
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Upadhyay, Rashmi; Sanchez-Hidalgo, Andrea; Wilusz, Carol J et al. (2018) Host Directed Therapy for Chronic Tuberculosis via Intrapulmonary Delivery of Aerosolized Peptide Inhibitors Targeting the IL-10-STAT3 Pathway. Sci Rep 8:16610
Gonzalez-Juarrero, Mercedes (2012) Immunity to TB and targets for immunotherapy. Immunotherapy 4:187-99
González-Juarrero, Mercedes; O'Sullivan, Mary P (2011) Optimization of inhaled therapies for tuberculosis: the role of macrophages and dendritic cells. Tuberculosis (Edinb) 91:86-92
Rosas-Taraco, Adrian G; Higgins, David M; Sánchez-Campillo, Joaquín et al. (2011) Local pulmonary immunotherapy with siRNA targeting TGF?1 enhances antimicrobial capacity in Mycobacterium tuberculosis infected mice. Tuberculosis (Edinb) 91:98-106