title: Disruption of granulocyte macrophage-colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection.
abstract: Mice lacking expression of granulocyte macrophage-colony stimulating factor (GM-CSF KO) are unable to contain Mycobacterium tuberculosis (M. tuberculosis) growth and succumb to infection by 35 days following pulmonary challenge. GM-CSF KO mice do not express normal levels of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) nor the chemokines, regulated on activation, normal T expressed and secreted (RANTES), macrophage-inflammatory protein-1beta (MIP-1beta), MIP-1alpha, and lymphotactin, which are required for recruitment of lymphocytes and expression of a T helper cell type 1 (TH1) response within the lungs. In contrast, transgenic mice overexpressing GM-CSF in the lungs but with a lack of GM-CSF in other organs (GM+) are able to recruit lymphocytes and to express a TH1 response with production of TNF-alpha and interferon-gamma in the lungs. However, GM+ mice succumb to infection between 60 and 90 days post-challenge, as they are unable to develop a normal granulomatous response. Although GM+ mice are able to express the chemokine RANTES, they lack the ability to express other inflammatory chemokines such as lymphotactin and MIP-1beta. We conclude that GM-CSF is essential to the recruitment of lymphocytes and expression of a TH1 response in the lung, to the generation of a normal mononuclear granuloma, and most importantly, to the containment of M. tuberculosis bacterial growth.
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, 80523, USA. malba@lamar.colostate.edu
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gonzalez-Juarrero
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Hattle
authors.forename: Angelo
authors.initials: A
authors.lastname: Izzo
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Junqueira-Kipnis
authors.forename: Tae S
authors.initials: TS
authors.lastname: Shim
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cooper
authors.forename: Ian M
authors.initials: IM
authors.lastname: Orme
mesh_terms: D000818:Animals; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D019744:Chemokines, C / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009169:Mycobacterium tuberculosis; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology*
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019744:Chemokines, C; D019402:Macrophage Inflammatory Proteins; C486249:Xcl1 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor