Elemental Ingredients in the Macrophage Cocktail: Role of ZIP8 in Host Response to Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is a global epidemic caused by the infection of human macrophages with the world’s most deadly single bacterial pathogen, Mycobacterium tuberculosis (M.tb). M.tb resides in a phagosomal niche within macrophages, where trace element concentrations impact the immune response, bacterial metal metabolism, and bacterial survival. The manipulation of micronutrients is a critical mechanism of host defense against infection. In particular, the human zinc transporter Zrt-/Irt-like protein 8 (ZIP8), one of 14 ZIP family members, is important in the flux of divalent cations, including zinc, into the cytoplasm of macrophages. It also has been observed to exist on the membrane of cellular organelles, where it can serve as an efflux pump that transports zinc into the cytosol. ZIP8 is highly inducible in response to M.tb infection of macrophages, and we have observed its localization to the M.tb phagosome. The expression, localization, and function of ZIP8 and other divalent cation transporters within macrophages have important implications for TB prevention and dissemination and warrant further study. In particular, given the importance of zinc as an essential nutrient required for humans and M.tb, it is not yet clear whether ZIP-guided zinc transport serves as a host protective factor or, rather, is targeted by M.tb to enable its phagosomal survival.

Localization of all four ZnT zinc transporters in Dictyostelium and impact of ZntA and ZntB knockout on bacteria killing

“…For example, Zn 2+ has been observed to accumulate in phagolysosomes containing the nonpathogenic bacteria Escherichia coli, contributing to their killing. In addition, Zn 2+ transporters are upregulated in macrophages infected with Mycobacterium tuberculosis and, after a cytosolic burst, free Zn 2+ is delivered and accumulates into the Mycobacterium-containing vacuole (MCV) 24 h after infection (Botella et al, 2011;Pyle et al, 2017;Wagner et al, 2005). Interestingly, vice versa, the expression of the P 1 -type Zn 2+ -exporting ATPase CtpC of M. tuberculosis, the Zn 2+ -exporting P 1B -type ATPase ZntA of E. coli and Salmonella enterica serovar typhimurium, and the Zn 2+ cation diffusion facilitator of Streptococcus pyogenes increases during infection of human macrophages and neutrophils (Botella et al, 2011;Kapetanovic et al, 2016;Ong et al, 2014).…”

Zn2+ intoxication of Mycobacterium marinum during Dictyostelium discoideum infection is counteracted by induction of the pathogen Zn2+ exporter CtpC

“…3A, B). Strikingly, previous studies have shown that the expression of ZNT1, the homolog of ZntB, decreases in fish granulomas after two weeks of infection with M. marinum, but it increases in human macrophages after 18 and 72 hours of infection with Mtb (Botella et al, 2011;Cronan et al, 2016;Pyle et al, 2017). This suggests that distinct hosts respond differently to the infection and that, at least with regard to Zn 2+ immunity, D. discoideum reacts to the invasion by pathogenic mycobacteria in a manner more similar to that of mammals than of fish.…”

“…Apart from the defence mechanisms mentioned above, little is known about other aspects of the chemical warfare between M. marinum and its hosts, and especially about the manipulation of transition metals by both parties. In the case of Mtb, it has been shown that immune cells deprive the bacteria from essential nutrients such as iron and manganese, whilst they intoxicate the mycobacteria by accumulating copper and zinc inside the MCV (Neyrolles et al, 2015;Pyle et al, 2017;Wagner et al, 2005;Wolschendorf et al, 2011). However, Mtb resists this metal fight with an arsenal of metal-binding proteins, oxidases and efflux transporters.…”

Essential Role of Zinc and Zinc Transporters in Myeloid Cell Function and Host Defense against Infection

“…Further, ZIP8 was vital to immune function because knockdown inhibited LPS-driven Zn accumulation and reduced Zn-dependent reduction of IL-10 release [ 41 ]. Similarly, Mtb infection of macrophages was shown to induce the expression of ZIP8 with a very little effect on other ZIPs although it remains to be determined whether ZIP8 enhances Zn uptake in favor of the host or pathogen [ 72 ]. Taken together, Zn transporter-mediated Zn redistribution via ZIP8 and ZIP14 upon infection likely serves multiple purposes [ 73 ].…”