Manganese sequestration is also thought important for the control of the growth of pathogens such as Borrelia which have evolved to use this metal rather than iron as the metalloprotein vital for cell replication. Lyme disease bacteria have shown great adaptability in surviving in the host environment, so it should come as no surprise that Borrelia has evolved to make use of the second most abundant transition metal found in vertebrate hosts, including humans. The body has also adapted however and attempts to hide zinc in order to inhibit microbial growth when infected.
Zinc Distribution in Bodily Tissues
Using imaging techniques that can detect levels of metal distribution in vertebrate tissues, researchers have looked at the differences between healthy tissue, and tissues infected with zinc-dependent bacteria. They found that tissues infected with organisms (such as Staphylococcus aureus) that use zinc as a metalloprotein (like the Lyme disease bacteria) show lower levels of zinc than do surrounding healthy tissues. Effectively, the lack of nutrient zinc within the abscesses is thought to demonstrate an immune system strategy to inhibit and control infection. Extracellular zinc sequestration is not the only tactic employed in vertebrates to deprive Lyme disease bacteria of zinc.
Zinc transporters, some of which (ZIP8, for instance) are expressed by immune system cells such as macrophages and interferon-gamma stimulated T cells, are also used to decrease the amount of zinc in certain cells, and cellular components, of the body. ZIP8, for example, plays a role in moving zinc from the lysosome into the cytoplasm of a cell. Moving the zinc around in the cells and the tissues in such a way appears to be a mechanism designed to disrupt zinc-dependent bacterial processes and reduce the spread of infection with bacteria such as the ones which cause Lyme disease.
Lyme Disease, Zinc, and Immunity
How effective these mechanisms are at inhibiting the spread of Lyme disease infection remains to be seen. Altered zinc concentrations also affect the health of the body’s own immune system cells and other cell processes including T-cell development, and dendritic cell activation and growth, which makes it difficult for scientists to assess the impact of lowered zinc levels on bacterial growth and virulence. Some effect is thought likely however, as bacteria are estimated to use zinc in around 4-6% of all proteins. The bacteria attempt to fight the body’s sequestration of zinc by expressing high-affinity zinc transporters such as the ZnuABC transport systems in Escherichia coli.
Inhibiting Borrelial Growth
Although all this research on the need for zinc by Lyme disease bacteria may seem academic it could provide clinicians with a way of inhibiting the growth and spread of infection at some point in the future. In understanding the way the body attempts to control infection naturally, and the ways that bacteria such as Borrelia try to overcome these strategies, it may be that these zinc-acquisition systems employed by the bacteria can become a target for treatment. Genome sequencing of Borrelia burgdorferi has found that the Lyme disease bacteria lacks genes encoding iron-acquisition systems which suggests that the bacteria may not require iron to thrive, unlike conventional bacteria (Ouyang, et al, 2009). One chromosomal gene, bb0219, present in Borrelia bacteria does appear to be involved in the uptake of one or more transition metals however, such as manganese and zinc, and researchers may be able to use such gene encoding to alter the ability of the bacteria to infect ticks and mice, and possibly humans.
Other researchers are looking at peptide deformylase (PDF) as a possible target for the development of antibacterial agents, including treatment for Lyme disease. PDF is a catalyst in the removal of N-terminal formyl groups from nascent ribosome-synthesized polypeptides; basically, this means that PDF is needed for bacterial proteins to be made and, therefore, for the survival of bacteria. Somewhat surprisingly for researchers, Borellial PDF appear to choose zinc over iron when both are equally present, whereas other bacteria tend to choose iron and only rely on zinc if iron levels are low (Nguyen, et al, 2008). Some practitioners are investigating potential links between pyroluria, Lyme disease and zinc, sometimes referred to as the Mauve Factor, although no clear treatment strategy can be devised given the lack of evidence and the possible dangers of high doses of zinc. Lyme disease, zinc, manganese, and the relationship between them appears significantly more complex than some practitioners and supplement-peddlers would like us to believe.
Zhen Ma, Faith E. Jacobsen, and David P. Giedroc, Metal Transporters and Metal Sensors: How Coordination Chemistry Controls Bacterial Metal Homeostasis, Chem Rev. 2009 October; 109(10): 4644–4681.
Thomas E. Kehl-Fie and Eric P. Skaar, Nutritional immunity beyond iron: a role for manganese and zinc, Curr Opin Chem Biol. 2010 April; 14(2): 218–224.
Zhiming Ouyang, Ming He, Tara Oman, X. Frank Yang, and Michael V. Norgard, A manganese transporter, BB0219 (BmtA), is required for virulence by the Lyme disease spirochete,Borrelia burgdorferi, Proc Natl Acad Sci U S A. 2009 March 3; 106(9): 3449–3454.
Kiet T. Nguyen, Jen-Chieh Wu, Julie A. Boylan, Frank C. Gherardini, and Dehua Pei, Zinc Is the Metal Cofactor of Borrelia burgdorferi Peptide Deformylase, Arch Biochem Biophys, 2007 December 15; 468(2): 217–225.