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Intrapulmonary Delivery of XCL1-Targeting Small Interfering RNA in Mice Chronically Infected with Mycobacterium tuberculosis

Adrian G. Rosas-Taraco^1,*, David M. Higgins¹, Joaquín Sánchez-Campillo^1,, Eric J. Lee¹, Ian M. Orme¹ and Mercedes González-Juarrero¹

¹ Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado

Correspondence and requests for reprints should be addressed to Mercedes González-Juarrero, Ph.D., Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523-1682. E-mail: malba{at}mail.colostate.edu

Mice infected for 60 days with Mycobacterium tuberculosis were treated with aerosolized XCL1-targeting small interfering RNA (siRNA) to induce local and transient suppression of XCL1/lymphotactin (an important chemokine in tuberculoid granuloma formation). The local pulmonary siRNA therapy resulted in a 50% decrease in the total amount of xcl1 gene transcripts at 3 days, and 40 to 50% protein suppression 3 and 5 days after treatment. Reduced XCL1 expression in the lungs was associated with decreased numbers of T lymphocytes, reduction in the IFN- response, disorganized granulomatous lesions, and higher fibrosis when compared with control mice treated with either PBS or nontargeting siRNA. This indicates that a transient but strong modulation of the production of XCL1 in the lungs has a significant effect on the influx of IFN-–secreting T cells, as well as local pathology, but without significantly altering containment of the infection.

Key Words: tuberculosis • small interfering RNA • lymphotactin • XCL1 • aerosol delivery

CLINICAL RELEVANCE We demonstrate, for the first time, in a murine tuberculosis model, that it is possible to modulate the local environment and the lung immunopathology using small interfering RNA. Currently, a variety of acute and chronic lung diseases have been shown to have altered expression of cytokines/chemokines or other important factors, many of which could be directly involved in lung pathology. Therefore, workers in many other respiratory diseases will clearly be able to use the approaches described here to elucidate the role of different molecules in pathogenesis. These same approaches may be exploited as immunotherapeutic alternatives for respiratory diseases.