Siderocalin inhibits the intracellular replication ofMycobacterium tuberculosisin macrophages

Abstract

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.

The role of iron in the immune response to bacterial infection

“…In keeping with this finding, Saiga et al demonstrated that siderocalin is involved in inhibiting M. tuberculosis multiplication in vitro and in vivo [77]. In similar studies, we found that the growth of M. tuberculosis , either in bacterial medium or within mouse macrophages, was significantly suppressed by the addition of recombinant siderocalin [78]. Siderocalin may also play a role in protection against tuberculosis in humans.…”

Hydrogen sulfide and ischemia–reperfusion injury

“…However, some evidence suggests calcium-activated potassium channels are targets of CO in the context of vasorelaxation [20]. The cytoprotective effects of CO are also not limited to the heart, as it has been shown that CO contributes to central nervous system mediated blood pressure regulation [21], protects against pulmonary [22] and renovascular hypertension [23], modulates atherosclerosis [24], improves both allograft and xenograft survival following organ transplantation [25], and exerts a restorative effect on the pathologic remodeling response after balloon angioplasty [26]. …”

Characterization of Heme Ligation Properties of Rv0203, a Secreted Heme Binding Protein Involved in Mycobacterium tuberculosis Heme Uptake

“…This pathway, however, is metabolically costly since mycobactin biosynthesis requires at least eleven different enzymes (6). Moreover, the human innate immune system features a siderophore binding protein, siderocalin, which sequesters siderophores and has been shown to inhibit Mtb replication in macrophages by disrupting the bacterium's siderophore-mediated iron scavenging abilities (7). …”