Siderocalin inhibits the intracellular replication of Mycobacterium tuberculosis in macrophages.
Siderocalin is a secreted protein that binds to siderophores to prevent bacterial iron acquisition. While it has been shown to inhibit the growth of Mycobacterium tuberculosis (M.tb) in extracellular cultures, its effect on this pathogen within macrophages is not clear. Here, we show that siderocalin expression is upregulated following M.tb infection of mouse macrophage cell lines and primary murine alveolar macrophages. Furthermore, siderocalin added exogenously as a recombinant protein or overexpressed in the RAW264.7 macrophage cell line inhibited the intracellular growth of the pathogen. A variant form of siderocalin, which is expressed only in the macrophage cytosol, inhibited intracellular M.tb growth as effectively as the normal, secreted form, an observation that provides mechanistic insight into how siderocalin might influence iron acquisition by the bacteria in the phagosome. Our findings are consistent with an important role for siderocalin in protection against M.tb infection and suggest that exogenously administered siderocalin may have therapeutic applications in tuberculosis.
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA.
Erin E
EE
Johnson
Chittur V
CV
Srikanth
Andreas
A
Sandgren
Lynne
L
Harrington
Estela
E
Trebicka
Lijian
L
Wang
Niels
N
Borregaard
Megan
M
Murray
Bobby J
BJ
Cherayil
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology
D002352:Carrier Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins