Intrapulmonary delivery of XCL1-targeting small interfering RNA in mice chronically infected with Mycobacterium tuberculosis.
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-gamma 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-gamma-secreting T cells, as well as local pathology, but without significantly altering containment of the infection.
Rosas-Taraco
Adrian G
AG
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
Higgins
David M
DM
Sánchez-Campillo
Joaquín
J
Lee
Eric J
EJ
Orme
Ian M
IM
González-Juarrero
Mercedes
M
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D019744:Chemokines, C / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014018:Tissue Distribution; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000473:pathology
D000336:Aerosols; D019744:Chemokines, C; D034741:RNA, Small Interfering; C486249:Xcl1 protein, mouse; D007371:Interferon-gamma