IntracellularMycobacterium aviumIntersect Transferrin in the Rab11⁺Recycling Endocytic Pathway and Avoid Lipocalin 2 Trafficking to the Lysosomal Pathway

Abstract

Iron is an essential nutrient for microbes and many pathogenic bacteria depend on siderophores to obtain iron. The mammalian innate immunity protein lipocalin 2 (Lcn2, NGAL, 24p3, Siderocalin) binds the siderophore carboxymycobactin, an essential component of the iron acquisition apparatus of mycobacteria. Here we show that Lcn2 suppressed growth of Mycobacterium avium in culture, and M. avium induced Lcn2 production from mouse macrophages. Lcn2 was also elevated and initially limited the growth of M. avium in the blood of infected mice, but did not impede growth in tissues and during long-term infections. M. avium is an intracellular pathogen. Subcellular imaging of infected macrophages revealed that Lcn2 trafficked to lysosomes separate from M. avium, whereas transferrin was efficiently transported to the mycobacteria. Thus mycobacteria seem to reside in the Rab11+ endocytic recycling pathway, thereby retaining access to nutrition and avoiding endocytosed immunoproteins like Lcn2.

Intracellular Trafficking of AIP56, an NF-κB-Cleaving Toxin from Photobacterium damselae subsp. piscicida

“…Alexa 647-transferrin was used as a marker of the recycling route. In macrophages (43)(44)(45)(46)(47)(48), similar to what occurs in other cells (49), transferrin is recycled back to the cell surface using two kinetically distinguishable mechanisms of recycling (fast and slow recycling). This supports the use of transferrin as a marker for the recycling pathway in macrophages and in, particular, in mBMDM.…”

Microparticles from Mycobacteria-Infected Macrophages Promote Inflammation and Cellular Migration

“…Within macrophages, M. tuberculosis bacilli interact with multiple Rab proteins (40,41). Rab proteins are involved in endosome trafficking within the cell and have an integral role in the pathogenesis of bacteria like M. tuberculosis.…”

Mammalian Siderophores, Siderophore-binding Lipocalins, and the Labile Iron Pool

“…Siderocalins often bind siderophores with subnanomolar affinities (54 -60), using, in the cases of Scn and the avian siderocalins, calyces lined with positively charged lysine and arginine side chains to interact, through cation-and Coulombic interactions, with negatively charged siderophores with aromatic catecholate groups. To broaden the range of this antibacterial defense, Scn, the best characterized member of the family, uses a highly polyspecific recognition mechanism to sequester both a wide range of related Ent-like siderophores and the chemically distinct carboxymycobactins (54 -60); Scn knock-out mice are significantly more susceptible to infections with bacteria that rely on these siderophores for iron acquisition in the absence of any other gross phenotype (61)(62)(63). Pathogenic bacteria have evolved responses to these defenses by using multiple siderophores that include examples that do not bind to Scn or by modifying siderophores in ways to block Scn binding, allowing iron to be acquired even in the presence of Scn and explaining much of the previously mysterious association of variant siderophores with virulence (54,58,59,62,64).…”