Disruption of granulocyte macrophage-colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection.
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.
Gonzalez-Juarrero
Mercedes
M
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, 80523, USA. malba@lamar.colostate.edu
Hattle
Jessica M
JM
Izzo
Angelo
A
Junqueira-Kipnis
Ana Paula
AP
Shim
Tae S
TS
Trapnell
Bruce C
BC
Cooper
Andrea M
AM
Orme
Ian M
IM
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*
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